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Príncipe LA, Marchi PH, Cesar CGL, Amaral AR, Duarte KKS, Finardi GLF, Souza JM, Balieiro JCC, Vendramini THA. Evaluation of enzymatically hydrolyzed poultry byproduct meal effects on fecal microbiota and pressure variables in elderly obese cats. Front Vet Sci 2025; 12:1530260. [PMID: 40191086 PMCID: PMC11969457 DOI: 10.3389/fvets.2025.1530260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 01/17/2025] [Indexed: 04/09/2025] Open
Abstract
Arterial hypertension is influenced by the intestinal microbiota and its metabolites, which play a crucial role in host health. Dietary peptides are multifunctional molecules with therapeutic potential for managing hypertension. This study aimed to evaluate the impact of incorporating enzymatically hydrolyzed poultry byproduct meal (EHPM-c) into extruded dry diets on the fecal microbiota and blood pressure parameters of elderly obese cats. Eighteen owners of neutered, clinically healthy male and female cats of various breeds were randomly assigned to two groups: control (30.8%, conventional poultry byproduct meal-CPM-c) and test (17.07%, CPM-c + 12.0% EHPM-c). Clinical values of systolic blood pressure, serum aldosterone concentrations, angiotensin-converting enzyme I activity, and fecal microbiota using 16S rRNA were measured. Data were processed using SAS software (PROC MIXED, PROC GLIMMIX, and PROC CORR; p < 0.05). Both groups exhibited high microbial alpha diversity, with no significant differences in beta diversity. Although the inclusion of 12.0% EHPM-c had no measurable effect on blood pressure, both diets promoted beneficial modulation of the fecal microbiota, improving intestinal health. These findings underscore the importance of diet in maintaining gut homeostasis in obese senior cats. While the inclusion of 12.0% EHPM-c did not significantly alter blood pressure parameters, the modulation of the fecal microbiota suggests a potential role in maintaining intestinal health. These results highlight the need for further studies to explore different inclusion levels and longer intervention periods.
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Affiliation(s)
- Leonardo A. Príncipe
- Pet Nutrology Research Center, Department of Animal Nutrition and Production, School of Veterinary Medicine and Animal Science, University of São Paulo, Pirassununga, Brazil
| | - Pedro H. Marchi
- Pet Nutrology Research Center, Department of Animal Nutrition and Production, School of Veterinary Medicine and Animal Science, University of São Paulo, Pirassununga, Brazil
| | - Cinthia G. L. Cesar
- Pet Nutrology Research Center, Department of Animal Nutrition and Production, School of Veterinary Medicine and Animal Science, University of São Paulo, Pirassununga, Brazil
| | - Andressa R. Amaral
- Veterinary Nutrology Service, Veterinary Teaching Hospital, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil
| | - Kelly K. S. Duarte
- Pet Nutrology Research Center, Department of Animal Nutrition and Production, School of Veterinary Medicine and Animal Science, University of São Paulo, Pirassununga, Brazil
| | - Gabriela L. F. Finardi
- Pet Nutrology Research Center, Department of Animal Nutrition and Production, School of Veterinary Medicine and Animal Science, University of São Paulo, Pirassununga, Brazil
| | - Jennifer M. Souza
- Pet Nutrology Research Center, Department of Animal Nutrition and Production, School of Veterinary Medicine and Animal Science, University of São Paulo, Pirassununga, Brazil
| | - Júlio C. C. Balieiro
- Pet Nutrology Research Center, Department of Animal Nutrition and Production, School of Veterinary Medicine and Animal Science, University of São Paulo, Pirassununga, Brazil
| | - Thiago H. A. Vendramini
- Pet Nutrology Research Center, Department of Animal Nutrition and Production, School of Veterinary Medicine and Animal Science, University of São Paulo, Pirassununga, Brazil
- Veterinary Nutrology Service, Veterinary Teaching Hospital, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil
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Hasebe Y, Yokota S, Fukushi I, Takeda K, Yoshizawa M, Onimaru H, Kono Y, Sugama S, Uchiyama M, Koizumi K, Horiuchi J, Kakinuma Y, Pokorski M, Toda T, Izumizaki M, Mori Y, Sugita K, Okada Y. Persistence of post-stress blood pressure elevation requires activation of astrocytes. Sci Rep 2024; 14:22984. [PMID: 39363030 PMCID: PMC11450218 DOI: 10.1038/s41598-024-73345-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Accepted: 09/16/2024] [Indexed: 10/05/2024] Open
Abstract
The reflexive excitation of the sympathetic nervous system in response to psychological stress leads to elevated blood pressure, a condition that persists even after the stress has been alleviated. This sustained increase in blood pressure, which may contribute to the pathophysiology of hypertension, could be linked to neural plasticity in sympathetic nervous activity. Given the critical role of astrocytes in various forms of neural plasticity, we investigated their involvement in maintaining elevated blood pressure during the post-stress phase. Specifically, we examined the effects of arundic acid, an astrocytic inhibitor, on blood pressure and heart rate responses to air-jet stress. First, we confirmed that the inhibitory effect of arundic acid is specific to astrocytes. Using c-Fos immunohistology, we then observed that psychological stress activates neurons in cardiovascular brain regions, and that this stress-induced neuronal activation was suppressed by arundic acid pre-treatment in rats. By evaluating astrocytic process thickness, we also confirmed that astrocytes in the cardiovascular brain regions were activated by stress, and this activation was blocked by arundic acid pre-treatment. Next, we conducted blood pressure measurements on unanesthetized, unrestrained rats. Air-jet stress elevated blood pressure, which remained high for a significant period during the post-stress phase. However, pre-treatment with arundic acid, which inhibited astrocytic activation, suppressed stress-induced blood pressure elevation both during and after stress. In contrast, arundic acid had no significant impact on heart rate. These findings suggest that both neurons and astrocytes play integral roles in stress-induced blood pressure elevation and its persistence after stress, offering new insights into the pathophysiological mechanisms underlying hypertension.
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Affiliation(s)
- Yohei Hasebe
- Department of Pediatrics, School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
- Clinical Research Center, Murayama Medical Center, 2-37-1 Gakuen, Musashimurayama, Tokyo, 208-0011, Japan
| | - Shigefumi Yokota
- Department of Anatomy and Morphological Neuroscience, Shimane University School of Medicine, Izumo, Shimane, Japan
| | - Isato Fukushi
- Clinical Research Center, Murayama Medical Center, 2-37-1 Gakuen, Musashimurayama, Tokyo, 208-0011, Japan
- Graduate School of Health Sciences, Aomori University of Health and Welfare, Aomori, Japan
| | - Kotaro Takeda
- Clinical Research Center, Murayama Medical Center, 2-37-1 Gakuen, Musashimurayama, Tokyo, 208-0011, Japan
- Faculty of Rehabilitation, School of Health Sciences, Fujita Health University, Toyoake, Aichi, Japan
| | - Masashi Yoshizawa
- Department of Pediatrics, School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
- Clinical Research Center, Murayama Medical Center, 2-37-1 Gakuen, Musashimurayama, Tokyo, 208-0011, Japan
| | - Hiroshi Onimaru
- Department of Physiology, Showa University, School of Medicine, Tokyo, Japan
| | - Yosuke Kono
- Department of Pediatrics, School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
- Clinical Research Center, Murayama Medical Center, 2-37-1 Gakuen, Musashimurayama, Tokyo, 208-0011, Japan
| | - Shuei Sugama
- Center for Medical Sciences, International University of Health and Welfare, Otawara, Tochigi, Japan
| | - Makoto Uchiyama
- Department of Synthetic Chemistry and Biological Chemistry Graduate School of Engineering, Kyoto University, Kyoto, Japan
| | - Keiichi Koizumi
- Department of Pediatrics, School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Jouji Horiuchi
- Department of Biomedical Engineering, Graduate School of Science and Engineering, Toyo University, Saitama, Japan
| | | | | | - Takako Toda
- Department of Pediatrics, School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Masahiko Izumizaki
- Department of Physiology, Showa University, School of Medicine, Tokyo, Japan
| | - Yasuo Mori
- Department of Synthetic Chemistry and Biological Chemistry Graduate School of Engineering, Kyoto University, Kyoto, Japan
| | - Kanji Sugita
- Department of Pediatrics, School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Yasumasa Okada
- Clinical Research Center, Murayama Medical Center, 2-37-1 Gakuen, Musashimurayama, Tokyo, 208-0011, Japan.
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Vashisht A, Vashisht V, Singh H, Ahluwalia P, Mondal AK, Williams C, Farmaha J, Woodall J, Kolhe R. Neurological Complications of COVID-19: Unraveling the Pathophysiological Underpinnings and Therapeutic Implications. Viruses 2024; 16:1183. [PMID: 39205157 PMCID: PMC11359204 DOI: 10.3390/v16081183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 07/11/2024] [Accepted: 07/23/2024] [Indexed: 09/04/2024] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease (COVID-19), induced a global pandemic with a diverse array of clinical manifestations. While the acute phase of the pandemic may be waning, the intricacies of COVID-19's impact on neurological health remain a crucial area of investigation. Early recognition of the spectrum of COVID-19 symptoms, ranging from mild fever and cough to life-threatening respiratory distress and multi-organ failure, underscored the significance of neurological complications, including anosmia, seizures, stroke, disorientation, encephalopathy, and paralysis. Notably, patients requiring intensive care unit (ICU) admission due to neurological challenges or due to them exhibiting neurological abnormalities in the ICU have shown increased mortality rates. COVID-19 can lead to a range of neurological complications such as anosmia, stroke, paralysis, cranial nerve deficits, encephalopathy, delirium, meningitis, seizures, etc., in affected patients. This review elucidates the burgeoning landscape of neurological sequelae associated with SARS-CoV-2 infection and explores the underlying neurobiological mechanisms driving these diverse manifestations. A meticulous examination of potential neuroinvasion routes by SARS-CoV-2 underscores the intricate interplay between the virus and the nervous system. Moreover, we dissect the diverse neurological manifestations emphasizing the necessity of a multifaceted approach to understanding the disease's neurological footprint. In addition to elucidating the pathophysiological underpinnings, this review surveys current therapeutic modalities and delineates prospective avenues for neuro-COVID research. By integrating epidemiological, clinical, and diagnostic parameters, we endeavor to foster a comprehensive analysis of the nexus between COVID-19 and neurological health, thereby laying the groundwork for targeted therapeutic interventions and long-term management strategies.
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Affiliation(s)
- Ashutosh Vashisht
- Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (A.V.); (V.V.); (H.S.); (P.A.); (A.K.M.); (J.F.); (J.W.)
| | - Vishakha Vashisht
- Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (A.V.); (V.V.); (H.S.); (P.A.); (A.K.M.); (J.F.); (J.W.)
| | - Harmanpreet Singh
- Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (A.V.); (V.V.); (H.S.); (P.A.); (A.K.M.); (J.F.); (J.W.)
| | - Pankaj Ahluwalia
- Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (A.V.); (V.V.); (H.S.); (P.A.); (A.K.M.); (J.F.); (J.W.)
| | - Ashis K. Mondal
- Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (A.V.); (V.V.); (H.S.); (P.A.); (A.K.M.); (J.F.); (J.W.)
| | - Colin Williams
- Lincoln Memorial DeBusk College of Osteopathic Medicine, Lincoln Memorial University, Knoxville, TN 37902, USA;
| | - Jaspreet Farmaha
- Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (A.V.); (V.V.); (H.S.); (P.A.); (A.K.M.); (J.F.); (J.W.)
| | - Jana Woodall
- Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (A.V.); (V.V.); (H.S.); (P.A.); (A.K.M.); (J.F.); (J.W.)
| | - Ravindra Kolhe
- Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (A.V.); (V.V.); (H.S.); (P.A.); (A.K.M.); (J.F.); (J.W.)
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Mendiola-Salazar XA, Munguía-Laguna MA, Franco M, Cano-Martínez A, Santamaría Sosa J, Bautista-Pérez R. SARS-CoV-2 Spike Protein Enhances Carboxypeptidase Activity of Angiotensin-Converting Enzyme 2. Int J Mol Sci 2024; 25:6276. [PMID: 38892464 PMCID: PMC11172802 DOI: 10.3390/ijms25116276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Revised: 05/30/2024] [Accepted: 06/04/2024] [Indexed: 06/21/2024] Open
Abstract
In this study, we investigated whether severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein may modify angiotensin-converting enzyme 2 (ACE2) activity in the plasma, heart, kidney, liver, lung, and six brain regions (amygdala, brain stem, cortex, hippocampus, hypothalamus, and striatum) of diabetic and hypertensive rats. We determine ACE2 activity in the plasma and lysates of heart, kidney, liver, lung, and six brain regions. MLN-4760 inhibits ACE2 activity in the plasma and all organs. On the other hand, soluble ACE2 (sACE2) activity increased in the plasma of diabetic rats, and there was no change in the plasma of hypertensive rats. ACE2 activity was augmented in the liver, brain stem, and striatum, while it decreased in the kidney, amygdala, cortex, and hippocampus of diabetic rats. ACE2 activity increased in the kidney, liver, and lung, while it decreased in the heart, amygdala, cortex, and hypothalamus of hypertensive rats. We measured the ACE2 content via enzyme-linked immunosorbent assay and found that ACE2 protein levels increased in the heart, while it decreased in the plasma, kidney, brain stem, cortex, hippocampus, hypothalamus, and striatum of diabetic rats. ACE2 protein levels decreased in the brain stem, cortex, hippocampus, and hypothalamus of hypertensive rats. Our data showed that the spike protein enhanced ACE2 activity in the liver and lungs of diabetic rats, as well as in the heart and three of the brain regions (cortex, hypothalamus, and striatum) of hypertensive rats.
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Affiliation(s)
- Xóchitl Andrea Mendiola-Salazar
- Department of Molecular Biology, Instituto Nacional de Cardiología “Ignacio Chávez”, Mexico City 14080, Mexico (M.A.M.-L.)
- Carrera de Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Mexico City 54090, Mexico
| | - Melanie A. Munguía-Laguna
- Department of Molecular Biology, Instituto Nacional de Cardiología “Ignacio Chávez”, Mexico City 14080, Mexico (M.A.M.-L.)
| | - Martha Franco
- Department of Cardio-Renal Pathophysiology, Instituto Nacional de Cardiología “Ignacio Chávez”, Mexico City 14080, Mexico; (M.F.); (J.S.S.)
| | - Agustina Cano-Martínez
- Department of Physiology, Instituto Nacional de Cardiología “Ignacio Chávez”, Mexico City 14080, Mexico;
| | - José Santamaría Sosa
- Department of Cardio-Renal Pathophysiology, Instituto Nacional de Cardiología “Ignacio Chávez”, Mexico City 14080, Mexico; (M.F.); (J.S.S.)
| | - Rocío Bautista-Pérez
- Department of Molecular Biology, Instituto Nacional de Cardiología “Ignacio Chávez”, Mexico City 14080, Mexico (M.A.M.-L.)
