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Mazi AR, Karakoc Y, Demirtas C, Aykin U, Yildirim M. Extracellular Matrix Alterations Due to Early-Life Adversity: Implications for Auditory Learning in Male Sprague-Dawley Rats. Mol Neurobiol 2025; 62:6490-6502. [PMID: 39812993 PMCID: PMC11953085 DOI: 10.1007/s12035-025-04690-2] [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: 07/24/2024] [Accepted: 01/05/2025] [Indexed: 01/16/2025]
Abstract
This study aimed to investigate the impact of early childhood chronic stress on the development of the brain extracellular matrix (ECM) and how alterations in the ECM following early-life adversity (ELA) affect auditory learning and cognitive flexibility. ELA was induced through a combination of maternal separation and neonatal isolation in male Sprague-Dawley rats, and the success of the ELA model was assessed behaviorally and biochemically. A cortex-dependent go/no-go task with two phases was used to determine the impact of ELA on auditory learning and cognitive flexibility. The effects of the ECM on cognition were tested via the enzymatic removal of the ECM. The molecular structure of the adult ECM was examined via immunohistochemistry. ELA impaired initial auditory learning but did not significantly affect cognitive flexibility. Hyase injection into the auditory cortex (ACx) restored initial learning. ELA rats display a reduced perineural net (PNN) and parvalbumin + cell density. Our findings reveal that ELA induces significant alterations in the ECM within the ACx, accompanied by impaired initial auditory learning. Although PNN density is already lower in ELA rats, degrading the ECM facilitates the repair of auditory learning. A reduced PNN number in ELA rats fails to enhance learning unless supplemented with Hyase injection.
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Affiliation(s)
- Aise Rumeysa Mazi
- Department of Biophysics, Hamidiye Faculty of Medicine, University of Health Sciences, Selimiye Mah. Tibbiye Cad. No:38, 34668, Uskudar, Istanbul, Turkey.
| | - Yunus Karakoc
- Department of Biophysics, Hamidiye Faculty of Medicine, University of Health Sciences, Selimiye Mah. Tibbiye Cad. No:38, 34668, Uskudar, Istanbul, Turkey
| | - Cumaali Demirtas
- Department of Physiology, Hamidiye Faculty of Medicine, University of Health Sciences, Istanbul, Turkey
| | - Ugur Aykin
- Department of Physiology, Hamidiye Faculty of Medicine, University of Health Sciences, Istanbul, Turkey
| | - Mehmet Yildirim
- Department of Physiology, Hamidiye Faculty of Medicine, University of Health Sciences, Istanbul, Turkey
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Demirtas C, Akca M, Aykin U, Surmeneli YE, Yildirim H, Yildirim M. Effective Protection Against Status Epilepticus Caused by Lithium-Pilocarpine: Combination of Midazolam and Lacosamide. Brain Behav 2025; 15:e70546. [PMID: 40350720 PMCID: PMC12066809 DOI: 10.1002/brb3.70546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 04/04/2025] [Accepted: 04/21/2025] [Indexed: 05/14/2025] Open
Abstract
AIM Status epilepticus causes the most severe condition related to epilepsy in terms of high mortality rate. Although status epilepticus treatment guidelines specify a treatment process based on three-stage monotherapy, effective control cannot yet be achieved in all cases. In the presented study, with electrophysiological and behavioral tests, it was aimed to investigate the effectiveness of the combination of midazolam (MDZ), one of the most commonly used benzodiazepines in the first-line treatment of status epilepticus, with the second-line antiepileptics levetiracetam (LEV), lacosamide (LCM), valproic acid (VPA), and fosphenytoin (fPHT). METHODS A status epilepticus model was created with lithium-pilocarpine (5 mEq/kg-320 mg/kg) in adult male Sprague-Dawley rats with implanted electroencephalography (EEG) electrodes. MDZ (9 mg/kg) alone or in dual combinations with antiepileptic drugs (200 mg/kg LEV, 50 mg/kg LCM, 300 mg/kg VPA, 100 mg/kg fPHT) was injected i.p. to the experiment groups with status epilepticus. After video-EEG recordings were taken from the rats during and after status, the effects of drug interactions on cognitive and motor behaviors were examined by applying behavioral tests (open field, Rotarod, radial arm maze, and passive avoidance). RESULTS Compared with the untreated status epilepticus group, it was determined that MDZ alone and the combination of four antiepileptic drugs administered with MDZ significantly reduced the mortality rate, spike frequency, and spike amplitude of epileptic seizures and suppressed epileptic seizures at certain levels (p < 0.01). Compared to MDZ monotherapy, it was determined that the mortality rate and spike frequency and amplitude decreased significantly in the MDZ + LCM group (p < 0.01), whereas on the other hand, mortality and spike frequency increased in the MDZ + LEV group (p < 0.01). No negative effects were observed in learning and memory in all treatment groups, but it was determined that the motor functions of the animals treated with MDZ + fPHT were impaired compared to both the control group without any treatment and the MDZ group (p < 0.01). CONCLUSION In the status epilepticus model induced by lithium-pilocarpine, the combination of MDZ + LCM was found to be the most effective polytherapy option in reducing seizures and mortality. Additionally, it was observed that LEV, LCM, and VPA administered together with MDZ did not negatively affect both cognitive and motor functions.