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5
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Bertollo AG, Leite Galvan AC, Dama Mingoti ME, Dallagnol C, Ignácio ZM. Impact of COVID-19 on Anxiety and Depression - Biopsychosocial Factors. CNS & NEUROLOGICAL DISORDERS DRUG TARGETS 2024; 23:122-133. [PMID: 36809942 DOI: 10.2174/1871527322666230210100048] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 11/16/2022] [Accepted: 12/16/2022] [Indexed: 02/17/2023]
Abstract
Anxiety and depression are prevalent mental disorders around the world. The etiology of both diseases is multifactorial, involving biological and psychological issues. The COVID-19 pandemic settled in 2020 and culminated in several changes in the routine of individuals around the world, affecting mental health. People infected with COVID-19 are at greater risk of developing anxiety and depression, and individuals previously affected by these disorders have worsened the condition. In addition, individuals diagnosed with anxiety or depression before being affected by COVID-19 developed the severe illness at higher rates than individuals without mental disorders. This harmful cycle involves several mechanisms, including systemic hyper-inflammation and neuroinflammation. Furthermore, the context of the pandemic and some previous psychosocial factors can aggravate or trigger anxiety and depression. Disorders are also risks for a more severe picture of COVID-19. This review discusses research on a scientific basis, which brings evidence on biopsychosocial factors from COVID-19 and the context of the pandemic involved in anxiety and depression disorders.
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Affiliation(s)
- Amanda Gollo Bertollo
- Laboratory of Physiology Pharmacology and Psychopathology, Graduate Program in Biomedical Sciences, Federal University of the Southern Frontier, Chapecó, SC, Brazil
| | - Agatha Carina Leite Galvan
- Laboratory of Physiology Pharmacology and Psychopathology, Graduate Program in Biomedical Sciences, Federal University of the Southern Frontier, Chapecó, SC, Brazil
| | - Maiqueli Eduarda Dama Mingoti
- Laboratory of Physiology Pharmacology and Psychopathology, Graduate Program in Biomedical Sciences, Federal University of the Southern Frontier, Chapecó, SC, Brazil
| | - Claudia Dallagnol
- Laboratory of Physiology Pharmacology and Psychopathology, Graduate Program in Biomedical Sciences, Federal University of the Southern Frontier, Chapecó, SC, Brazil
| | - Zuleide Maria Ignácio
- Laboratory of Physiology Pharmacology and Psychopathology, Graduate Program in Biomedical Sciences, Federal University of the Southern Frontier, Chapecó, SC, Brazil
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Cappelletti P, Gallo G, Marino R, Palaniappan S, Corbo M, Savoia C, Feligioni M. From cardiovascular system to brain, the potential protective role of Mas Receptors in COVID-19 infection. Eur J Pharmacol 2023; 959:176061. [PMID: 37775018 DOI: 10.1016/j.ejphar.2023.176061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 09/15/2023] [Accepted: 09/18/2023] [Indexed: 10/01/2023]
Abstract
Coronavirus disease 2019 (COVID-19) has been declared a new pandemic in March 2020. Although most patients are asymptomatic, those with underlying cardiovascular comorbidities may develop a more severe systemic infection which is often associated with fatal pneumonia. Nonetheless, neurological and cardiovascular manifestations could be present even without respiratory symptoms. To date, no COVID-19-specific drugs are able for preventing or treating the infection and generally, the symptoms are relieved with general anti-inflammatory drugs. Angiotensin-converting-enzyme 2 (ACE2) may function as the receptor for virus entry within the cells favoring the progression of infection in the organism. On the other hand, ACE2 is a relevant enzyme in renin angiotensin system (RAS) cascade fostering Ang1-7/Mas receptor activation which promotes protective effects in neurological and cardiovascular systems. It is known that RAS is composed by two functional countervailing axes the ACE/AngII/AT1 receptor and the ACE/AngII/AT2 receptor which counteracts the actions mediated by AngII/AT1 receptor by inducing anti-inflammatory, antioxidant and anti-growth functions. Subsequently an "alternative" ACE2/Ang1-7/Mas receptor axis has been described with functions similar to the latter protective arm. Here, we discuss the neurological and cardiovascular effects of COVID-19 highlighting the role of the stimulation of the RAS "alternative" protective arm in attenuating pulmonary, cerebral and cardiovascular damages. In conclusion, only two clinical trials are running for Mas receptor agonists but few other molecules are in preclinical phase and if successful these drugs might represent a successful strategy for the treatment of the acute phase of COVID-19 infection.
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Affiliation(s)
- Pamela Cappelletti
- Department of Neuro-Rehabilitation Sciences, Casa di Cura Igea, Milan, Italy.
| | - Giovanna Gallo
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy
| | - Rachele Marino
- European Brain Research Institute (EBRI) Rita Levi Montalcini Foundation, Rome, Italy
| | | | - Massimo Corbo
- Department of Neuro-Rehabilitation Sciences, Casa di Cura Igea, Milan, Italy
| | - Carmine Savoia
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy
| | - Marco Feligioni
- Department of Neuro-Rehabilitation Sciences, Casa di Cura Igea, Milan, Italy; European Brain Research Institute (EBRI) Rita Levi Montalcini Foundation, Rome, Italy.
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Adin D, Atkins C, Domenig O, Glahn C, DeFrancesco T, Meurs K. Evaluation of Renin-Angiotensin-Aldosterone System Components and Enzymes in Systemically Hypertensive Cats Receiving Amlodipine. Animals (Basel) 2023; 13:3479. [PMID: 38003097 PMCID: PMC10668637 DOI: 10.3390/ani13223479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 09/23/2023] [Accepted: 11/01/2023] [Indexed: 11/26/2023] Open
Abstract
BACKGROUND Chronic renin-angiotensin-aldosterone system (RAAS) activation is harmful. Amlodipine activates RAAS in humans and dogs, but contradictory data exist for systemically hypertensive (SHT) cats. HYPOTHESIS Cats with SHT and chronic kidney disease treated with amlodipine (SHT/CKD-A) are RAAS activated. ANIMALS Client-owned cats: unmedicated normotensive (NT) cats (n = 9); SHT/CKD-A cats (n = 5) with median systolic blood pressure of 170 mmHg (vs. 195 mmHg, pre-treatment), chronic kidney disease, and receiving no RAAS-suppressive therapy. METHODS Serum was frozen (-80 °C) until RAAS analysis via equilibrium analysis. The RAAS variables (reported as median (minimum-maximum)) were compared between groups, using Mann-Whitney U test. RESULTS Angiotensin 1, angiotensin 1,7, angiotensin III, and angiotensin 1,5, and angiotensin-converting enzyme (ACE)-2 activity were higher in SHT/CKD-A cats compared to NT cats, while ACE activity was lower in SHT/CKD-A cats compared to NT cats (p < 0.05 all). A marker for alternative RAAS influence (ALT-S) was significantly higher (69; 58-73 pmol/pmol) in SHT/CKD-A cats compared to NT cats (35; 14-63 pmol/pmol; p = 0.001). Aldosterone concentrations were significantly higher (393; 137-564 pmol/L) in SHT/CKD-A cats compared to NT cats (129; 28-206 pmol/L; p = 0.007). CONCLUSION AND CLINICAL IMPORTANCE Circulating RAAS is activated in systemically hypertensive cats receiving amlodipine. Although this study did not parse out the individual contributions of SHT, chronic kidney disease, and amlodipine, the findings suggest that the use of concurrent RAAS-suppressant therapy, specifically aldosterone antagonism, in amlodipine-treated SHT cats with chronic kidney disease might be indicated.
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Affiliation(s)
- Darcy Adin
- College of Veterinary Medicine, University of Florida, Gainesville, FL 32608, USA
| | - Clarke Atkins
- College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606, USA (K.M.)
| | | | | | - Teresa DeFrancesco
- College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606, USA (K.M.)
| | - Kathryn Meurs
- College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606, USA (K.M.)
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Thakur A, Sharma V, Averbek S, Liang L, Pandya N, Kumar G, Cili A, Zhang K. Immune landscape and redox imbalance during neurological disorders in COVID-19. Cell Death Dis 2023; 14:593. [PMID: 37673862 PMCID: PMC10482955 DOI: 10.1038/s41419-023-06102-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 08/13/2023] [Accepted: 08/22/2023] [Indexed: 09/08/2023]
Abstract
The outbreak of Coronavirus Disease 2019 (COVID-19) has prompted the scientific community to explore potential treatments or vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes the illness. While SARS-CoV-2 is mostly considered a respiratory pathogen, several neurological complications have been reported, raising questions about how it may enter the Central Nervous System (CNS). Receptors such as ACE2, CD147, TMPRSS2, and NRP1 have been identified in brain cells and may be involved in facilitating SARS-CoV-2 entry into the CNS. Moreover, proteins like P2X7 and Panx-1 may contribute to the pathogenesis of COVID-19. Additionally, the role of the immune system in the gravity of COVID-19 has been investigated with respect to both innate and adaptive immune responses caused by SARS-CoV-2 infection, which can lead to a cytokine storm, tissue damage, and neurological manifestations. A redox imbalance has also been linked to the pathogenesis of COVID-19, potentially causing mitochondrial dysfunction, and generating proinflammatory cytokines. This review summarizes different mechanisms of reactive oxygen species and neuro-inflammation that may contribute to the development of severe COVID-19, and recent progress in the study of immunological events and redox imbalance in neurological complications of COVID-19, and the role of bioinformatics in the study of neurological implications of COVID-19.
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Affiliation(s)
- Abhimanyu Thakur
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation-CAS Limited, Hong Kong SAR, Hong Kong.
| | - Vartika Sharma
- Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Sera Averbek
- GSI Helmholtzzentrum für Schwerionenforschung GmbH, Darmstadt, Germany
- Technische Universität Darmstadt, Darmstadt, Germany
| | - Lifan Liang
- University of Pittsburgh, Pittsburgh, PA, USA
| | - Nirali Pandya
- Department of Chemistry, Faculty of Sciences, National University of Singapore, Singapore, Singapore
| | - Gaurav Kumar
- School of Biosciences and Biomedical Engineering, Department of Clinical Research, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Alma Cili
- Clinic of Hematology, University of Medicine, University Hospital center "Mother Teresa", Tirane, Albania
| | - Kui Zhang
- State Key Laboratory of Resource Insects, College of Sericulture, Textile and Biomass sciences, Southwest University, Chongqing, China.
- Cancer Centre, Medical Research Institute, Southwest University, Chongqing, China.
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9
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Steardo L, Steardo L, Scuderi C. Astrocytes and the Psychiatric Sequelae of COVID-19: What We Learned from the Pandemic. Neurochem Res 2023; 48:1015-1025. [PMID: 35922744 PMCID: PMC9362636 DOI: 10.1007/s11064-022-03709-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 07/01/2022] [Accepted: 07/22/2022] [Indexed: 11/05/2022]
Abstract
COVID-19, initially regarded as specific lung disease, exhibits an extremely broad spectrum of symptoms. Extrapulmonary manifestations of the disease also include important neuropsychiatric symptoms with atypical characteristics. Are these disturbances linked to stress accompanying every systemic infection, or are due to specific neurobiological changes associated with COVID-19? Evidence accumulated so far indicates that the pathophysiology of COVID-19 is characterized by systemic inflammation, hypoxia resulting from respiratory failure, and neuroinflammation (either due to viral neurotropism or in response to cytokine storm), all affecting the brain. It is reasonable to hypothesize that all these events may initiate or worsen psychiatric and cognitive disorders. Damage to the brain triggers a specific type of reactive response mounted by neuroglia cells, in particular by astrocytes which are the homeostatic cell par excellence. Astrocytes undergo complex morphological, biochemical, and functional remodeling aimed at mobilizing the regenerative potential of the central nervous system. If the brain is not directly damaged, resolution of systemic pathology usually results in restoration of the physiological homeostatic status of neuroglial cells. The completeness and dynamics of this process in pathological conditions remain largely unknown. In a subset of patients, glial cells could fail to recover after infection thus promoting the onset and progression of COVID-19-related neuropsychiatric diseases. There is evidence from post-mortem examinations of the brains of COVID-19 patients of alterations in both astrocytes and microglia. In conclusion, COVID-19 activates a huge reactive response of glial cells, that physiologically act as the main controller of the inflammatory, protective and regenerative events. However, in some patients the restoration of glial physiological state does not occur, thus compromising glial function and ultimately resulting in homeostatic failure underlying a set of specific neuropsychiatric symptoms related to COVID-19.
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Affiliation(s)
- Luca Steardo
- Psychiatric Unit, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Luca Steardo
- Department of Physiology and Pharmacology "Vittorio Erspamer", SAPIENZA University of Rome, Rome, Italy
- Università Giustino Fortunato, Benevento, Italy
| | - Caterina Scuderi
- Department of Physiology and Pharmacology "Vittorio Erspamer", SAPIENZA University of Rome, Rome, Italy.
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10
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Musavi H, Abazari O, Barartabar Z, Kalaki-Jouybari F, Hemmati-Dinarvand M, Esmaeili P, Mahjoub S. The benefits of Vitamin D in the COVID-19 pandemic: biochemical and immunological mechanisms. Arch Physiol Biochem 2023; 129:354-362. [PMID: 33030073 DOI: 10.1080/13813455.2020.1826530] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
In December 2019, a new infectious complication called CoronaVirus Infectious Disease-19, briefly COVID-19, caused by SARS-COV-2, is identified in Wuhan, China. It spread all over the world and became a pandemic. In many individuals who had suffered SARS-COV-2 infection, cytokine storm starts through cytokine overproduction and leads to Acute Respiratory Syndrome (ARS), organ failure, and death. According to the obtained evidence, Vitamin D (VitD) enhances the ACE2/Ang(1-7)/MasR pathway activity, and it also reduces cytokine storms and the ARS risk. Therefore, VitD intake may be beneficial for patients with SARS-COV-2 infection exposed to cytokine storm but do not suffer hypotension. In the present review, we have explained the effects of VitD on the renin-angiotensin system (RAS) function and angiotensin-converting enzyme2 (ACE2) expression. Furthermore, we have reviewed the biochemical and immunological effects of VitD on immune function in the underlying diseases and its role in the COVID-19 pandemic.
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Affiliation(s)
- Hadis Musavi
- Department of Clinical Biochemistry, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Omid Abazari
- Department of Clinical Biochemistry, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Zeinab Barartabar
- Department of Clinical Biochemistry, School of Medicine, Hamedan University of Medical Sciences, Hamedan, Iran
| | - Fatemeh Kalaki-Jouybari
- Department of Clinical Biochemistry, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Mohsen Hemmati-Dinarvand
- Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Parisa Esmaeili
- Department of Immunology and Microbiology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Soleiman Mahjoub
- Department of Clinical Biochemistry, School of Medicine, Babol University of Medical Sciences, Babol, Iran
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
- Department of Pathology, University of Kiel, Kiel, Germany
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11
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Tiwari V, Singh J, Tiwari P, Chaturvedi S, Gupta S, Mishra A, Singh S, Wahajuddin M, Hanif K, Shukla S. ACE2/ANG-(1-7)/Mas receptor axis activation prevents inflammation and improves cognitive functions in streptozotocin induced rat model of Alzheimer's disease-like phenotypes. Eur J Pharmacol 2023; 946:175623. [PMID: 36871666 DOI: 10.1016/j.ejphar.2023.175623] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 01/25/2023] [Accepted: 02/23/2023] [Indexed: 03/06/2023]
Abstract
Activation of the renin-angiotensin system (RAS), by Angiotensin converting enzyme/Angiotensin II/Angiotensin receptor-1 (ACE/Ang II/AT1 R) axis elicits amyloid deposition and cognitive impairment. Furthermore, ACE2 induced release of Ang-(1-7) binds with the Mas receptor and autoinhibits ACE/Ang II/AT1 axis activation. Inhibition of ACE by perindopril has been reported to improve memory in preclinical settings. However, the functional significance and mechanism by which ACE2/Mas receptor regulate cognitive functions and amyloid pathology is not known. The present study is aimed to determine the role of ACE2/Ang-(1-7)/Mas receptor axis in STZ induced rat model of Alzheimer's disease (AD). We have used pharmacological, biochemical and behavioural approaches to identify the role of ACE2/Ang-(1-7)/Mas receptor axis activation on AD-like pathology in both in vitro and invivo models. STZ treatment enhances ROS formation, inflammation markers and NFκB/p65 levels which are associated with reduced ACE2/Mas receptor levels, acetylcholine activity and mitochondrial membrane potential in N2A cells. DIZE mediated ACE2/Ang-(1-7)/Mas receptor axis activation resulted in reduced ROS generation, astrogliosis, NFκB level and inflammatory molecules and improved mitochondrial functions along with Ca2+ influx in STZ treated N2A cells. Interestingly, DIZE induced activation of ACE2/Mas receptor significantly restored acetylcholine levels and reduced amyloid-beta and phospho-tau deposition in cortex and hippocampus that resulted in improved cognitive function in STZ induced rat model of AD-like phenotypes. Our data indicate that ACE2/Mas receptor activation is sufficient to prevented cognitive impairment and progression of amyloid pathology in STZ induced rat model of AD-like phenotypes. These findings suggest the potential role of ACE2/Ang-(1-7)/Mas axis in AD pathophysiology by regulating inflammation cognitive functions.
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Affiliation(s)
- Virendra Tiwari
- Division of Neuroscience and Ageing Biology, CSIR- Central Drug Research Institute, Lucknow, 226031, (U.P), India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Jitendra Singh
- Division of Neuroscience and Ageing Biology, CSIR- Central Drug Research Institute, Lucknow, 226031, (U.P), India
| | - Priya Tiwari
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India; Division of Pharmacology, CSIR- Central Drug Research Institute, Lucknow, 226031, (U.P), India
| | - Swati Chaturvedi
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India; Division of Pharmaceutics and Pharmacokinetics, CSIR - Central Drug Research Institute, Lucknow, 226031, (U.P), India
| | - Shivangi Gupta
- Division of Neuroscience and Ageing Biology, CSIR- Central Drug Research Institute, Lucknow, 226031, (U.P), India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Akanksha Mishra
- Division of Neuroscience and Ageing Biology, CSIR- Central Drug Research Institute, Lucknow, 226031, (U.P), India; Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, 01595, USA
| | - Sonu Singh
- Division of Neuroscience and Ageing Biology, CSIR- Central Drug Research Institute, Lucknow, 226031, (U.P), India; Department of Neuroscience, School of Medicine, University of Connecticut (Uconn) Health Center, 263 Farmington Avenue, L-4078, Farmington, CT, 06030, USA
| | - Muhammad Wahajuddin
- Division of Pharmaceutics and Pharmacokinetics, CSIR - Central Drug Research Institute, Lucknow, 226031, (U.P), India; Institute of Cancer Therapeutics, University of Bradford, Bradford, BD7 1DP, United Kingdom
| | - Kashif Hanif
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India; Division of Pharmacology, CSIR- Central Drug Research Institute, Lucknow, 226031, (U.P), India
| | - Shubha Shukla
- Division of Neuroscience and Ageing Biology, CSIR- Central Drug Research Institute, Lucknow, 226031, (U.P), India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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12
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Kobusiak-Prokopowicz M, Fułek K, Fułek M, Kaaz K, Mysiak A, Kurpas D, Beszłej JA, Brzecka A, Leszek J. Cardiovascular, Pulmonary, and Neuropsychiatric Short- and Long-Term Complications of COVID-19. Cells 2022; 11:3882. [PMID: 36497138 PMCID: PMC9735460 DOI: 10.3390/cells11233882] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Revised: 11/28/2022] [Accepted: 11/29/2022] [Indexed: 12/05/2022] Open
Abstract
Beginning with the various strategies of the SARS-CoV-2 virus to invade our bodies and manifest infection, and ending with the recent long COVID, we are witnessing the evolving course of the disease in addition to the pandemic. Given the partially controlled course of the COVID-19 pandemic, the greatest challenge currently lies in managing the short- and long-term complications of COVID-19. We have assembled current knowledge of the broad spectrum of cardiovascular, pulmonary, and neuropsychiatric sequelae following SARS-CoV-2 infection to understand how these clinical manifestations collectively lead to a severe form of the disease. The ultimate goal would be to better understand these complications and find ways to prevent clinical deterioration.
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Affiliation(s)
| | - Katarzyna Fułek
- Lower Silesian Oncology, Pulmonology and Hematology Center, 53-413 Wroclaw, Poland
| | - Michał Fułek
- Department and Clinic of Internal Medicine, Occupational Diseases, Hypertension and Clinical Oncology, Wroclaw Medical University, 50-556 Wroclaw, Poland
| | - Konrad Kaaz
- Department of Cardiology, Institute of Heart Diseases, Wroclaw Medical University, 50-556 Wroclaw, Poland
| | - Andrzej Mysiak
- Department of Cardiology, Institute of Heart Diseases, Wroclaw Medical University, 50-556 Wroclaw, Poland
| | - Donata Kurpas
- Department and Clinic of Family Medicine, Wroclaw Medical University, 51-141 Wroclaw, Poland
| | | | - Anna Brzecka
- Department of Pulmonology and Lung Oncology, Wroclaw Medical University, 53-439 Wroclaw, Poland
| | - Jerzy Leszek
- Department and Clinic of Psychiatry, Wroclaw Medical University, 50-367 Wroclaw, Poland
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13
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Hsu PC, Shahed-Al-Mahmud M. SARS-CoV-2 mediated neurological disorders in COVID-19: Measuring the pathophysiology and immune response. Life Sci 2022; 308:120981. [PMID: 36150465 PMCID: PMC9490490 DOI: 10.1016/j.lfs.2022.120981] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 09/07/2022] [Accepted: 09/16/2022] [Indexed: 11/17/2022]
Abstract
The emergence of beta-coronavirus SARS-CoV-2 gets entry into its host cells by recognizing angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRESS2) receptors, which are responsible for coronavirus diseases-2019 (COVID-19). Global communities have been affected by COVID-19, especially caused the neurological complications and other critical medical issues. COVID-19 associated complications appear in aged people with underlying neurological states, especially in Parkinson's disease (PD) and Alzheimer's disease (AD). ACE2 receptors abundantly expressed in dopamine neurons may worsen the motor symptoms in PD and upregulates in SARS-CoV-2 infected aged patients' brain with AD. Immune-mediated cytokines released in SARS-CoV-2 infection lead to an indirect immune response that damages the central nervous system. Extreme cytokines release (cytokine storm) occurs due to aberrant immune pathways, and activation in microglial propagates CNS damage in COVID-19 patients. Here, we have explored the pathophysiology, immune responses, and long-term neurological impact on PD and AD patients with COVID-19. It is also a crucial step to understanding COVID-19 pathogenesis to reduce fatal outcomes of neurodegenerative diseases.
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Affiliation(s)
- Pi-Ching Hsu
- Workplace Heath Promotion Center, Changhua Christian Hospital, Changhua, Taiwan
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14
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Togha M, Hashemi SM, Yamani N, Martami F, Salami Z. A Review on Headaches Due to COVID-19 Infection. Front Neurol 2022; 13:942956. [PMID: 35911910 PMCID: PMC9327440 DOI: 10.3389/fneur.2022.942956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 06/20/2022] [Indexed: 11/13/2022] Open
Abstract
Since December 2019, the time when the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was spotted, numerous review studies have been published on COVID-19 and its neuro invasion. A growing number of studies have reported headaches as a common neurological manifestation of COVID-19. Although several hypotheses have been proposed regarding the association between headache and the coronavirus, no solid evidence has been presented for the mechanism and features of headache in COVID-19. Headache also is a common complaint with the omicron variant of the virus. COVID-19 vaccination also is a cause of new-onset headaches or aggravation of the previous headache in migraine or tension headache sufferers. In this review study, the types of headaches reported in previous studies and their possible pathogenic mechanisms are outlined. To accomplish this objective, various types of headaches are classified and their patterns are discussed according to ICHD-3 diagnostic criteria, including, headaches attributed to systemic viral infection, viral meningitis or encephalitis, non-infectious inflammatory intracranial disease, hypoxia and/or hypercapnia, cranial or cervical vascular disorder, increased cerebrospinal fluid (CSF) pressure, refractive error, external-compression headache, and cough headache. Then, their pathogeneses are categorized into three main categories, direct trigeminal involvement, vascular invasion, and inflammatory mediators. Furthermore, persistent headache after recovery and the predictors of intensity is further investigated. Post-vaccination headache is also discussed in this review.
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Affiliation(s)
- Mansoureh Togha
- Headache Department, Iranian Center of Neurological Researches, Institute of Neuroscience, Tehran University of Medical Sciences, Tehran, Iran
- Headache Department, Neurology Ward, Sina Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyedeh Melika Hashemi
- Headache Department, Iranian Center of Neurological Researches, Institute of Neuroscience, Tehran University of Medical Sciences, Tehran, Iran
| | - Nooshin Yamani
- Neurology Department, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Fahimeh Martami
- Headache Department, Iranian Center of Neurological Researches, Institute of Neuroscience, Tehran University of Medical Sciences, Tehran, Iran
| | - Zhale Salami
- Headache Department, Iranian Center of Neurological Researches, Institute of Neuroscience, Tehran University of Medical Sciences, Tehran, Iran
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15
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Sánchez-Luquez KY, Carpena MX, Karam SM, Tovo-Rodrigues L. The contribution of whole-exome sequencing to intellectual disability diagnosis and knowledge of underlying molecular mechanisms: A systematic review and meta-analysis. MUTATION RESEARCH. REVIEWS IN MUTATION RESEARCH 2022; 790:108428. [PMID: 35905832 DOI: 10.1016/j.mrrev.2022.108428] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 07/21/2022] [Accepted: 07/23/2022] [Indexed: 01/01/2023]
Abstract
Whole-exome sequencing (WES) is useful for molecular diagnosis, family genetic counseling, and prognosis of intellectual disability (ID). However, ID molecular diagnosis ascertainment based on WES is highly dependent on de novo mutations (DNMs) and variants of uncertain significance (VUS). The quantification of DNM frequency in ID molecular diagnosis ascertainment and the biological mechanisms common to genes with VUS may provide objective information about WES use in ID diagnosis and etiology. We aimed to investigate and estimate the rate of ID molecular diagnostic assessment by WES, quantify the contribution of DNMs to this rate, and biologically and functionally characterize the genes whose mutations were identified through WES. A PubMed/Medline, Web of Science, Scopus, Science Direct, BIREME, and PsycINFO systematic review and meta-analysis was performed, including studies published between 2010 and 2022. Thirty-seven articles with data on ID molecular diagnostic yield using the WES approach were included in the review. WES testing accounted for an overall diagnostic rate of 42% (Confidence interval (CI): 35-50%), while the estimate restricted to DNMs was 11% (CI: 6-18%). Genetic information on mutations and genes was extracted and split into two groups: (1) genes whose mutation was used for positive molecular diagnosis, and (2) genes whose mutation led to uncertain molecular diagnosis. After functional enrichment analysis, in addition to their expected roles in neurodevelopment, genes from the first group were enriched in epigenetic regulatory mechanisms, immune system regulation, and circadian rhythm control. Genes from uncertain diagnosis cases were enriched in the renin angiotensin pathway. Taken together, our results support WES as an important approach to the molecular diagnosis of ID. The results also indicated relevant pathways that may underlie the pathogenesis of ID with the renin-angiotensin pathway being suggested to be a potential pathway underlying the pathogenesis of ID.
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Affiliation(s)
| | - Marina Xavier Carpena
- Postgraduate Program in Epidemiology, Universidade Federal de Pelotas, Pelotas, Brazil.
| | - Simone M Karam
- Postgraduate Program in Public Health, Universidade Federal do Rio Grande, Rio Grande, Brazil.
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16
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Jalodia R, Antoine D, Braniff RG, Dutta RK, Ramakrishnan S, Roy S. Opioid-Use, COVID-19 Infection, and Their Neurological Implications. Front Neurol 2022; 13:884216. [PMID: 35677336 PMCID: PMC9169980 DOI: 10.3389/fneur.2022.884216] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 04/25/2022] [Indexed: 01/08/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an imminent threat to human health and public safety. ACE2 and transmembrane serine protease 2 proteins on host cells provide the viral entry point to SARS-CoV-2. Although SARS-CoV-2 mainly infects the respiratory system, there have been reports of viral neurotropism and central nervous system injury as indicated by plasma biomarkers, including neurofilament light chain protein and glial fibrillary acidic protein. Even with a small proportion of infections leading to neurological manifestation, the overall number remains high. Common neurological manifestations of SARS-CoV-2 infection include anosmia, ageusia, encephalopathy, and stroke, which are not restricted to only the most severe infection cases. Opioids and opioid antagonists bind to the ACE2 receptor and thereby have been hypothesized to have therapeutic potential in treating COVID-19. However, in the case of other neurotropic viral infections such as human immunodeficiency virus (HIV), opioid use has been established to exacerbate HIV-mediated central nervous system pathogenesis. An analysis of electronic health record data from more than 73 million patients shows that people with Substance Use Disorders are at higher risk of contracting COVID-19 and suffer worse consequences then non-users. Our in-vivo and in-vitro unpublished studies show that morphine treatment causes increased expression of ACE2 in murine lung and brain tissue as early as 24 h post treatment. At the same time, we also observed morphine and lipopolysaccharides treatment lead to a synergistic increase in ACE2 expression in the microglial cell line, SIM-A9. This data suggests that opioid treatment may potentially increase neurotropism of SARS-CoV-2 infection. We have previously shown that opioids induce gut microbial dysbiosis. Similarly, gut microbiome alterations have been reported with SARS-CoV-2 infection and may play a role in predicting COVID-19 disease severity. However, there are no studies thus far linking opioid-mediated dysbiosis with the severity of neuron-specific COVID-19 infection.