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Affiliation(s)
- Cumaali Demirtas
- Department of Physiology, Hamidiye Faculty of MedicineUniversity of Health SciencesİstanbulTürkiye
| | - Metehan Akca
- Department of Physiology, Faculty of MedicineTokat Gaziosmanpaşa UniversityTokatTürkiye
| | - Ugur Aykin
- Department of Physiology, Hamidiye Faculty of MedicineUniversity of Health SciencesİstanbulTürkiye
| | - Yunus Emre Surmeneli
- Department of Physiology, Hamidiye Faculty of MedicineUniversity of Health SciencesİstanbulTürkiye
| | - Hava Yildirim
- Department of Medical Biology, Hamidiye Faculty of MedicineUniversity of Health SciencesİstanbulTürkiye
| | - Mehmet Yildirim
- Department of Physiology, Hamidiye Faculty of MedicineUniversity of Health SciencesİstanbulTürkiye
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Sofía-Avendaño-Lopez S, Rodríguez-Marín AJ, Lara-Castillo M, Agresott-Carrillo J, Lara-Cortés LE, Sánchez-Almanzar JF, Villamil-Cruz S, Rojas-Rodríguez LC, Ariza-Salamanca DF, Gaviria-Carrillo M, Calderon-Ospina CA, Rodríguez-Quintana J. Molecular, Pathophysiological, and Clinical Aspects of Corticosteroid-Induced Neuropsychiatric Effects: From Bench to Bedside. Biomedicines 2024; 12:2131. [PMID: 39335644 PMCID: PMC11429036 DOI: 10.3390/biomedicines12092131] [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: 08/15/2024] [Revised: 09/08/2024] [Accepted: 09/12/2024] [Indexed: 09/30/2024] Open
Abstract
Corticosteroids are frequently prescribed across medical disciplines, yet they are associated with various adverse effects, including neuropsychiatric symptoms, documented since their introduction over 60 years ago. The cellular mechanisms underlying neuropsychiatric symptoms are complex and somewhat obscure, involving multiple pathways. Notably, they include changes in excitability, cellular death of hippocampal and striatal neurons, and increased inflammation and oxidative stress. Clinical presentation varies, encompassing affective disorders (anxiety, euphoria, depression), psychotic episodes, and cognitive deficits. It is crucial to note that these manifestations often go unnoticed by treating physicians, leading to delayed detection of severe symptoms, complications, and underreporting. Discontinuation of corticosteroids constitutes the cornerstone of treatment, resolving symptoms in up to 80% of cases. Although the literature on this topic is scant, isolated cases and limited studies have explored the efficacy of psychotropic medications for symptomatic control and prophylaxis. Pharmacological intervention may be warranted in situations where corticosteroid reduction or withdrawal is not feasible or beneficial for the patient.
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Affiliation(s)
- Sara Sofía-Avendaño-Lopez
- Social Epidemiology Research Team, Institut Pierre Louis d'Epidémiologie et de Santé Publique, INSERM, Sorbonne Université, F 75012 Paris, France
- Pharmacology Unit, Department of Biomedical Sciences, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá 111221, Colombia
| | - Angela Johanna Rodríguez-Marín
- Pharmacology Unit, Department of Biomedical Sciences, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá 111221, Colombia
| | - Mateo Lara-Castillo
- Pharmacology Unit, Department of Biomedical Sciences, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá 111221, Colombia
| | - Juanita Agresott-Carrillo
- Pharmacology Unit, Department of Biomedical Sciences, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá 111221, Colombia
| | - Luna Estefanía Lara-Cortés
- Pharmacology Unit, Department of Biomedical Sciences, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá 111221, Colombia
| | - Juan Felipe Sánchez-Almanzar
- Center for Research in Genetics and Genomics (CIGGUR), Institute of Translational Medicine (IMT), School of Medicine and Health Sciences, Universidad del Rosario, Bogotá 111221, Colombia
| | - Sophya Villamil-Cruz
- Center for Research in Genetics and Genomics (CIGGUR), Institute of Translational Medicine (IMT), School of Medicine and Health Sciences, Universidad del Rosario, Bogotá 111221, Colombia
- Research Group in Applied Biomedical Sciences (UR Biomed), School of Medicine and Health Sciences, Universidad del Rosario, Bogotá 111221, Colombia
| | - Luis Carlos Rojas-Rodríguez
- Pharmacology Unit, Department of Biomedical Sciences, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá 111221, Colombia
| | - Daniel Felipe Ariza-Salamanca
- Department of Pharmacobiology, Center for Research and Advanced Studies (Cinvestav), National Polytechnic Institute, Mexico City 14300, Mexico
| | - Mariana Gaviria-Carrillo
- Neuroscience Research Group (NeURos), NeuroVitae Center for Neuroscience, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá 111221, Colombia
| | - Carlos Alberto Calderon-Ospina
- Pharmacology Unit, Department of Biomedical Sciences, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá 111221, Colombia
- Center for Research in Genetics and Genomics (CIGGUR), Institute of Translational Medicine (IMT), School of Medicine and Health Sciences, Universidad del Rosario, Bogotá 111221, Colombia
- Research Group in Applied Biomedical Sciences (UR Biomed), School of Medicine and Health Sciences, Universidad del Rosario, Bogotá 111221, Colombia
| | - Jesús Rodríguez-Quintana
- Fundacion CardioInfantil-Instituto de Cardiología, Bogotá 111156, Colombia
- Hospital Universitario Mayor Mederi, Bogotá 111411, Colombia
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Baş O, İlhan H, Hancı H, Çelikkan H, Ekinci D, Değermenci M, Karapınar BO, Warille AA, Çankaya S, Özkasapoğlu S. To what extent are orally ingested nanoplastics toxic to the hippocampus in young adult rats? J Chem Neuroanat 2023; 132:102314. [PMID: 37473873 DOI: 10.1016/j.jchemneu.2023.102314] [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: 05/13/2023] [Revised: 07/16/2023] [Accepted: 07/17/2023] [Indexed: 07/22/2023]
Abstract
As the use of plastic-containing materials in our daily lives becomes increasingly common, exposure to nanoplastics accordingly becomes inevitable. Micro and nanoplastics released from large amounts of plastic waste constitute a serious environmental problem. Therefore, this study aimed to examine the effects of polystyrene nanoplastic (PS-NP) on the hippocampus. MATERIAL AND METHOD: Thirty Wistar albino rats, 15 male and 15 female, aged 6-8 weeks, were used in the research. These were randomly divided into three groups of five males and five females each. A five-minute open field test was applied to all rats on the first and last days of the study. Three groups of rats (Control, NP1 and NP2) received the standard chow and water. Additionally, rats in the first neoplastic group (NP1) received 25 mg/kg PS-NP and rats in the second nanoplastic group (NP2) received 50 mg/kg PS-NP, at the same time each day by oral gavage. The rats were sacrificed under deep anesthesia at the end of four weeks. The hippocampi were removed and subjected to histopathological and biochemical analyses. RESULTS: Green fluorescent dots were detected in the hippocampi of both dose groups receiving nanoplastics (NPs) administered orally to female and male rats. Histopathological examination revealed neuronal degeneration in the hippocampi of male and female rats from both dose groups. However, while no significant difference was observed among the groups in terms of changes in antioxidant enzyme values and open-field test data in male rats, significant differences in peroxidase (POD) and glutathione S-transferase (GST) values and fecal boli and grooming numbers were determined in female rats exposed to NPs. In conclusion, exposure to NP substances extend as far as the hippocampus, causing neuronal damage and behavioral problems.
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Affiliation(s)
- Orhan Baş
- Department of Anatomy, Faculty of Medicine, Samsun University, Samsun, Turkey.