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Affiliation(s)
| | | | | | | | | | - Sabita Roy
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, United States
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17
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Impaired Vagal Activity in Long-COVID-19 Patients. Viruses 2022; 14:v14051035. [PMID: 35632776 PMCID: PMC9147759 DOI: 10.3390/v14051035] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/03/2022] [Accepted: 05/11/2022] [Indexed: 12/13/2022] Open
Abstract
Long-COVID-19 refers to the signs and symptoms that continue or develop after the “acute COVID-19” phase. These patients have an increased risk of multiorgan dysfunction, readmission, and mortality. In Long-COVID-19 patients, it is possible to detect a persistent increase in D-Dimer, NT-ProBNP, and autonomic nervous system dysfunction. To verify the dysautonomia hypothesis in Long-COVID-19 patients, we studied heart rate variability using 12-lead 24-h ECG monitoring in 30 Long-COVID-19 patients and 20 No-COVID patients. Power spectral analysis of heart rate variability was lower in Long-COVID-19 patients both for total power (7.46 ± 0.5 vs. 8.08 ± 0.6; p < 0.0001; Cohens-d = 1.12) and for the VLF (6.84 ± 0.8 vs. 7.66 ± 0.6; p < 0.0001; Cohens-d = 1.16) and HF (4.65 ± 0.9 vs. 5.33 ± 0.9; p = 0.015; Cohens-d = 0.76) components. The LF/HF ratio was significantly higher in Long-COVID-19 patients (1.46 ± 0.27 vs. 1.23 ± 0.13; p = 0.001; Cohens-d = 1.09). On multivariable analysis, Long-COVID-19 is significantly correlated with D-dimer (standardized β-coefficient = 0.259), NT-ProBNP (standardized β-coefficient = 0.281), HF component of spectral analysis (standardized β-coefficient = 0.696), and LF/HF ratio (standardized β-coefficient = 0.820). Dysautonomia may explain the persistent symptoms in Long COVID-19 patients. The persistence of a procoagulative state and an elevated myocardial strain could explain vagal impairment in these patients. In Long-COVID-19 patients, impaired vagal activity, persistent increases of NT-ProBNP, and a prothrombotic state require careful monitoring and appropriate intervention.
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18
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Kitchen LC, Berman M, Halper J, Chazot P. Rationale for 1068 nm Photobiomodulation Therapy (PBMT) as a Novel, Non-Invasive Treatment for COVID-19 and Other Coronaviruses: Roles of NO and Hsp70. Int J Mol Sci 2022; 23:ijms23095221. [PMID: 35563611 PMCID: PMC9105035 DOI: 10.3390/ijms23095221] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 04/27/2022] [Accepted: 05/04/2022] [Indexed: 01/08/2023] Open
Abstract
Researchers from across the world are seeking to develop effective treatments for the ongoing coronavirus disease 2019 (COVID-19) outbreak, which arose as a major public health issue in 2019, and was declared a pandemic in early 2020. The pro-inflammatory cytokine storm, acute respiratory distress syndrome (ARDS), multiple-organ failure, neurological problems, and thrombosis have all been linked to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) fatalities. The purpose of this review is to explore the rationale for using photobiomodulation therapy (PBMT) of the particular wavelength 1068 nm as a therapy for COVID-19, investigating the cellular and molecular mechanisms involved. Our findings illustrate the efficacy of PBMT 1068 nm for cytoprotection, nitric oxide (NO) release, inflammation changes, improved blood flow, and the regulation of heat shock proteins (Hsp70). We propose, therefore, that PBMT 1068 is a potentially effective and innovative approach for avoiding severe and critical illness in COVID-19 patients, although further clinical evidence is required.
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Affiliation(s)
- Lydia C. Kitchen
- Department of Biosciences, Durham University, Durham DH1 3LE, UK;
| | - Marvin Berman
- Quietmind Foundation, Philadelphia, PA 19147, USA; (M.B.); (J.H.)
| | - James Halper
- Quietmind Foundation, Philadelphia, PA 19147, USA; (M.B.); (J.H.)
| | - Paul Chazot
- Department of Biosciences, Durham University, Durham DH1 3LE, UK;
- Correspondence:
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19
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Razi O, Tartibian B, Laher I, Govindasamy K, Zamani N, Rocha-Rodrigues S, Suzuki K, Zouhal H. Multimodal Benefits of Exercise in Patients With Multiple Sclerosis and COVID-19. Front Physiol 2022; 13:783251. [PMID: 35492581 PMCID: PMC9048028 DOI: 10.3389/fphys.2022.783251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Accepted: 03/31/2022] [Indexed: 11/24/2022] Open
Abstract
Multiple sclerosis (MS) is a demyelinating disease characterized by plaque formation and neuroinflammation. The plaques can present in various locations, causing a variety of clinical symptoms in patients with MS. Coronavirus disease-2019 (COVID-19) is also associated with systemic inflammation and a cytokine storm which can cause plaque formation in several areas of the brain. These concurring events could exacerbate the disease burden of MS. We review the neuro-invasive properties of SARS-CoV-2 and the possible pathways for the entry of the virus into the central nervous system (CNS). Complications due to this viral infection are similar to those occurring in patients with MS. Conditions related to MS which make patients more susceptible to viral infection include inflammatory status, blood-brain barrier (BBB) permeability, function of CNS cells, and plaque formation. There are also psychoneurological and mood disorders associated with both MS and COVID-19 infections. Finally, we discuss the effects of exercise on peripheral and central inflammation, BBB integrity, glia and neural cells, and remyelination. We conclude that moderate exercise training prior or after infection with SARS-CoV-2 can produce health benefits in patients with MS patients, including reduced mortality and improved physical and mental health of patients with MS.
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Affiliation(s)
- Omid Razi
- Department of Exercise Physiology, Faculty of Physical Education and Sport Sciences, Razi University, Kermanshah, Iran
| | - Bakhtyar Tartibian
- Department of Sports Injuries, Faculty of Physical Education and Sports Sciences, Allameh Tabataba’i University, Tehran, Iran
| | - Ismail Laher
- Department of Anesthesiology, Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Karuppasamy Govindasamy
- Department of Physical Education & Sports Science, SRM Institute of Science and Technology, Kattankulathur, India
| | - Nastaran Zamani
- Department of Biology, Faculty of Science, Payame-Noor University, Tehran, Iran
| | - Silvia Rocha-Rodrigues
- Escola Superior de Desporto e Lazer, Instituto Politécnico de Viana do Castelo, Viana do Castelo, Portugal
- Research Centre in Sports Sciences, Health Sciences and Human Development (CIDESD), Quinta de Prados, Edifício Ciências de Desporto, Vila Real, Portugal
- Tumor & Microenvironment Interactions Group, i3S, Porto, Portugal
| | | | - Hassane Zouhal
- Laboratoire Mouvement, Sport, Santé, University of Rennes, Rennes, France
- Institut International des Sciences du Sport (2I2S), Irodouer, France
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20
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Shir D, Day GS. Deciphering the contributions of neuroinflammation to neurodegeneration: lessons from antibody-mediated encephalitis and coronavirus disease 2019. Curr Opin Neurol 2022; 35:212-219. [PMID: 35102125 PMCID: PMC8896289 DOI: 10.1097/wco.0000000000001033] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
PURPOSE OF REVIEW Does neuroinflammation promote neurodegeneration? Does neurodegeneration promote neuroinflammation? Or, is the answer to both questions, yes? These questions have proven challenging to answer in patients with typical age-related neurodegenerative diseases in whom the onset of neuroinflammation and neurodegeneration are largely unknown. Patients recovering from diseases associated with abrupt-onset neuroinflammation, including rare forms of antibody-mediated encephalitis (AME) and common complications of novel coronavirus disease 2019 (COVID-19), provide a unique opportunity to untangle the relationship between neuroinflammation and neurodegeneration. This review explores the lessons learned from patients with AME and COVID-19. RECENT FINDINGS Persistent cognitive impairment is increasingly recognized in patients recovering from AME or COVID-19, yet the drivers of impairment remain largely unknown. Clinical observations, neuroimaging and biofluid biomarkers, and pathological studies imply a link between the severity of acute neuroinflammation, subsequent neurodegeneration, and disease-associated morbidity. SUMMARY Data from patients with AME and COVID-19 inform key hypotheses that may be evaluated through future studies incorporating longitudinal biomarkers of neuroinflammation and neurodegeneration in larger numbers of recovering patients. The results of these studies may inform the contributors to cognitive impairment in patients with AME and COVID-19, with potential diagnostic and therapeutic applications in patients with age-related neurodegenerative diseases.
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Affiliation(s)
- Dror Shir
- Department of Neurology, Mayo Clinic, Rochester, Minnesota
| | - Gregory S. Day
- Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA
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21
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Sandeep B, Xiao Z, Gao K, Mao L, Chen J, Ping W, Hong W, Zhang Z. Role and interaction between ACE1, ACE2 and their related genes in cardiovascular disorders. Curr Probl Cardiol 2022:101162. [PMID: 35245599 DOI: 10.1016/j.cpcardiol.2022.101162] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 02/25/2022] [Indexed: 12/18/2022]
Abstract
Cardiovascular disease is the greatest health care burden and one of the most common causes of death worldwide. Less is known about the genetic factors that are responsible for predisposition to cardiovascular disease thus; the molecular and genetic mechanisms underlying cardiovascular diseases remain obscure. One important regulator of blood pressure homeostasis is the renin-angiotensin system (RAS). The protease renin cleaves angiotensinogen into the inactive decameric peptide angiotensin I (AngI). Angiotensin-converting enzyme (ACE) catalyzes the cleavage of the Ang I into the active octomer angiotensin II (Ang II). In humans, can ACE polymorphism has been associated with determinants of renal and cardiovascular function and pharmacological inhibition of ACE and Ang II receptors are effective in lowering blood pressure and preventing kidney disease. In addition, inhibition of ACE and Ang II receptors has beneficial effects in heart failure. A homologue of ACE, termed ACE2, has been identified; it is predominantly expressed in the vascular endothelial cells of the kidney and heart. Unlike ACE, ACE2 functions as a carboxypeptidase, cleaving a single residue from AngI, generating Ang1-9, and a single residue from AngII to generate Ang1-7. Nevertheless, the in vivo role of ACE2 in the cardiovascular system and the RAS is not known.
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Affiliation(s)
- Bhushan Sandeep
- Department of Cardiothoracic Surgery, Chengdu Second People's Hospital, Chengdu, Sichuan, 610017.
| | - Zongwei Xiao
- Department of Cardiothoracic Surgery, Chengdu Second People's Hospital, Chengdu, Sichuan, 610017
| | - Ke Gao
- Department of Cardiothoracic Surgery, Chengdu Second People's Hospital, Chengdu, Sichuan, 610017
| | - Long Mao
- Department of Cardiothoracic Surgery, Chengdu Second People's Hospital, Chengdu, Sichuan, 610017
| | - Jian Chen
- Department of Cardiothoracic Surgery, Chengdu Second People's Hospital, Chengdu, Sichuan, 610017
| | - Wu Ping
- Department of Cardiothoracic Surgery, Chengdu Second People's Hospital, Chengdu, Sichuan, 610017
| | - Wang Hong
- Department of Cardiothoracic Surgery, Chengdu Second People's Hospital, Chengdu, Sichuan, 610017
| | - Zhengwei Zhang
- Department of Critical Care Unit, Chengdu Second People's Hospital, Chengdu, Sichuan, 610017
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22
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Sandeep B, Xiao Z, Gao K, Mao L, Chen J, Ping W, Hong W, Zhang Z. Role and interaction between ACE1, ACE2 and their related genes in cardiovascular disorders. Curr Probl Cardiol 2022. [DOI: https://doi.org/10.1016/j.cpcardiol.2022.101162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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23
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Rothan HA, Kumari P, Stone S, Natekar JP, Arora K, Auroni TT, Kumar M. SARS-CoV-2 Infects Primary Neurons from Human ACE2 Expressing Mice and Upregulates Genes Involved in the Inflammatory and Necroptotic Pathways. Pathogens 2022; 11:pathogens11020257. [PMID: 35215199 PMCID: PMC8876293 DOI: 10.3390/pathogens11020257] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 02/05/2022] [Accepted: 02/15/2022] [Indexed: 02/01/2023] Open
Abstract
Transgenic mice expressing human angiotensin-converting enzyme 2 under the cytokeratin 18 promoter (K18-hACE2) have been extensively used to investigate the pathogenesis and tissue tropism of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Neuroinvasion and the replication of SARS-CoV-2 within the central nervous system (CNS) of K18-hACE2 mice is associated with increased mortality; although, the mechanisms by which this occurs remain unclear. In this study, we generated primary neuronal cultures from K18-hACE2 mice to investigate the effects of a SARS-CoV-2 infection. We also evaluated the immunological response to SARS-CoV-2 infection in the CNS of K18-hACE2 mice and mouse neuronal cultures. Our data show that neuronal cultures obtained from K18-hACE2 mice are permissive to SARS-CoV-2 infection and support productive virus replication. Furthermore, SARS-CoV-2 infection upregulated the expression of genes involved in innate immunity and inflammation, including IFN-α, ISG-15, CXCL10, CCL2, IL-6 and TNF-α, in the neurons and mouse brains. In addition, we found that SARS-CoV-2 infection of neurons and mouse brains activates the ZBP1/pMLKL-regulated necroptosis pathway. Together, our data provide insights into the neuropathogenesis of SARS-CoV-2 infection in K18-hACE2 mice.
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24
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He X, Wu Y, Huang H, Guo F. A novel histone deacetylase inhibitor‐based approach to eliminate microglia and retain astrocyte properties in glial cell culture. J Neurochem 2022; 161:405-416. [PMID: 35092690 DOI: 10.1111/jnc.15581] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 01/04/2022] [Accepted: 01/25/2022] [Indexed: 11/28/2022]
Affiliation(s)
- Xi‐Biao He
- Laboratory of Stem Cell Biology and Epigenetics, School of Basic Medical Sciences Shanghai University of Medicine and Health Sciences Shanghai China
| | - Yi Wu
- Speech Therapy Department, The Second Rehabilitation Hospital of Shanghai Shanghai China
| | - Haozhi Huang
- Department of Orthopaedic Surgery, Shanghai Tenth People’s Hospital Affiliated to Tongji University Shanghai China
| | - Fang Guo
- Laboratory of Stem Cell Biology and Epigenetics, School of Basic Medical Sciences Shanghai University of Medicine and Health Sciences Shanghai China
- Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital Shanghai China
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25
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Valenza M, Steardo L, Steardo L, Verkhratsky A, Scuderi C. Systemic Inflammation and Astrocyte Reactivity in the Neuropsychiatric Sequelae of COVID-19: Focus on Autism Spectrum Disorders. Front Cell Neurosci 2021; 15:748136. [PMID: 34912192 PMCID: PMC8666426 DOI: 10.3389/fncel.2021.748136] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 11/02/2021] [Indexed: 01/05/2023] Open
Affiliation(s)
- Marta Valenza
- Department of Physiology and Pharmacology "Vittorio Erspamer", SAPIENZA University of Rome, Rome, Italy
| | - Luca Steardo
- Psychiatric Unit, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Luca Steardo
- Department of Physiology and Pharmacology "Vittorio Erspamer", SAPIENZA University of Rome, Rome, Italy.,Università Telematica Giustino Fortunato, Benevento, Italy
| | - Alexei Verkhratsky
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom.,Achucarro Center for Neuroscience, IKERBASQUE, Bilbao, Spain.,Department of Stem Cell Biology, State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania
| | - Caterina Scuderi
- Department of Physiology and Pharmacology "Vittorio Erspamer", SAPIENZA University of Rome, Rome, Italy
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26
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Li T, Huang HY, Wang H, Gao CC, Liang H, Deng CL, Zhao X, Han YL, Zhou ML. Restoration of Brain Angiotensin-Converting Enzyme 2 Alleviates Neurological Deficits after Severe Traumatic Brain Injury via Mitigation of Pyroptosis and Apoptosis. J Neurotrauma 2021; 39:423-434. [PMID: 34861788 DOI: 10.1089/neu.2021.0382] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Clinically, the renin-angiotensin-aldosterone system is intensely activated in moderate to severe traumatic brain injury (TBI) patients. Increased angiotensin II in circulatory blood after TBI can enter the brain through the disrupted blood-brain barrier. Angiotensin-converting enzyme 2 (ACE2) is an enzyme that metabolizes angiotensin II into angiotensin (1-7), which has been shown to have neuroprotective results. However, the expression and role of ACE2 in the brain after TBI remains elusive. We found that ACE2 protein abundance was downregulated around the contusional area in the brains of both humans and mice. Endogenous ACE2 was expressed in neurons, astrocytes, and microglia in the cortex of the mouse brain. Administration of recombinant human ACE2 intracerebroventricularly alleviated neurological defects after TBI in mice. Treatment of recombinant human ACE2 suppressed TBI-induced increase of angiotensin II and the decrease of angiotensin (1-7) in the brain, mitigated neural cell death, reduced the activation of NLRP3 and Caspase3, decreased phosphorylation of mitogen-activated protein kinases, and nuclear factor kappa B, and reduced inflammatory cytokines TNF-α and IL-1β. Administration of ACE2 enzyme activator diminazene aceturate intraperitoneally rescued downregulation of ACE2 enzymatic activity and protein abundance in the brain. Diminazene aceturate treatment once per day in the acute stage after TBI alleviated long-term cognitive defects and neuronal loss in mice. Collectively, these results indicated that restoration of ACE2 alleviated neurological deficits after TBI by mitigation of pyroptosis and apoptosis.
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Affiliation(s)
- Tao Li
- Nanjing Medical University, 12461, Department of Neurosurgery, Jinling Hospital, Jinling School of Clinical Medicine,, Nanjing, Jiangsu, China;
| | - Han-Yu Huang
- Nanjing Medical University, 12461, Department of Neurosurgery, Jinling Hospital, Jinling School of Clinical Medicine,, Nanjing, Jiangsu, China;
| | - Handong Wang
- Nanjing Medical University, 12461, neurosurgery of jinling hospital, Nanjing, Jiangsu, China;
| | - Chao-Chao Gao
- Nanjing Medical University, 12461, Department of Neurosurgery, Jinling Hospital, Jinling School of Clinical Medicine,, Nanjing, Jiangsu, China;
| | - Hui Liang
- Nanjing University, 12581, Department of Neurosurgery, Jinling Hospital, Nanjing, Jiangsu, China;
| | - Chu-Lei Deng
- Nanjing Jinling Hospital, 144990, Department of Neurosurgery, Nanjing, Jiangsu, China;
| | - Xin Zhao
- Nanjing University, 12581, Department of Neurosurgery, Jinling Hospital, Nanjing, Jiangsu, China;
| | - Yan-Lin Han
- Nanjing University, 12581, Department of Neurosurgery, Jinling Hospital, Nanjing, Jiangsu, China;
| | - Meng-Liang Zhou
- Nanjing University, 12581, Department of Neurosurgery, Jinling Hospital, Nanjing, Jiangsu, China;
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27
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Dąbrowska E, Galińska-Skok B, Waszkiewicz N. Depressive and Neurocognitive Disorders in the Context of the Inflammatory Background of COVID-19. Life (Basel) 2021; 11:1056. [PMID: 34685427 PMCID: PMC8541562 DOI: 10.3390/life11101056] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 10/01/2021] [Accepted: 10/03/2021] [Indexed: 02/07/2023] Open
Abstract
The dysfunctional effects of the coronavirus disease 2019 (COVID-19) infection on the nervous system are established. The manifestation of neuropsychiatric symptoms during and after infection is influenced by the neuroinvasive and neurotrophic properties of SARS-CoV-2 as well as strong inflammation characterised by a specific "cytokine storm". Research suggests that a strong immune response to a SARS-CoV-2 infection and psychological stressors related to the pandemic may cause chronic inflammatory processes in the body with elevated levels of inflammatory markers contributing to the intensification of neurodegenerative processes. It is suggested that neuroinflammation and associated central nervous system changes may significantly contribute to the etiopathogenesis of depressive disorders. In addition, symptoms after a COVID-19 infection may persist for up to several weeks after an acute infection as a post-COVID-19 syndrome. Moreover, previous knowledge indicates that among SSRI (selective serotonin reuptake inhibitor) group antidepressants, fluoxetine is a promising drug against COVID-19. In conclusion, further research, observation and broadening of the knowledge of the pathomechanism of a SARS-CoV-2 infection and the impact on potential complications are necessary. It is essential to continue research in order to assess the long-term neuropsychiatric effects in COVID-19 patients and to find new therapeutic strategies.
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Affiliation(s)
- Eliza Dąbrowska
- Department of Psychiatry, Medical University of Bialystok, pl. Brodowicza 1, 16-070 Choroszcz, Poland; (B.G.-S.); (N.W.)
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28
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Schou TM, Joca S, Wegener G, Bay-Richter C. Psychiatric and neuropsychiatric sequelae of COVID-19 - A systematic review. Brain Behav Immun 2021; 97:328-348. [PMID: 34339806 PMCID: PMC8363196 DOI: 10.1016/j.bbi.2021.07.018] [Citation(s) in RCA: 261] [Impact Index Per Article: 65.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 07/22/2021] [Accepted: 07/24/2021] [Indexed: 12/12/2022] Open
Abstract
It has become evident that coronavirus disease 2019 (COVID-19) has a multi-organ pathology that includes the brain and nervous system. Several studies have also reported acute psychiatric symptoms in COVID-19 patients. An increasing number of studies are suggesting that psychiatric deficits may persist after recovery from the primary infection. In the current systematic review, we provide an overview of the available evidence and supply information on potential risk factors and underlying biological mechanisms behind such psychiatric sequelae. We performed a systematic search for psychiatric sequelae in COVID-19 patients using the databases PubMed and Embase. Included primary studies all contained information on the follow-up period and provided quantitative measures of mental health. The search was performed on June 4th 2021. 1725 unique studies were identified. Of these, 66 met the inclusion criteria and were included. Time to follow-up ranged from immediately after hospital discharge up to 7 months after discharge, and the number of participants spanned 3 to 266,586 participants. Forty studies reported anxiety and/or depression, 20 studies reported symptoms- or diagnoses of post-traumatic stress disorder (PTSD), 27 studies reported cognitive deficits, 32 articles found fatigue at follow-up, and sleep disturbances were found in 23 studies. Highlighted risk factors were disease severity, duration of symptoms, and female sex. One study showed brain abnormalities correlating with cognitive deficits, and several studies reported inflammatory markers to correlate with symptoms. Overall, the results from this review suggest that survivors of COVID-19 are at risk of psychiatric sequelae but that symptoms generally improve over time.
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Affiliation(s)
- Thor Mertz Schou
- Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, 8000 Aarhus C, Denmark
| | - Samia Joca
- Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark
| | - Gregers Wegener
- Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, 8000 Aarhus C, Denmark
| | - Cecilie Bay-Richter
- Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, 8000 Aarhus C, Denmark.
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29
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Karnik M, Beeraka NM, Uthaiah CA, Nataraj SM, Bettadapura ADS, Aliev G, Madhunapantula SV. A Review on SARS-CoV-2-Induced Neuroinflammation, Neurodevelopmental Complications, and Recent Updates on the Vaccine Development. Mol Neurobiol 2021; 58:4535-4563. [PMID: 34089508 PMCID: PMC8179092 DOI: 10.1007/s12035-021-02399-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 04/19/2021] [Indexed: 02/08/2023]
Abstract
Coronavirus disease 2019 (COVID-19) is a devastating viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The incidence and mortality of COVID-19 patients have been increasing at an alarming rate. The mortality is much higher in older individuals, especially the ones suffering from respiratory distress, cardiac abnormalities, renal diseases, diabetes, and hypertension. Existing evidence demonstrated that SARS-CoV-2 makes its entry into human cells through angiotensin-converting enzyme 2 (ACE-2) followed by the uptake of virions through cathepsin L or transmembrane protease serine 2 (TMPRSS2). SARS-CoV-2-mediated abnormalities in particular cardiovascular and neurological ones and the damaged coagulation systems require extensive research to develop better therapeutic modalities. As SARS-CoV-2 uses its S-protein to enter into the host cells of several organs, the S-protein of the virus is considered as the ideal target to develop a potential vaccine. In this review, we have attempted to highlight the landmark discoveries that lead to the development of various vaccines that are currently under different stages of clinical progression. Besides, a brief account of various drug candidates that are being tested to mitigate the burden of COVID-19 was also covered. Further, in a dedicated section, the impact of SARS-CoV-2 infection on neuronal inflammation and neuronal disorders was discussed. In summary, it is expected that the content covered in this article help to understand the pathophysiology of COVID-19 and the impact on neuronal complications induced by SARS-CoV-2 infection while providing an update on the vaccine development.
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Affiliation(s)
- Medha Karnik
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR), Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka, India
| | - Narasimha M Beeraka
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR), Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka, India
- Sechenov First Moscow State Medical University (Sechenov University), St. Trubetskaya, 8, bld. 2, Moscow, 119991, Russia
| | - Chinnappa A Uthaiah
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR), Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka, India
| | - Suma M Nataraj
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR), Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka, India
| | - Anjali Devi S Bettadapura
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR), Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka, India
| | - Gjumrakch Aliev
- Sechenov First Moscow State Medical University (Sechenov University), St. Trubetskaya, 8, bld. 2, Moscow, 119991, Russia
- Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, Moscow Region, 142432, Russia
- Research Institute of Human Morphology, 3 Tsyurupy Street, Moscow, 117418, Russia
- GALLY International Research Institute, 7733 Louis Pasteur Drive, San Antonio, TX, #330, USA
| | - SubbaRao V Madhunapantula
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR), Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka, India.
- Special Interest Group in Cancer Biology and Cancer Stem Cells (SIG-CBCSC), JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka, India.
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30
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Williams ME, Fielding BC. Insult to Injury-Potential Contribution of Coronavirus Disease-19 to Neuroinflammation and the Development of HIV-Associated Neurocognitive Disorders. AIDS Res Hum Retroviruses 2021; 37:601-609. [PMID: 32993321 DOI: 10.1089/aid.2020.0136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 is responsible for a new coronavirus disease known as coronavirus disease-19 (COVID-19). SARS-CoV-2 reports neurotropic properties and may have neurological implications, and this creates another health burden for people living with HIV. As yet, the impact of COVID-19 on (neuro)inflammation and the development of HIV-associated neurocognitive disorders (HAND) is not fully known. Here, we reviewed preliminary evidence that provides clues that COVID-19 may exacerbate inflammatory mechanisms related to the development of HAND.
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Affiliation(s)
| | - Burtram Clinton Fielding
- Molecular Biology and Virology Research Laboratory, Department of Medical Biosciences, University of the Western Cape, Cape Town, South Africa
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31
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Zanza C, Tassi MF, Romenskaya T, Piccolella F, Abenavoli L, Franceschi F, Piccioni A, Ojetti V, Saviano A, Canonico B, Montanari M, Zamai L, Artico M, Robba C, Racca F, Longhitano Y. Lock, Stock and Barrel: Role of Renin-Angiotensin-Aldosterone System in Coronavirus Disease 2019. Cells 2021; 10:1752. [PMID: 34359922 PMCID: PMC8306543 DOI: 10.3390/cells10071752] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 06/21/2021] [Accepted: 07/09/2021] [Indexed: 02/06/2023] Open
Abstract
Since the end of 2019, the medical-scientific community has been facing a terrible pandemic caused by a new airborne viral agent known as SARS-CoV2. Already in the early stages of the pandemic, following the discovery that the virus uses the ACE2 cell receptor as a molecular target to infect the cells of our body, it was hypothesized that the renin-angiotensin-aldosterone system was involved in the pathogenesis of the disease. Since then, numerous studies have been published on the subject, but the exact role of the renin-angiotensin-aldosterone system in the pathogenesis of COVID-19 is still a matter of debate. RAAS represents an important protagonist in the pathogenesis of COVID-19, providing the virus with the receptor of entry into host cells and determining its organotropism. Furthermore, following infection, the virus is able to cause an increase in plasma ACE2 activity, compromising the normal function of the RAAS. This dysfunction could contribute to the establishment of the thrombo-inflammatory state characteristic of severe forms of COVID-19. Drugs targeting RAAS represent promising therapeutic options for COVID-19 sufferers.