| | - Hasan İlhan
- Department of Chemistry, Faculty of Science, Ordu University, Ordu, Turkey
| | - Hatice Hancı
- Department of Histology and Embryology, Faculty of Medicine, Ordu University, Ordu, Turkey
| | - Hüseyin Çelikkan
- Department of Chemistry, Faculty of Science, Gazi University, Ankara, Turkey
| | - Deniz Ekinci
- Department of Agricultural Biotechnology, Faculty of Agriculture, Ondokuz Mayis University, Samsun, Turkey
| | | | - Burak Oğuzhan Karapınar
- Department of Medical Services and Techniques, Vocational School of Health Services, Ondokuz Mayıs University, Samsun, Turkey
| | - Aymen A Warille
- Department of Anatomy, Faculty of Medicine, Ondokuz Mayıs University, Samsun, Turkey
| | - Soner Çankaya
- Department of Sports Management, Faculty of Sport Sciences, Ondokuz Mayıs University, Samsun, Turkey
| | - Sezgin Özkasapoğlu
- Turkish Energy, Nuclear and Mineral Research Agency Boron Research Institute, Ankara, Turkey
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Gedikli Ö, Akca M, Yildirim M. Electroencephalographic investigation of the effects of Ginkgo biloba on spike-wave discharges in rats with genetic absence epilepsy. Epilepsy Behav 2021; 122:108165. [PMID: 34343959 DOI: 10.1016/j.yebeh.2021.108165] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 05/31/2021] [Accepted: 06/08/2021] [Indexed: 11/25/2022]
Abstract
OBJECTIVE EGb 761, a plant extract obtained from the leaves of the Ginkgo biloba tree, is widely used in modern medicine and traditional medicine applications in the treatment of many diseases. However, in some clinical case reports, it has been suggested that G. biloba causes epileptic seizures. A limited number of experimental animal studies related to the effects of G. biloba on epileptic seizures do not provide sufficient information on the solution of a serious clinical problem with contrasting findings. We aimed to investigate the effects of EGb 761 administered in different doses to adult male Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats which is the genetic animal model of absence epilepsy, on absence seizures using in vivo electrophysiological method. In addition, the effects of EGb 761 doses on locomotor behavior of WAG/Rij rats were evaluated with open-field and rotarod behavioral tests. METHODS 50, 100, 200, and 400 mg/kg doses of EGb 761 were administered to male WAG/Rij rats with implanted EEG electrodes by oral gavage for 28 days. Evaluation of absence seizures was performed on spike-wave discharges (SWDs) in EEG recorded for 4 h each week. The number of SWDs, the total duration of SWDs, and the mean duration of SWD were determined for the analysis. RESULTS In the group treated with 400 mg/kg EGb 761, the number of SWDs and the mean duration of SWD at the 1st and 7th doses and the total duration of SWDs at the 1st, 7th and 14th doses were significantly increased (p < 0.05). In all experimental groups treated with EGb 761 doses, there was no significant change in locomotor activity in the open-field and the rotarod tests. CONCLUSION Ginkgo biloba extract EGb 761 increased the epileptic SWD parameters of WAG/Rij rats at high doses (400 mg/kg), causing a pro-epileptic effect on absence seizures. It should be noted that in patients with epilepsy and in high-dose applications, G. biloba extract EGb 761 may lead to an increase in neuronal excitability.
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Affiliation(s)
- Öznur Gedikli
- Department of Physiology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey.
| | - Metehan Akca
- Electroneurophysiology Program, Hamidiye Vocational School of Health Services, University of Health Sciences, Istanbul, Turkey
| | - Mehmet Yildirim
- Department of Physiology, Hamidiye Faculty of Medicine, University of Health Sciences, Istanbul, Turkey
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Luft C, Levices IP, da Costa MS, de Oliveira JR, Donadio MVF. Effects of running before pregnancy on long-term memory and hippocampal alterations induced by prenatal stress. Neurosci Lett 2021; 746:135659. [PMID: 33482306 DOI: 10.1016/j.neulet.2021.135659] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 01/05/2021] [Accepted: 01/10/2021] [Indexed: 12/22/2022]
Abstract
Studies have shown that an adverse environment in utero influences fetal growth and development, leading to several neuroendocrine and behavioral changes in adult life. Nevertheless, the mechanisms involved in the long-term benefits of pregestational exercise are still poorly understood. Thus, this study aimed to evaluate the effects of physical exercise before the gestational period on memory behavior and gene expression in the hippocampus of adult mice submitted to prenatal stress. Female Balb/c mice were divided into three groups: control (CON), prenatal restraint stress (PNS), and exercise before the gestational period plus PNS (EX + PNS). When adults, male and female offspring were submitted to the object recognition test followed by the hippocampal evaluation of BDNF exons I and IV mRNA expression, as well as hypothalamic-pituitary-adrenal axis related genes. Pregestational exercise did not prevent the decreased recognition index, as well as GR and CRHR1 gene expression observed in PNS males. Conversely, prenatal stress did not influence female memory behavior. Moreover, exercise attenuated the effects of prenatal stress on female BDNF IV gene expression. The results indicate that pregestational exercise was able to prevent the effects of maternal stress on hippocampal BDNF IV gene expression in females, although no effects were seen on the stress-induced memory impairment in males.
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Affiliation(s)
- Carolina Luft
- Laboratory of Pediatric Physical Activity, Infant Center, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil; Laboratory of Cellular Biophysics and Inflammation, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Isadora Perez Levices
- Laboratory of Pediatric Physical Activity, Infant Center, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Mariana Severo da Costa
- Laboratory of Pediatric Physical Activity, Infant Center, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Jarbas Rodrigues de Oliveira
- Laboratory of Cellular Biophysics and Inflammation, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Márcio Vinícius Fagundes Donadio
- Laboratory of Pediatric Physical Activity, Infant Center, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil; Laboratory of Cellular Biophysics and Inflammation, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.
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Suhovskih AV, Molodykh OP, Ushakov VS, Politko MO, Sokolov DK, Koldysheva EV, Grigorieva EV. Long-Term Exposure to Temozolomide Affects Locomotor Activity and Cartilage Structure of Elderly Experimental Rats. Biomedicines 2020; 8:biomedicines8120541. [PMID: 33255948 PMCID: PMC7760849 DOI: 10.3390/biomedicines8120541] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 11/16/2020] [Accepted: 11/24/2020] [Indexed: 11/16/2022] Open
Abstract
Chemotherapy with temozolomide (TMZ) is an essential part of anticancer therapy of various malignant tumours; however, its long-term effects on patients’ health and life quality need to be further investigated. Here, we studied the effects of TMZ and/or companion drug dexamethasone (DXM) on the locomotor activity and cartilage structure of elderly Wistar rats (n = 40). Long-term TMZ treatment selectively inhibited the horizontal, but not vertical locomotor activity of the rats (6.7-fold, p < 0.01) and resulted in delamination of the superficial epiphyseal cartilage of the femoral epiphysis of knee joints, a 2-fold decrease in mean thickness of epiphyseal cartilage (p < 0.001), and changes in the proliferative and maturation cartilage zones ratio. The simultaneous use of DXM attenuated TMZ-induced changes in cartilage thickness and integrity and compensated the decrease in horizontal locomotor activity of experimental animals. Nevertheless, combined TMZ/DXM treatment still significantly affected the structure of proximal tibial, but not distal femoral epiphysis of knee joints of the rats. These changes were accompanied by the increased content of total glycosaminoglycans (GAGs) and their partial re-localisation from chondrocytes into tissue matrix, as well as the decrease in sulfated GAGs content in both compartments. Taken together, the results demonstrate that long-term treatment with TMZ results in a significant decrease in locomotor activity of elderly Wistar rats and the reorganisation of their knee joint cartilage structure, while DXM treatment attenuates those effects. So, use of DXM or chondroprotective drugs might be beneficial to maintain quality of life for TMZ-treated cancer patients.
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Affiliation(s)
- Anastasia V. Suhovskih
- Department of Molecular Biology and Biophysics, Federal Research Center of Fundamental and Translational Medicine, 2/12, Timakova str., 630117 Novosibirsk, Russia; (V.S.U.); (M.O.P.); (D.K.S.); (E.V.G.)
- Department of Natural Sciences, V. Zelman Institute for Medicine and Psychology, Novosibirsk State University, 1, Pirogova str., 630090 Novosibirsk, Russia
- Correspondence: ; Tel.: +7-383-333-5011
| | - Olga P. Molodykh
- Department of Molecular Pathology and Pathomorphology, Federal Research Center of Fundamental and Translational Medicine, 2, Timakova str., 630117 Novosibirsk, Russia; (O.P.M.); (E.V.K.)
| | - Victor S. Ushakov
- Department of Molecular Biology and Biophysics, Federal Research Center of Fundamental and Translational Medicine, 2/12, Timakova str., 630117 Novosibirsk, Russia; (V.S.U.); (M.O.P.); (D.K.S.); (E.V.G.)
| | - Maxim O. Politko
- Department of Molecular Biology and Biophysics, Federal Research Center of Fundamental and Translational Medicine, 2/12, Timakova str., 630117 Novosibirsk, Russia; (V.S.U.); (M.O.P.); (D.K.S.); (E.V.G.)
| | - Dmitry K. Sokolov
- Department of Molecular Biology and Biophysics, Federal Research Center of Fundamental and Translational Medicine, 2/12, Timakova str., 630117 Novosibirsk, Russia; (V.S.U.); (M.O.P.); (D.K.S.); (E.V.G.)
| | - Elena V. Koldysheva
- Department of Molecular Pathology and Pathomorphology, Federal Research Center of Fundamental and Translational Medicine, 2, Timakova str., 630117 Novosibirsk, Russia; (O.P.M.); (E.V.K.)
| | - Elvira V. Grigorieva
- Department of Molecular Biology and Biophysics, Federal Research Center of Fundamental and Translational Medicine, 2/12, Timakova str., 630117 Novosibirsk, Russia; (V.S.U.); (M.O.P.); (D.K.S.); (E.V.G.)