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Affiliation(s)
- Christian Zanza
- Department of Emergency Medicine, Foundation of Policlinico Agostino Gemelli-IRCCS, Catholic University of Sacred Heart, 00168 Rome, Italy; (F.F.); (A.P.); (V.O.); (A.S.)
- Department of Anesthesia and Critical Care, AON SS Antonio e Biagio e Cesare Arrigo, 15121 Alessandria, Italy; (T.R.); (F.P.); (F.R.); (Y.L.)
- Foundation Ospedale Alba-Bra and Department of Anesthesia, Critical Care and Emergency Medicine, Pietro and Michele Ferrero Hospital, 12051 Verduno, Italy
| | - Michele Fidel Tassi
- Department of Emergency Medicine, AON SS Antonio e Biagio e Cesare Arrigo, 15121 Alessandria, Italy;
| | - Tatsiana Romenskaya
- Department of Anesthesia and Critical Care, AON SS Antonio e Biagio e Cesare Arrigo, 15121 Alessandria, Italy; (T.R.); (F.P.); (F.R.); (Y.L.)
| | - Fabio Piccolella
- Department of Anesthesia and Critical Care, AON SS Antonio e Biagio e Cesare Arrigo, 15121 Alessandria, Italy; (T.R.); (F.P.); (F.R.); (Y.L.)
| | - Ludovico Abenavoli
- Department of Health Sciences, University Magna Graecia, 88100 Catanzaro, Italy;
| | - Francesco Franceschi
- Department of Emergency Medicine, Foundation of Policlinico Agostino Gemelli-IRCCS, Catholic University of Sacred Heart, 00168 Rome, Italy; (F.F.); (A.P.); (V.O.); (A.S.)
| | - Andrea Piccioni
- Department of Emergency Medicine, Foundation of Policlinico Agostino Gemelli-IRCCS, Catholic University of Sacred Heart, 00168 Rome, Italy; (F.F.); (A.P.); (V.O.); (A.S.)
| | - Veronica Ojetti
- Department of Emergency Medicine, Foundation of Policlinico Agostino Gemelli-IRCCS, Catholic University of Sacred Heart, 00168 Rome, Italy; (F.F.); (A.P.); (V.O.); (A.S.)
| | - Angela Saviano
- Department of Emergency Medicine, Foundation of Policlinico Agostino Gemelli-IRCCS, Catholic University of Sacred Heart, 00168 Rome, Italy; (F.F.); (A.P.); (V.O.); (A.S.)
| | - Barbara Canonico
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy; (B.C.); (M.M.); (L.Z.)
| | - Mariele Montanari
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy; (B.C.); (M.M.); (L.Z.)
| | - Loris Zamai
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy; (B.C.); (M.M.); (L.Z.)
- National Institute for Nuclear Physics (INFN)-Gran Sasso National Laboratory (LNGS), 67100 Assergi L’Aquila, Italy
| | - Marco Artico
- Department of Sensory Organs, Sapienza University of Rome, 00185 Rome, Italy;
| | - Chiara Robba
- Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genoa, 16132 Genoa, Italy;
| | - Fabrizio Racca
- Department of Anesthesia and Critical Care, AON SS Antonio e Biagio e Cesare Arrigo, 15121 Alessandria, Italy; (T.R.); (F.P.); (F.R.); (Y.L.)
| | - Yaroslava Longhitano
- Department of Anesthesia and Critical Care, AON SS Antonio e Biagio e Cesare Arrigo, 15121 Alessandria, Italy; (T.R.); (F.P.); (F.R.); (Y.L.)
- Foundation Ospedale Alba-Bra and Department of Anesthesia, Critical Care and Emergency Medicine, Pietro and Michele Ferrero Hospital, 12051 Verduno, Italy
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Marazziti D, Cianconi P, Mucci F, Foresi L, Chiarantini I, Della Vecchia A. Climate change, environment pollution, COVID-19 pandemic and mental health. THE SCIENCE OF THE TOTAL ENVIRONMENT 2021; 773:145182. [PMID: 33940721 PMCID: PMC7825818 DOI: 10.1016/j.scitotenv.2021.145182] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 01/10/2021] [Accepted: 01/11/2021] [Indexed: 05/06/2023]
Abstract
Converging data would indicate the existence of possible relationships between climate change, environmental pollution and epidemics/pandemics, such as the current one due to SARS-CoV-2 virus. Each of these phenomena has been supposed to provoke detrimental effects on mental health. Therefore, the purpose of this paper was to review the available scientific literature on these variables in order to suggest and comment on their eventual synergistic effects on mental health. The available literature report that climate change, air pollution and COVID-19 pandemic might influence mental health, with disturbances ranging from mild negative emotional responses to full-blown psychiatric conditions, specifically, anxiety and depression, stress/trauma-related disorders, and substance abuse. The most vulnerable groups include elderly, children, women, people with pre-existing health problems especially mental illnesses, subjects taking some types of medication including psychotropic drugs, individuals with low socio-economic status, and immigrants. It is evident that COVID-19 pandemic uncovers all the fragility and weakness of our ecosystem, and inability to protect ourselves from pollutants. Again, it underlines our faults and neglect towards disasters deriving from climate change or pollution, or the consequences of human activities irrespective of natural habitats and constantly increasing the probability of spillover of viruses from animals to humans. In conclusion, the psychological/psychiatric consequences of COVID-19 pandemic, that currently seem unavoidable, represent a sharp cue of our misconception and indifference towards the links between our behaviour and their influence on the "health" of our planet and of ourselves. It is time to move towards a deeper understanding of these relationships, not only for our survival, but for the maintenance of that balance among man, animals and environment at the basis of life in earth, otherwise there will be no future.
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Affiliation(s)
- Donatella Marazziti
- Department of Clinical and Experimental Medicine, Section of Psychiatry, University of Pisa, Italy; UniCamillus - Saint Camillus University of Health Sciences, Rome, Italy
| | - Paolo Cianconi
- Institute of Psychiatry, Department of Neurosciences, Catholic University, Rome, Italy
| | - Federico Mucci
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Italy; Department of Psychiatry, North-Western Tuscany Region, NHS Local Health Unit, Italy
| | - Lara Foresi
- Department of Clinical and Experimental Medicine, Section of Psychiatry, University of Pisa, Italy
| | - Ilaria Chiarantini
- Department of Clinical and Experimental Medicine, Section of Psychiatry, University of Pisa, Italy
| | - Alessandra Della Vecchia
- Department of Clinical and Experimental Medicine, Section of Psychiatry, University of Pisa, Italy.
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Khedr EM, Shoyb A, Mohammaden M, Saber M. Acute symptomatic seizures and COVID-19: Hospital-based study. Epilepsy Res 2021; 174:106650. [PMID: 33993018 PMCID: PMC8096525 DOI: 10.1016/j.eplepsyres.2021.106650] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 04/01/2021] [Accepted: 05/02/2021] [Indexed: 12/24/2022]
Abstract
Background and purpose Post COVID-19 seizures are relatively rare. The aim of the present study was to estimate the frequency of acute symptomatic seizures among patients with COVID-19 and to discuss possible pathophysiological mechanisms. Material and methods Out of 439 cases with COVID-19 that were admitted to Assiut and Aswan University hospitals during the period from 1 June to 10 August 2020, 19 patients (4.3 %) presented with acute symptomatic seizures. Each patient underwent computed tomography (CT) or magnetic resonance imaging (MRI) of the brain and conventional electroencephalography (EEG). Laboratory investigations included: blood gases, complete blood picture, serum D-Dimer, Ferritin, C-reactive protein, renal and liver functions, and coagulation profile. Results Of the 19 patients, 3 had new onset seizures without underlying pathology (0.68 % out of the total 439 patients); 2 others (0.46 %) had previously diagnosed controlled epilepsy with breakthrough seizures. The majority of cases (14 patients, 3.19 %) had primary pathology that could explain the occurrence of seizures: 5 suffered a post COVID-19 stroke (3 ischemic and 2 hemorrhagic stroke); 6 patients had COVID-related encephalitis; 2 patients were old ischemic stroke patients; 1 patient had a brain tumor and developed seizures post COVID-19. Conclusion acute symptomatic seizure is not a rare complication of post COVID-19 infection. Both new onset seizures and seizures secondary to primary brain insult (post COVID encephalitis or recent stroke) were observed.
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Affiliation(s)
- Eman M Khedr
- Department of Neuropsychiatry, Faculty of Medicine, Assiut University, Egypt.
| | - Ahmed Shoyb
- Department of Neuropsychiatry, Faculty of Medicine, Aswan University, Egypt
| | - Mahmoud Mohammaden
- Department of Neuropsychiatry, Faculty of Medicine, South Valley University, Egypt
| | - Mostafa Saber
- Department of Neuropsychiatry, Faculty of Medicine, Aswan University, Egypt
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Elhamzaoui H, Rebahi H, Hachimi A. Coronavirus disease 2019 (COVID-19) pathogenesis: a concise narrative review. Pan Afr Med J 2021; 39:8. [PMID: 34178236 PMCID: PMC8197062 DOI: 10.11604/pamj.2021.39.8.23546] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 08/01/2020] [Indexed: 01/08/2023] Open
Abstract
SARS-CoV-2 is the third zoonotic coronavirus. Since December 2019, it has spread through the globe and infects more than four million patients (as of May 10th, 2020). The disease was named coronavirus disease 2019 (COVID-19) by the World Health Organization (WHO). It involves many organs and systems in the human organism. We aimed to describe the pathogenesis of the COVID-19.
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Affiliation(s)
- Hamza Elhamzaoui
- Critical Care Department, Mohammed VIth University Hospital of Marrakech, Cadi Ayyad University, Marrakech, Morocco
| | - Houssam Rebahi
- Critical Care Department, Mohammed VIth University Hospital of Marrakech, Cadi Ayyad University, Marrakech, Morocco
| | - Abdelhamid Hachimi
- Critical Care Department, Mohammed VIth University Hospital of Marrakech, Cadi Ayyad University, Marrakech, Morocco
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Nordvig AS, Fong KT, Willey JZ, Thakur KT, Boehme AK, Vargas WS, Smith CJ, Elkind MSV. Potential Neurologic Manifestations of COVID-19. Neurol Clin Pract 2021; 11:e135-e146. [PMID: 33842082 PMCID: PMC8032406 DOI: 10.1212/cpj.0000000000000897] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 06/12/2020] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW Neurologic complications are increasingly recognized in the coronavirus disease 2019 (COVID-19) pandemic. COVID-19 is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This coronavirus is related to severe acute respiratory syndrome coronavirus (SARS-CoV) and other human coronavirus-related illnesses that are associated with neurologic symptoms. These symptoms raise the question of a neuroinvasive potential of SARS-CoV-2. RECENT FINDINGS Potential neurologic symptoms and syndromes of SARS-CoV-2 include headache, fatigue, dizziness, anosmia, ageusia, anorexia, myalgias, meningoencephalitis, hemorrhage, altered consciousness, Guillain-Barré syndrome, syncope, seizure, and stroke. In addition, we discuss neurologic effects of other coronaviruses, special considerations for management of neurologic patients, and possible long-term neurologic and public health sequelae. SUMMARY As SARS-CoV-2 is projected to infect a large part of the world's population, understanding the potential neurologic implications of COVID-19 will help neurologists and others recognize and intervene in neurologic morbidity during and after the pandemic of 2020.
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Affiliation(s)
- Anna S Nordvig
- Department of Neurology (ASN, KTF, JZW, KTT, AKB, WSV, MSVE), Vagelos College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital; Department of Epidemiology (AKB, MSVE), Mailman School of Public Health, Columbia University, New York, NY; Division of Cardiovascular Sciences (CJS), Lydia Becker Institute of Immunology and Inflammation, University of Manchester; and Manchester Centre for Clinical Neurosciences (CJS), Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Salford, United Kingdom
| | - Kathryn T Fong
- Department of Neurology (ASN, KTF, JZW, KTT, AKB, WSV, MSVE), Vagelos College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital; Department of Epidemiology (AKB, MSVE), Mailman School of Public Health, Columbia University, New York, NY; Division of Cardiovascular Sciences (CJS), Lydia Becker Institute of Immunology and Inflammation, University of Manchester; and Manchester Centre for Clinical Neurosciences (CJS), Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Salford, United Kingdom
| | - Joshua Z Willey
- Department of Neurology (ASN, KTF, JZW, KTT, AKB, WSV, MSVE), Vagelos College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital; Department of Epidemiology (AKB, MSVE), Mailman School of Public Health, Columbia University, New York, NY; Division of Cardiovascular Sciences (CJS), Lydia Becker Institute of Immunology and Inflammation, University of Manchester; and Manchester Centre for Clinical Neurosciences (CJS), Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Salford, United Kingdom
| | - Kiran T Thakur
- Department of Neurology (ASN, KTF, JZW, KTT, AKB, WSV, MSVE), Vagelos College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital; Department of Epidemiology (AKB, MSVE), Mailman School of Public Health, Columbia University, New York, NY; Division of Cardiovascular Sciences (CJS), Lydia Becker Institute of Immunology and Inflammation, University of Manchester; and Manchester Centre for Clinical Neurosciences (CJS), Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Salford, United Kingdom
| | - Amelia K Boehme
- Department of Neurology (ASN, KTF, JZW, KTT, AKB, WSV, MSVE), Vagelos College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital; Department of Epidemiology (AKB, MSVE), Mailman School of Public Health, Columbia University, New York, NY; Division of Cardiovascular Sciences (CJS), Lydia Becker Institute of Immunology and Inflammation, University of Manchester; and Manchester Centre for Clinical Neurosciences (CJS), Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Salford, United Kingdom
| | - Wendy S Vargas
- Department of Neurology (ASN, KTF, JZW, KTT, AKB, WSV, MSVE), Vagelos College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital; Department of Epidemiology (AKB, MSVE), Mailman School of Public Health, Columbia University, New York, NY; Division of Cardiovascular Sciences (CJS), Lydia Becker Institute of Immunology and Inflammation, University of Manchester; and Manchester Centre for Clinical Neurosciences (CJS), Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Salford, United Kingdom
| | - Craig J Smith
- Department of Neurology (ASN, KTF, JZW, KTT, AKB, WSV, MSVE), Vagelos College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital; Department of Epidemiology (AKB, MSVE), Mailman School of Public Health, Columbia University, New York, NY; Division of Cardiovascular Sciences (CJS), Lydia Becker Institute of Immunology and Inflammation, University of Manchester; and Manchester Centre for Clinical Neurosciences (CJS), Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Salford, United Kingdom
| | - Mitchell S V Elkind
- Department of Neurology (ASN, KTF, JZW, KTT, AKB, WSV, MSVE), Vagelos College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital; Department of Epidemiology (AKB, MSVE), Mailman School of Public Health, Columbia University, New York, NY; Division of Cardiovascular Sciences (CJS), Lydia Becker Institute of Immunology and Inflammation, University of Manchester; and Manchester Centre for Clinical Neurosciences (CJS), Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Salford, United Kingdom
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Brain angiotensin system: a new promise in the management of epilepsy? Clin Sci (Lond) 2021; 135:725-730. [PMID: 33729497 DOI: 10.1042/cs20201296] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 03/03/2021] [Accepted: 03/08/2021] [Indexed: 12/30/2022]
Abstract
Epilepsy is a highly prevalent neurological disease and anti-epileptic drugs (AED) are almost the unique clinical treatment option. A disbalanced brain renin-angiotensin system (RAS) has been proposed in epilepsy and several reports have shown that angiotensin II (Ang II) receptor-1 (ATR1) activation is pro-inflammatory and pro-epileptogenic. In agreement, ATR1 blockage with the repurposed drug losartan has shown benefits in animal models of epilepsy. Processing of Ang II by ACE2 enzyme renders Ang-(1-7), a metabolite that activates the mitochondrial assembly (Mas) receptor (MasR) pathway. MasR activation presents beneficial effects, facilitating vasodilatation, increasing anti-inflammatory and antioxidative responses. In a recent paper published in Clinical Science, Gomes and colleagues (Clin. Sci. (Lond.) (2020) 134, 2263-2277) performed intracerebroventricular (icv) infusion of Ang-(1-7) in animals subjected to the pilocarpine model of epilepsy, starting after the first spontaneous motor seizure (SMS). They showed that this approach reduced the frequency of SMS, restored animal anxiety, increased exploration, and augmented the hippocampal expression of protective catalase enzyme and antiapoptotic protein B-cell lymphoma 2 (Bcl-2). Interestingly, but surprisingly, Gomes and colleagues showed that MasR expression and mTor activity were reduced in the hippocampus of the epileptic Ang-(1-7) treated animals. These results show that Ang-(1-7) administration could represent a new avenue for developing strategies for the management of epilepsy in clinical settings. However, future work is necessary to evaluate the levels of RAS metabolites and the activity of key enzymes in these experimental interventions to completely understand the therapeutic potential of the brain RAS manipulation in epilepsy.