- Department of Natural Sciences, V. Zelman Institute for Medicine and Psychology, Novosibirsk State University, 1, Pirogova str., 630090 Novosibirsk, Russia
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Heck SO, Zborowski VA, Pinton S, Nogueira CW. Pro-apoptotic cell signaling in the prefrontal cortex contributes to depressive-/anxiogenic-like behavioral phenotype of mice subchronically exposed to dexamethasone. J Chem Neuroanat 2019; 100:101663. [PMID: 31374258 DOI: 10.1016/j.jchemneu.2019.101663] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Revised: 07/19/2019] [Accepted: 07/29/2019] [Indexed: 12/19/2022]
Affiliation(s)
- Suélen Osório Heck
- Laboratory of Synthesis, Reactivity, Pharmacological and Toxicological Evaluation of Organochalcogen Compounds, Department of Biochemistry and Molecular Biology, Center of Natural and Exact Sciences, Federal University of Santa Maria, Santa Maria, RS, 97105-900, Brazil
| | - Vanessa Angonesi Zborowski
- Laboratory of Synthesis, Reactivity, Pharmacological and Toxicological Evaluation of Organochalcogen Compounds, Department of Biochemistry and Molecular Biology, Center of Natural and Exact Sciences, Federal University of Santa Maria, Santa Maria, RS, 97105-900, Brazil
| | - Simone Pinton
- Federal University of Pampa, Campus Uruguaiana, RS, 97500-701, Brazil
| | - Cristina Wayne Nogueira
- Laboratory of Synthesis, Reactivity, Pharmacological and Toxicological Evaluation of Organochalcogen Compounds, Department of Biochemistry and Molecular Biology, Center of Natural and Exact Sciences, Federal University of Santa Maria, Santa Maria, RS, 97105-900, Brazil.
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High dose of dexamethasone protects against EAE-induced motor deficits but impairs learning/memory in C57BL/6 mice. Sci Rep 2019; 9:6673. [PMID: 31040362 PMCID: PMC6491620 DOI: 10.1038/s41598-019-43217-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Accepted: 03/17/2019] [Indexed: 12/24/2022] Open
Abstract
Multiple sclerosis (MS) is an autoimmune and neuroinflammatory disease characterized by demyelination of the Central Nervous System. Immune cells activation and release of pro-inflammatory cytokines play a crucial role in the disease modulation, decisively contributing to the neurodegeneration observed in MS and the experimental autoimmune encephalomyelitis (EAE), the widely used MS animal model. Synthetic glucocorticoids, commonly used to treat the MS attacks, have controversial effects on neuroinflammation and cognition. We sought to verify the influence of dexamethasone (DEX) on the EAE progression and on EAE-induced cognitive deficits. In myelin oligodendrocyte glycoprotein peptide (MOG35-55)-induced EAE female mice, treated once with DEX (50 mg/kg) or not, on the day of immunization, DEX decreased EAE-induced motor clinical scores, infiltrating cells in the spinal cord and delayed serum corticosterone peak. At the asymptomatic phase (8-day post-immunization), DEX did not protected from the EAE-induced memory consolidation deficits, which were accompanied by increased glucocorticoid receptor (GR) activity and decreased EGR-1 expression in the hippocampus. Blunting hippocampal GR genomic activation with DnGR vectors prevented DEX effects on EAE-induced memory impairment. These data suggest that, although DEX improves clinical signs, it decreases cognitive and memory capacity by diminishing neuronal activity and potentiating some aspects of neuroinflammation in EAE.
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Keleş Aİ, Yıldırım M, Gedikli Ö, Çolakoğlu S, Kaya H, Baş O, Sönmez OF, Odacı E. The effects of a continuous 1-h a day 900-MHz electromagnetic field applied throughout early and mid-adolescence on hippocampus morphology and learning behavior in late adolescent male rats. J Chem Neuroanat 2018; 94:46-53. [PMID: 30189239 DOI: 10.1016/j.jchemneu.2018.08.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Revised: 08/28/2018] [Accepted: 08/28/2018] [Indexed: 12/26/2022]
Abstract
The purpose of this study was to investigate hippocampus morphology and changes in learning behavior in male rats in late adolescence exposed to the effect of a continuous 1-h a day 900-megahertz (MHz) electromagnetic field (EMF). Twenty-four male Sprague Dawley rats aged 3-weeks were divided equally into control, sham and EMF groups. EMF group rats were exposed to a 900-MHz EMF inside an EMF cage, while the sham group rats were placed in the same cage but were not exposed to such an effect. No procedure was performed on the control group. Following 25-day application of EMF, passive avoidance, 8-arm radial maze and Y-maze tests were applied to determine rats' learning and memory performances. Open field and rotarod tests were applied to assess locomotor activity. At the end of the tests, the animals' brains were removed. Sections were taken and stained with toluidine blue. The regions of the hippocampus were subjected to histopathological evaluation. At histopathological examination, impairments of pyramidal and granular cell structures were observed in the EMF group hippocampus. No significant change was observed in learning, memory or locomotor behavior in any group. In conclusion, 900-MHz EMF applied in early and mid-adolescence causes no changes in learning, memory or locomotor behavior.
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Affiliation(s)
- Ayşe İkinci Keleş
- Department of Histology and Embryology, Faculty of Medicine, Niğde Ömer Halisdemir University, Niğde, Turkey.
| | - Mehmet Yıldırım
- Department of Physiology, Faculty of Medicine, Health Sciences University, İstanbul, Turkey
| | - Öznur Gedikli
- Department of Physiology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
| | - Sedar Çolakoğlu
- Department of Anatomy, Faculty of Medicine, Düzce University, Düzce, Turkey
| | - Haydar Kaya
- Department of Electrical and Electronics, Faculty of Engineering, Karadeniz Technical University, Trabzon, Turkey
| | - Orhan Baş
- Department of Anatomy, Faculty of Medicine, Ordu University, Ordu, Turkey
| | - Osman Fikret Sönmez
- Department of of Neurosurgery, Tepecik Education and Research Hospital, İzmir, Turkey
| | - Ersan Odacı
- Department of Histology and Embryology, Faculty of Medicine, Niğde Ömer Halisdemir University, Niğde, Turkey; Department of Physiology, Faculty of Medicine, Health Sciences University, İstanbul, Turkey; Department of Physiology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey; Department of Anatomy, Faculty of Medicine, Düzce University, Düzce, Turkey; Department of Electrical and Electronics, Faculty of Engineering, Karadeniz Technical University, Trabzon, Turkey; Department of Anatomy, Faculty of Medicine, Ordu University, Ordu, Turkey; Department of of Neurosurgery, Tepecik Education and Research Hospital, İzmir, Turkey
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Wu T, Jiang J, Yang L, Li H, Zhang W, Chen Y, Zhao B, Kong B, Lu P, Zhao Z, Zhu J, Fu Z. Timing of glucocorticoid administration determines severity of lipid metabolism and behavioral effects in rats. Chronobiol Int 2016; 34:78-92. [PMID: 27791398 DOI: 10.1080/07420528.2016.1238831] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Glucocorticoids (GCs) are a group of steroid hormones secreted by the adrenal glands in circadian cycles, and the dysregulation of GC signaling has been suggested to cause metabolic syndrome. Even though prolonged GC exposure is associated with serious side effects such as metabolic syndrome and central nervous system disorders, the use of GCs in anti-inflammatory and immunosuppressive therapies has been continuously rising. Meanwhile, the exact mechanisms by which GCs can influence the lipid metabolism as well as behavior and how they are affected by time remain unknown. In this study, the effects of two different long-term GC dosing regimens on lipid metabolism and behavior were investigated. Male Wistar rats received daily administrations of the GC dexamethasone sodium phosphate (DEX, 0.5 mg/kg body weight) at either ZT0 (Dex0) or ZT12 (Dex12). After 6 weeks of treatment, DEX-treated rats, especially those treated at ZT0, had higher hepatic lipid accumulation and serum triglyceride levels and less locomotor activity than did control rats. In addition, serum levels of corticosterone, 5-hydroxy tryptamine and norepinephrine were decreased in the Dex0 group but not in the Dex12 group compared to the control group. Furthermore, quantitative real-time polymerase chain reaction analysis indicated that the chronic administration of GCs at ZT0 upregulated genes related to glycolysis and lipid synthesis and downregulated genes related to fatty acid β-oxidation in the liver more remarkably than administration at ZT12. Both DEX-treated groups displayed severely altered expression patterns of the core clock genes Bmal1 and Per2 in the liver and in fat. In addition, the expression of glutamate aspartate transporter, glial fibrillary acidic protein and glutamate transporter-1, astrocyte-related genes important for maintaining nervous system functions, was drastically decreased in the hippocampus of DEX-treated rats, especially when DEX was given at ZT0. In conclusion, our findings confirm that the severity of side effects, indicated by altered lipid metabolism and behavioral activity, depends on the timing of GC administration and is associated with the degree of glucocorticoid receptor dysfunction after dosing at disparate time points.