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Aslan C, Nikfarjam S, Asadzadeh M, Jafari R. Neurological manifestations of COVID-19: with emphasis on Iranian patients. J Neurovirol 2021; 27:217-227. [PMID: 33710597 PMCID: PMC7953513 DOI: 10.1007/s13365-021-00964-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 02/16/2021] [Accepted: 02/24/2021] [Indexed: 11/16/2022]
Abstract
The novel coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has instigated a global pandemic as a formidable and highly contagious infectious disease. Although the respiratory system remains the most frequently affected organ, several case reports have revealed that the complications are not merely limited to the respiratory system, and neurotropic and neuroinvasive properties have also been observed, leading to neurological diseases. In the present paper, it was intended to review the possible neuroinvasive routes of SARS-CoV-2 and its mechanisms that may cause neurological damage. Additionally, the neurological manifestations of COVID-19 across the globe were discussed with emphasis on Iran, while highlighting the impact of SARS-CoV-2 on the central and peripheral nervous systems.
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Affiliation(s)
- Cynthia Aslan
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sepideh Nikfarjam
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Asadzadeh
- Department of Radiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Reza Jafari
- Solid Tumor Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran.
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Yong SJ. Persistent Brainstem Dysfunction in Long-COVID: A Hypothesis. ACS Chem Neurosci 2021; 12:573-580. [PMID: 33538586 PMCID: PMC7874499 DOI: 10.1021/acschemneuro.0c00793] [Citation(s) in RCA: 132] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 02/01/2021] [Indexed: 02/07/2023] Open
Abstract
Long-COVID is a postviral illness that can affect survivors of COVID-19, regardless of initial disease severity or age. Symptoms of long-COVID include fatigue, dyspnea, gastrointestinal and cardiac problems, cognitive impairments, myalgia, and others. While the possible causes of long-COVID include long-term tissue damage, viral persistence, and chronic inflammation, the review proposes, perhaps for the first time, that persistent brainstem dysfunction may also be involved. This hypothesis can be split into two parts. The first is the brainstem tropism and damage in COVID-19. As the brainstem has a relatively high expression of ACE2 receptor compared with other brain regions, SARS-CoV-2 may exhibit tropism therein. Evidence also exists that neuropilin-1, a co-receptor of SARS-CoV-2, may be expressed in the brainstem. Indeed, autopsy studies have found SARS-CoV-2 RNA and proteins in the brainstem. The brainstem is also highly prone to damage from pathological immune or vascular activation, which has also been observed in autopsy of COVID-19 cases. The second part concerns functions of the brainstem that overlap with symptoms of long-COVID. The brainstem contains numerous distinct nuclei and subparts that regulate the respiratory, cardiovascular, gastrointestinal, and neurological processes, which can be linked to long-COVID. As neurons do not readily regenerate, brainstem dysfunction may be long-lasting and, thus, is long-COVID. Indeed, brainstem dysfunction has been implicated in other similar disorders, such as chronic pain and migraine and myalgic encephalomyelitis or chronic fatigue syndrome.
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Affiliation(s)
- Shin Jie Yong
- Department of Biological
Sciences, Sunway University, Petaling Jaya, Selangor 47500, Malaysia
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Wang Y, Takeshita H, Yamamoto K, Huang Y, Wang C, Nakajima T, Nozato Y, Fujimoto T, Yokoyama S, Hongyo K, Nakagami F, Akasaka H, Takami Y, Takeya Y, Sugimoto K, Rakugi H. A pressor dose of angiotensin II has no influence on the angiotensin-converting enzyme 2 and other molecules associated with SARS-CoV-2 infection in mice. FASEB J 2021; 35:e21419. [PMID: 33566370 PMCID: PMC7995007 DOI: 10.1096/fj.202100016r] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 01/16/2021] [Accepted: 01/21/2021] [Indexed: 02/06/2023]
Abstract
In the early phase of the Coronavirus disease 2019 (COVID‐19) pandemic, it was postulated that the renin‐angiotensin‐system inhibitors (RASi) increase the infection risk. This was primarily based on numerous reports, which stated that the RASi could increase the organ Angiotensin‐converting enzyme 2 (ACE2), the receptor of Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), in rodents. RASi can theoretically antagonize the potential influence of angiotensin II (Ang II) on ACE2. However, while Ang II decreases the ACE2 levels in cultured cells, there is little evidence that supports this phenomenon in living animals. In this study, we tested whether Ang II or Ang II combined with its antagonist would alter the ACE2 and other molecules associated with the infection of SARS‐CoV‐2. Male C57BL6/J mice were administered vehicle, Ang II (400 ng/kg/min), or Ang II with losartan (10 mg/kg/min) for 2 weeks. ACE2 knockout mice were used as a negative control for the ACE2 assay. We found that both Ang II, which elevated blood pressure by 30 mm Hg, and Ang II with losartan, had no effect on the expression or protein activity of ACE2 in the lung, left ventricle, kidney, and ileum. Likewise, these interventions had no effect on the expression of Transmembrane Protease Serine 2 (TMPRSS2) and Furin, proteases that facilitate the virus‐cell fusion, and the expression or activity of Tumor Necrosis Factor α‐Convertase (TACE) that cleaves cell‐surface ACE2. Collectively, physiological concentrations of Ang II do not modulate the molecules associated with SARS‐CoV‐2 infection. These results support the recent observational studies suggesting that the use of RASi is not a risk factor for COVID‐19.
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Affiliation(s)
- Yu Wang
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
| | - Hikari Takeshita
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
| | - Koichi Yamamoto
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yibin Huang
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
| | - Cheng Wang
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
| | - Tsuneo Nakajima
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yoichi Nozato
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
| | - Taku Fujimoto
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
| | - Serina Yokoyama
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
| | - Kazuhiro Hongyo
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
| | - Futoshi Nakagami
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
| | - Hiroshi Akasaka
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yoichi Takami
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yasushi Takeya
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
| | - Ken Sugimoto
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
| | - Hiromi Rakugi
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
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Septyaningtrias DE, Susilowati R. Neurological involvement of COVID-19: from neuroinvasion and neuroimmune crosstalk to long-term consequences. Rev Neurosci 2021; 32:427-442. [PMID: 33550780 DOI: 10.1515/revneuro-2020-0092] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 11/07/2020] [Indexed: 12/12/2022]
Abstract
As the coronavirus disease 2019 (COVID-19) pandemic continues to be a multidimensional threat to humanity, more evidence of neurological involvement associated with it has emerged. Neuroimmune interaction may prove to be important not only in the pathogenesis of neurological manifestations but also to prevent systemic hyperinflammation. In this review, we summarize reports of COVID-19 cases with neurological involvement, followed by discussion of possible routes of entry, immune responses against coronavirus infection in the central nervous system and mechanisms of nerve degeneration due to viral infection and immune responses. Possible mechanisms for neuroprotection and virus-associated neurological consequences are also discussed.
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Affiliation(s)
- Dian Eurike Septyaningtrias
- Department of Histology and Cell Biology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Jalan Farmako Sekip Utara, Yogyakarta55281, Indonesia
| | - Rina Susilowati
- Department of Histology and Cell Biology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Jalan Farmako Sekip Utara, Yogyakarta55281, Indonesia
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Alquisiras-Burgos I, Peralta-Arrieta I, Alonso-Palomares LA, Zacapala-Gómez AE, Salmerón-Bárcenas EG, Aguilera P. Neurological Complications Associated with the Blood-Brain Barrier Damage Induced by the Inflammatory Response During SARS-CoV-2 Infection. Mol Neurobiol 2021; 58:520-535. [PMID: 32978729 PMCID: PMC7518400 DOI: 10.1007/s12035-020-02134-7] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 09/16/2020] [Indexed: 01/08/2023]
Abstract
The main discussion above of the novel pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has focused substantially on the immediate risks and impact on the respiratory system; however, the effects induced to the central nervous system are currently unknown. Some authors have suggested that SARS-CoV-2 infection can dramatically affect brain function and exacerbate neurodegenerative diseases in patients, but the mechanisms have not been entirely described. In this review, we gather information from past and actual studies on coronaviruses that informed neurological dysfunction and brain damage. Then, we analyzed and described the possible mechanisms causative of brain injury after SARS-CoV-2 infection. We proposed that potential routes of SARS-CoV-2 neuro-invasion are determinant factors in the process. We considered that the hematogenous route of infection can directly affect the brain microvascular endothelium cells that integrate the blood-brain barrier and be fundamental in initiation of brain damage. Additionally, activation of the inflammatory response against the infection represents a critical step on injury induction of the brain tissue. Consequently, the virus' ability to infect brain cells and induce the inflammatory response can promote or increase the risk to acquire central nervous system diseases. Here, we contribute to the understanding of the neurological conditions found in patients with SARS-CoV-2 infection and its association with the blood-brain barrier integrity.
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Affiliation(s)
- Iván Alquisiras-Burgos
- Laboratorio de Patología Vascular Cerebral, Instituto Nacional de Neurología y Neurocirugía "Manuel Velasco Suárez", Insurgentes Sur #3877, 14269, Ciudad de México, Mexico
| | - Irlanda Peralta-Arrieta
- Laboratorio de Epigenómica del Cáncer y Enfermedades Pulmonares, Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, 54090, Tlanepantla, Estado de México, Mexico
| | - Luis Antonio Alonso-Palomares
- Molecular and Cellular Virology Laboratory, Virology Program, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, 8380453, Santiago, Chile
| | - Ana Elvira Zacapala-Gómez
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, 39070, Chilpancingo de los Bravo, Mexico
| | - Eric Genaro Salmerón-Bárcenas
- Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, 07360, Ciudad de México, Mexico
| | - Penélope Aguilera
- Laboratorio de Patología Vascular Cerebral, Instituto Nacional de Neurología y Neurocirugía "Manuel Velasco Suárez", Insurgentes Sur #3877, 14269, Ciudad de México, Mexico.
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Neuroinvasion and Encephalitis Following Intranasal Inoculation of SARS-CoV-2 in K18-hACE2 Mice. Viruses 2021; 13:v13010132. [PMID: 33477869 PMCID: PMC7832889 DOI: 10.3390/v13010132] [Citation(s) in RCA: 167] [Impact Index Per Article: 41.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/08/2021] [Accepted: 01/12/2021] [Indexed: 12/11/2022] Open
Abstract
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection can cause neurological disease in humans, but little is known about the pathogenesis of SARS-CoV-2 infection in the central nervous system (CNS). Herein, using K18-hACE2 mice, we demonstrate that SARS-CoV-2 neuroinvasion and encephalitis is associated with mortality in these mice. Intranasal infection of K18-hACE2 mice with 105 plaque-forming units of SARS-CoV-2 resulted in 100% mortality by day 6 after infection. The highest virus titers in the lungs were observed on day 3 and declined on days 5 and 6 after infection. By contrast, very high levels of infectious virus were uniformly detected in the brains of all the animals on days 5 and 6. Onset of severe disease in infected mice correlated with peak viral levels in the brain. SARS-CoV-2-infected mice exhibited encephalitis hallmarks characterized by production of cytokines and chemokines, leukocyte infiltration, hemorrhage and neuronal cell death. SARS-CoV-2 was also found to productively infect cells within the nasal turbinate, eye and olfactory bulb, suggesting SARS-CoV-2 entry into the brain by this route after intranasal infection. Our data indicate that direct infection of CNS cells together with the induced inflammatory response in the brain resulted in the severe disease observed in SARS-CoV-2-infected K18-hACE2 mice.
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Sharma R, Li J, Krishnan S, Richards E, Raizada M, Mohandas R. Angiotensin-converting enzyme 2 and COVID-19 in cardiorenal diseases. Clin Sci (Lond) 2021; 135:1-17. [PMID: 33399851 PMCID: PMC7796300 DOI: 10.1042/cs20200482] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 12/03/2020] [Accepted: 12/07/2020] [Indexed: 01/08/2023]
Abstract
The rapid spread of the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has brought into focus the key role of angiotensin-converting enzyme 2 (ACE2), which serves as a cell surface receptor required for the virus to enter cells. SARS-CoV-2 can decrease cell surface ACE2 directly by internalization of ACE2 bound to the virus and indirectly by increased ADAM17 (a disintegrin and metalloproteinase 17)-mediated shedding of ACE2. ACE2 is widely expressed in the heart, lungs, vasculature, kidney and the gastrointestinal (GI) tract, where it counteracts the deleterious effects of angiotensin II (AngII) by catalyzing the conversion of AngII into the vasodilator peptide angiotensin-(1-7) (Ang-(1-7)). The down-regulation of ACE2 by SARS-CoV-2 can be detrimental to the cardiovascular system and kidneys. Further, decreased ACE2 can cause gut dysbiosis, inflammation and potentially worsen the systemic inflammatory response and coagulopathy associated with SARS-CoV-2. This review aims to elucidate the crucial role of ACE2 both as a regulator of the renin-angiotensin system and a receptor for SARS-CoV-2 as well as the implications for Coronavirus disease 19 and its associated cardiovascular and renal complications.
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Affiliation(s)
- Ravindra K. Sharma
- Division of Nephrology, Hypertension and Renal Transplantation, Department of Medicine, University of Florida College of Medicine, Gainesville, FL 32610, U.S.A
| | - Jing Li
- Division of Nephrology, Hypertension and Renal Transplantation, Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL 32610, U.S.A
| | - Suraj Krishnan
- Division of Nephrology, Hypertension and Renal Transplantation, Department of Medicine, University of Florida College of Medicine, Gainesville, FL 32610, U.S.A
| | - Elaine M. Richards
- Division of Nephrology, Hypertension and Renal Transplantation, Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL 32610, U.S.A
| | - Mohan K. Raizada
- Division of Nephrology, Hypertension and Renal Transplantation, Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL 32610, U.S.A
| | - Rajesh Mohandas
- Division of Nephrology, Hypertension and Renal Transplantation, Department of Medicine, University of Florida College of Medicine, Gainesville, FL 32610, U.S.A
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Sadeghmousavi S, Rezaei N. COVID-19 infection and stroke risk. Rev Neurosci 2020; 32:341-349. [PMID: 33580645 DOI: 10.1515/revneuro-2020-0066] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 10/09/2020] [Indexed: 12/19/2022]
Abstract
Coronavirus disease 2019 (COVID-19), due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in Wuhan city, China in December 2019 and rapidly spread to other countries. The most common reported symptoms are fever, dry cough, myalgia and fatigue, headache, anorexia, and breathlessness. Anosmia and dysgeusia as well as gastrointestinal symptoms including nausea and diarrhea are other notable symptoms. This virus also can exhibit neurotropic properties and may also cause neurological diseases, including epileptic seizures, cerebrovascular accident, Guillian barre syndrome, acute transverse myelitis, and acute encephalitis. In this study, we discuss stroke as a complication of the new coronavirus and its possible mechanisms of damage.
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Affiliation(s)
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Tehran University of Medical Sciences, Children's Medical Center, Dr. Qarib St, Keshavarz Blvd, Tehran, 14194, Iran.,Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, 14194, Iran.,Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran1419783151, Iran
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Levine A, Sacktor N, Becker JT. Studying the neuropsychological sequelae of SARS-CoV-2: lessons learned from 35 years of neuroHIV research. J Neurovirol 2020; 26:809-823. [PMID: 32880873 PMCID: PMC7471564 DOI: 10.1007/s13365-020-00897-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 08/11/2020] [Accepted: 08/18/2020] [Indexed: 01/14/2023]
Abstract
The virology of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and the human immune response to the virus are under vigorous investigation. There are now several reports describing neurological symptoms in individuals who develop coronavirus disease 2019 (COVID-19), the syndrome associated with SARS-CoV-2 infection. The prevalence, incidence, and clinical course of these symptoms will become clearer in the coming months and years through epidemiological studies. However, the long-term neurological and cognitive consequence of SARS-CoV-2 infection will remain conjectural for some time and will likely require the creation of cohort studies that include uninfected individuals. Considering the early evidence for neurological involvement in COVID-19 it may prove helpful to compare SARS-CoV-2 with another endemic and neurovirulent virus, human immunodeficiency virus-1 (HIV-1), when designing such cohort studies and when making predictions about neuropsychological outcomes. In this paper, similarities and differences between SARS-CoV-2 and HIV-1 are reviewed, including routes of neuroinvasion, putative mechanisms of neurovirulence, and factors involved in possible long-term neuropsychological sequelae. Application of the knowledge gained from over three decades of neuroHIV research is discussed, with a focus on alerting researchers and clinicians to the challenges in determining the cause of neurocognitive deficits among long-term survivors.
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Affiliation(s)
- Andrew Levine
- Department of Neurology David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
| | - Ned Sacktor
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - James T Becker
- Departments of Psychiatry, Neurology, and Psychology, University of Pittsburgh, Pittsburgh, PA, 15260, USA
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Verkhratsky A, Li Q, Melino S, Melino G, Shi Y. Can COVID-19 pandemic boost the epidemic of neurodegenerative diseases? Biol Direct 2020; 15:28. [PMID: 33246479 PMCID: PMC7691955 DOI: 10.1186/s13062-020-00282-3] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 11/19/2020] [Indexed: 12/11/2022] Open
Abstract
The pandemic of Coronavirus Disease 2019 (COVID-19) presents the world with the medical challenge associated with multifactorial nature of this pathology. Indeed COVID-19 affects several organs and systems and presents diversified clinical picture. COVID-19 affects the brain in many ways including direct infection of neural cells with SARS-CoV-2, severe systemic inflammation which floods the brain with pro-inflammatory agents thus damaging nervous cells, global brain ischaemia linked to a respiratory failure, thromboembolic strokes related to increased intravascular clotting and severe psychological stress. Often the COVID-19 is manifested by neurological and neuropsychiatric symptoms that include dizziness, disturbed sleep, cognitive deficits, delirium, hallucinations and depression. All these indicate the damage to the nervous tissue which may substantially increase the incidence of neurodegenerative diseases and promote dementia.
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Affiliation(s)
- Alexei Verkhratsky
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT UK
- Achucarro Center for Neuroscience, IKERBASQUE, 48011 Bilbao, Spain
| | - Qing Li
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031 China
| | - Sonia Melino
- University of Rome Tor Vergata, via Cracovia 1, 00133 Rome, Italy
| | - Gerry Melino
- University of Rome Tor Vergata, via Cracovia 1, 00133 Rome, Italy
| | - Yufang Shi
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031 China
- State Key Laboratory of Radiation Medicine and Protection, The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University Medical College, Suzhou, 215123 Jiangsu China
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Rodriguez M, Soler Y, Perry M, Reynolds JL, El-Hage N. Impact of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in the Nervous System: Implications of COVID-19 in Neurodegeneration. Front Neurol 2020; 11:583459. [PMID: 33304309 PMCID: PMC7701115 DOI: 10.3389/fneur.2020.583459] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 10/16/2020] [Indexed: 12/12/2022] Open
Abstract
Coronavirus Disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2), began in December 2019, in Wuhan, China and was promptly declared as a pandemic by the World Health Organization (WHO). As an acute respiratory disease, COVID-19 uses the angiotensin-converting enzyme 2 (ACE2) receptor, which is the same receptor used by its predecessor, SARS-CoV, to enter and spread through the respiratory tract. Common symptoms of COVID-19 include fever, cough, fatigue and in a small population of patients, SARS-CoV-2 can cause several neurological symptoms. Neurological malaise may include severe manifestations, such as acute cerebrovascular disease and meningitis/encephalitis. Although there is evidence showing that coronaviruses can invade the central nervous system (CNS), studies are needed to address the invasion of SARS-CoV-2 in the CNS and to decipher the underlying neurotropic mechanisms used by SARS-CoV-2. This review summarizes current reports on the neurological manifestations of COVID-19 and addresses potential routes used by SARS-CoV-2 to invade the CNS.
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Affiliation(s)
- Myosotys Rodriguez
- Department of Immunology and Nano-medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, United States
| | - Yemmy Soler
- Department of Immunology and Nano-medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, United States
| | - Marissa Perry
- Department of Immunology and Nano-medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, United States
| | - Jessica L Reynolds
- Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, United States
| | - Nazira El-Hage
- Department of Immunology and Nano-medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, United States
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Tremblay ME, Madore C, Bordeleau M, Tian L, Verkhratsky A. Neuropathobiology of COVID-19: The Role for Glia. Front Cell Neurosci 2020; 14:592214. [PMID: 33304243 PMCID: PMC7693550 DOI: 10.3389/fncel.2020.592214] [Citation(s) in RCA: 104] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 10/07/2020] [Indexed: 12/18/2022] Open
Abstract
SARS-CoV-2, which causes the Coronavirus Disease 2019 (COVID-19) pandemic, has a brain neurotropism through binding to the receptor angiotensin-converting enzyme 2 expressed by neurones and glial cells, including astrocytes and microglia. Systemic infection which accompanies severe cases of COVID-19 also triggers substantial increase in circulating levels of chemokines and interleukins that compromise the blood-brain barrier, enter the brain parenchyma and affect its defensive systems, astrocytes and microglia. Brain areas devoid of a blood-brain barrier such as the circumventricular organs are particularly vulnerable to circulating inflammatory mediators. The performance of astrocytes and microglia, as well as of immune cells required for brain health, is considered critical in defining the neurological damage and neurological outcome of COVID-19. In this review, we discuss the neurotropism of SARS-CoV-2, the implication of neuroinflammation, adaptive and innate immunity, autoimmunity, as well as astrocytic and microglial immune and homeostatic functions in the neurological and psychiatric aspects of COVID-19. The consequences of SARS-CoV-2 infection during ageing, in the presence of systemic comorbidities, and for the exposed pregnant mother and foetus are also covered.
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Affiliation(s)
- Marie-Eve Tremblay
- Axe Neurosciences, Centre de Recherche du CHU de Québec, Université Laval, Québec City, QC, Canada
- Neurology and Neurosurgery Department, McGill University, Montréal, QC, Canada
- Department of Molecular Medicine, Université Laval, Québec City, QC, Canada
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, BC, Canada
| | - Charlotte Madore
- Univ. Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, Bordeaux, France
| | - Maude Bordeleau
- Axe Neurosciences, Centre de Recherche du CHU de Québec, Université Laval, Québec City, QC, Canada
- Neurology and Neurosurgery Department, McGill University, Montréal, QC, Canada
| | - Li Tian
- Department of Physiology, Faculty of Medicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
- Psychiatry Research Centre, Peking University Health Science Center, Beijing Huilongguan Hospital, Beijing, China
| | - Alexei Verkhratsky
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom
- Achucarro Center for Neuroscience, IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
- Department of Neurosciences, University of the Basque Country Universidad del País Vasco/Euskal Herriko Unibertsitatea, Leioa, Spain
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Sultana S, Ananthapur V. COVID-19 and its impact on neurological manifestations and mental health: the present scenario. Neurol Sci 2020; 41:3015-3020. [PMID: 32865638 PMCID: PMC7457899 DOI: 10.1007/s10072-020-04695-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 08/28/2020] [Indexed: 01/08/2023]
Abstract
Though the COVID-19 pandemic primarily affects pulmonary and cardiorenal functions, many healthcare and its allied groups reported neurological involvement of SARS-CoV-2 in combination with either pre-existing metabolic abnormalities, medical conditions, infections or even chronic to acute inflammatory episodes of the nervous system. The present review provides a fair outlook of the published literature and also the case reports with an emphasis on plausible mechanisms involved in neurological complications of the central and peripheral nervous systems. Awareness on the neuropsychiatric manifestations being discussed in this article should ideally help the medical community in early identification and effective management of potentially life-threatening neurological diseases.
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Affiliation(s)
- Shehnaz Sultana
- Department of Cell Biology, Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Begumpet, Hyderabad, Telangana, 500016, India
| | - Venkateshwari Ananthapur
- Department of Cell Biology, Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Begumpet, Hyderabad, Telangana, 500016, India.
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50
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Jarrahi A, Ahluwalia M, Khodadadi H, da Silva Lopes Salles E, Kolhe R, Hess DC, Vale F, Kumar M, Baban B, Vaibhav K, Dhandapani KM. Neurological consequences of COVID-19: what have we learned and where do we go from here? J Neuroinflammation 2020; 17:286. [PMID: 32998763 PMCID: PMC7525232 DOI: 10.1186/s12974-020-01957-4] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 09/21/2020] [Indexed: 12/19/2022] Open
Abstract
The coronavirus disease-19 (COVID-19) pandemic is an unprecedented worldwide health crisis. COVID-19 is caused by SARS-CoV-2, a highly infectious pathogen that is genetically similar to SARS-CoV. Similar to other recent coronavirus outbreaks, including SARS and MERS, SARS-CoV-2 infected patients typically present with fever, dry cough, fatigue, and lower respiratory system dysfunction, including high rates of pneumonia and acute respiratory distress syndrome (ARDS); however, a rapidly accumulating set of clinical studies revealed atypical symptoms of COVID-19 that involve neurological signs, including headaches, anosmia, nausea, dysgeusia, damage to respiratory centers, and cerebral infarction. These unexpected findings may provide important clues regarding the pathological sequela of SARS-CoV-2 infection. Moreover, no efficacious therapies or vaccines are currently available, complicating the clinical management of COVID-19 patients and emphasizing the public health need for controlled, hypothesis-driven experimental studies to provide a framework for therapeutic development. In this mini-review, we summarize the current body of literature regarding the central nervous system (CNS) effects of SARS-CoV-2 and discuss several potential targets for therapeutic development to reduce neurological consequences in COVID-19 patients.
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Affiliation(s)
- Abbas Jarrahi
- Department of Neurosurgery, Medical College of Georgia, Augusta University, 1120 15th Street, 30912, Augusta, Georgia
| | - Meenakshi Ahluwalia
- Department of Pathology, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Hesam Khodadadi
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, Georgia
| | - Evila da Silva Lopes Salles
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, Georgia
| | - Ravindra Kolhe
- Department of Pathology, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - David C Hess
- Department of Neurology, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Fernando Vale
- Department of Neurosurgery, Medical College of Georgia, Augusta University, 1120 15th Street, 30912, Augusta, Georgia
| | - Manish Kumar
- Department of Allied Health Science, Shri B. M. Patil Medical College, Hospital and Research Centre, BLDE (Deemed to be University), Vijayapura, Karnataka, India
| | - Babak Baban
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, Georgia
| | - Kumar Vaibhav
- Department of Neurosurgery, Medical College of Georgia, Augusta University, 1120 15th Street, 30912, Augusta, Georgia
| | - Krishnan M Dhandapani
- Department of Neurosurgery, Medical College of Georgia, Augusta University, 1120 15th Street, 30912, Augusta, Georgia.
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