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Affiliation(s)
- Tao Wu
- a College of Biotechnology and Bioengineering , Zhejiang University of Technology , Zhejiang , China
| | - Jianguo Jiang
- a College of Biotechnology and Bioengineering , Zhejiang University of Technology , Zhejiang , China
| | - Luna Yang
- a College of Biotechnology and Bioengineering , Zhejiang University of Technology , Zhejiang , China
| | - Haifeng Li
- b Children's Hospital , Zhejiang University School of Medicine , Zhejiang , China
| | - Wanjing Zhang
- a College of Biotechnology and Bioengineering , Zhejiang University of Technology , Zhejiang , China
| | - Yangyang Chen
- a College of Biotechnology and Bioengineering , Zhejiang University of Technology , Zhejiang , China
| | - Binggong Zhao
- a College of Biotechnology and Bioengineering , Zhejiang University of Technology , Zhejiang , China
| | - Boda Kong
- a College of Biotechnology and Bioengineering , Zhejiang University of Technology , Zhejiang , China
| | - Ping Lu
- a College of Biotechnology and Bioengineering , Zhejiang University of Technology , Zhejiang , China
| | - Zhenzhen Zhao
- a College of Biotechnology and Bioengineering , Zhejiang University of Technology , Zhejiang , China
| | - Jiawei Zhu
- a College of Biotechnology and Bioengineering , Zhejiang University of Technology , Zhejiang , China
| | - Zhengwei Fu
- a College of Biotechnology and Bioengineering , Zhejiang University of Technology , Zhejiang , China
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Zakaria R, Ahmad AH, Othman Z. The Potential Role of Melatonin on Memory Function: Lessons from Rodent Studies. Folia Biol (Praha) 2016; 62:181-187. [PMID: 27978412 DOI: 10.14712/fb2016062050181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
Pineal melatonin biosynthesis is regulated by the circadian clock located in the suprachiasmatic nucleus of the hypothalamus. Melatonin has been found to modulate the learning and memory process in human as well as in animals. Endogenous melatonin modulates the process of newly acquired information into long-term memory, while melatonin treatment has been found to reduce memory deficits in elderly people and in various animal models. However, the mechanisms mediating the enhancing effect of melatonin on memory remain elusive. This review intends to explore the possible mechanisms by looking at previous data on the effects of melatonin treatment on memory performance in rodents.
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Affiliation(s)
- R Zakaria
- Department of Physiology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
| | - A H Ahmad
- Department of Physiology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
| | - Z Othman
- Department of Psychiatry, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
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Zhang JW, Zhang GX, Chen HL, Liu GL, Owusu L, Wang YX, Wang GY, Xu CM. Therapeutic effect of Qingyi decoction in severe acute pancreatitis-induced intestinal barrier injury. World J Gastroenterol 2015; 21:3537-3546. [PMID: 25834318 PMCID: PMC4375575 DOI: 10.3748/wjg.v21.i12.3537] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2014] [Revised: 11/06/2014] [Accepted: 12/22/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of Qingyi decoction on the expression of secreted phospholipase A2 (sPLA2) in intestinal barrier injury.
METHODS: Fifty healthy Sprague-Dawley rats were randomly divided into control, severe acute pancreatitis (SAP), Qingyi decoction-treated (QYT), dexamethasone-treated (DEX), and verapamil-treated (VER) groups. The SAP model was induced by retrograde infusion of 1.5% sodium deoxycholate into the biliopancreatic duct of the rats. All rats were sacrificed 24 h post-SAP induction. Arterial blood, intestine, and pancreas from each rat were harvested for investigations. The levels of serum amylase (AMY) and diamine oxidase (DAO) were determined using biochemical methods, and serum tumor necrosis factor (TNF)-α level was measured by an enzyme linked immunosorbent assay. Pathologic changes in the harvested tissues were investigated by microscopic examination of hematoxylin and eosin-stained tissue sections. The expressions of sPLA2 at mRNA and protein levels were detected by reverse transcriptase PCR and Western blot, respectively. A terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay was used to investigate apoptosis of epithelial cells in the intestinal tissues.
RESULTS: Compared to the control group, the expression of sPLA2 at both the mRNA and protein levels increased significantly in the SAP group (0.36 ± 0.13 vs 0.90 ± 0.38, and 0.16 ± 0.05 vs 0.64 ± 0.05, respectively; Ps < 0.01). The levels of AMY, TNF-α and DAO in serum were also significantly increased (917 ± 62 U/L vs 6870 ± 810 U/L, 59.7 ± 14.3 ng/L vs 180.5 ± 20.1 ng/L, and 10.37 ± 2.44 U/L vs 37.89 ± 5.86 U/L, respectively; Ps < 0.01). The apoptosis index of intestinal epithelial cells also differed significantly between the SAP and control rats (0.05 ± 0.02 vs 0.26 ± 0.06; P < 0.01). The serum levels of DAO and TNF-α, and the intestinal apoptosis index significantly correlated with sPLA2 expression in the intestine (r = 0.895, 0.893 and 0.926, respectively; Ps < 0.05). The levels of sPLA2, AMY, TNF-α, and DAO in the QYT, VER, and DEX groups were all decreased compared with the SAP group, but not the control group. Qingyi decoction intervention, however, gave the most therapeutic effect against intestinal barrier damage, although the onset of its therapeutic effect was slower.
CONCLUSION: Qingyi decoction ameliorates acute pancreatitis-induced intestinal barrier injury by inhibiting the overexpression of intestinal sPLA2. This mechanism may be similar to that of verapamil.
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