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Ertik O, Koroglu P, Magaji UF, Bulan NO, Sacan O, Yanardag R. Treatment of oxidative damage caused by valproic acid in tongue tissue with ethanolic Moringa oleifera leaves extract and prediction of potential bioactive molecules with molecular docking. J Mol Histol 2024; 56:37. [PMID: 39661285 DOI: 10.1007/s10735-024-10277-3] [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: 08/13/2024] [Accepted: 11/06/2024] [Indexed: 12/12/2024]
Abstract
Moringa oleifera (M. oleifera) is a popular medicinal plant that has become a wide research area in recent years due to its detected biological effects and its bioactive compounds. Valproic acid (VPA) is a medication used in the treatment of epilepsy and bipolar disorder and high doses or prolonged use of VPA can result in oxidative stress in cells. Since M. oleifera has high biological activities and contains many bioactive compounds, it is necessary to understand whether it plays a role in reducing oxidative damage, especially that caused VPA. The relationship between VPA and tongue tissue needs to be investigated, since VPA has negative effects on oral health and it is known that tongue tissue plays an important role in the continuity of oral health. In the present study, 3.0-3.5 month-old female Sprague Dawley rats (160-250 g) were divided into four groups (Control, Moringa, VPA, VPA + M), and VPA was administered via gavage. The aim was to understand the protective/preventive effects of ethanolic M. oleifera leaves extract against oxidative stress through biochemical parameters. Additionally, molecular docking studies were conducted on niazicin-A, niazimin-A, and niazimin-B found in M. oleifera leaves based on in vivo results. The results indicate that M. oleifera extract treats oxidative damage to the tongue tissue, and niazimin-A and niazimin-B particularly show high binding affinities to myeloperoxidase (MPO) and lactate dehydrogenase (LDH) enzymes. Further studies may suggest that the use of M. oleifera leaves extract with VPA could prevent potential negative effects on tongue tissue.
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Affiliation(s)
- Onur Ertik
- Department of Chemistry, Faculty of Engineering, Istanbul University-Cerrahpaşa, Avcilar, Istanbul, Türkiye.
- Department of Chemistry, Faculty of Engineering and Science, Bursa Technical University, Yildirim, Bursa, Türkiye.
| | - Pınar Koroglu
- Department of Histology and Embryology, Faculty of Medicine, Halic University, Istanbul, Türkiye
| | - Umar Faruk Magaji
- Department of Biochemistry and Molecular Biology, Federal University Birnin Kebbi, Kebbi State, Birnin Kebbi, 1157, Nigeria
| | - Nihal Omur Bulan
- Department of Biology, Faculty of Science, Istanbul University, Vezneciler, Istanbul, Türkiye
| | - Ozlem Sacan
- Department of Chemistry, Faculty of Engineering, Istanbul University-Cerrahpaşa, Avcilar, Istanbul, Türkiye
| | - Refiye Yanardag
- Department of Chemistry, Faculty of Engineering, Istanbul University-Cerrahpaşa, Avcilar, Istanbul, Türkiye
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Li S, Zhang N, Li W, Zhang HL, Wang XX. Gastrointestinal problems in a valproic acid-induced rat model of autism: From maternal intestinal health to offspring intestinal function. World J Psychiatry 2024; 14:1095-1105. [PMID: 39050201 PMCID: PMC11262932 DOI: 10.5498/wjp.v14.i7.1095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 05/13/2024] [Accepted: 06/04/2024] [Indexed: 07/12/2024] Open
Abstract
BACKGROUND Autism spectrum disorder (ASD) is a developmental disorder characterized by social deficits and repetitive behavior. Gastrointestinal (GI) problems, such as constipation, diarrhea, and inflammatory bowel disease, commonly occur in patients with ASD. Previously, GI problems of ASD patients were attributed to intestinal inflammation and vertical mother-to-infant microbiome transmission. AIM To explore whether GI problems in ASD are related to maternal intestinal inflammation and gut microbiota abnormalities. METHODS An ASD rat model was developed using valproic acid (VPA). Enzyme-linked immunosorbent assay and fecal 16S rRNA sequencing were used to test GI changes. RESULTS VPA exposure during pregnancy led to pathological maternal intestinal changes, resulting in alterations in maternal gut microbiota. Additionally, the levels of inflammatory factors also increased. Moreover, prenatal exposure to VPA resulted in impaired duodenal motility in the offspring as well as increased levels of inflammatory factors. CONCLUSION GI problems in ASD may be associated with maternal intestinal inflammation and microbiota abnormality. Future research is required to find more evidence on the etiology and treatment of GI problems in ASD.
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Affiliation(s)
- Sha Li
- Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100000, China
- Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing 100000, China
| | - Nan Zhang
- Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100000, China
| | - Wang Li
- Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing 100000, China
| | - Han-Lai Zhang
- Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100000, China
| | - Xiao-Xi Wang
- Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100000, China
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Varley AN, Browning KN. Gastrointestinal dysfunction in the valproic acid induced model of social deficit in rats. Auton Neurosci 2024; 253:103161. [PMID: 38461695 PMCID: PMC11128350 DOI: 10.1016/j.autneu.2024.103161] [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: 12/06/2023] [Revised: 02/28/2024] [Accepted: 02/28/2024] [Indexed: 03/12/2024]
Abstract
Autism spectrum disorder (ASD) has increased in incidence over the past several decades, and is associated with a range of co-morbidities including gastrointestinal (GI) dysfunctions including gastroesophageal reflux, abdominal pain, bloating, constipation and/or diarrhea. Several animal models have been used that replicate several aspects of ASD but no single model has been able to replicate the entire disease pathophysiology. In humans, prenatal exposure to valproic acid (VPA) has been identified as a significant risk factor and rodent models have shown that in utero VPA exposure leads to behavioral deficits in offspring. The present study aimed to investigate whether in utero exposure to VPA induces GI dysfunction in rats. Timed pregnant Sprague-Dawley rats were injected with a single dose of VPA at embryonic day 12.5. Both male and female offspring subsequently underwent behavioral studies and assessment of GI function in adulthood. In utero VPA treatment induced social deficits in both male and female offspring, decreasing sociability and social novelty. Histological examination showed that VPA treated offspring had decreased thickness of GI muscle and mucosa, while immunohistochemical studies showed a decrease in myenteric neuron number in the fundus. Functional studies showed that both male and female VPA offspring had a delay in gastric emptying compared to vehicle treated offspring. Results of the current study suggest that the rat VPA model of behavioral deficits may be a convenient model by which both mechanistic and functional insights into GI dysfunction may be studied.
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Affiliation(s)
- Ashley N Varley
- Department of Comparative Medicine, Penn State College of Medicine, Hershey, PA, United States of America
| | - Kirsteen N Browning
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA, United States of America.
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Salari Z, Moslemizadeh A, Tezerji SS, Sabet N, Parizi AS, Khaksari M, Sheibani V, Jafari E, Shafieipour S, Bashiri H. Sex-dependent alterations of inflammatory factors, oxidative stress, and histopathology of the brain-gut axis in a VPA-induced autistic-like model of rats. Birth Defects Res 2024; 116:e2310. [PMID: 38563145 DOI: 10.1002/bdr2.2310] [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: 08/03/2023] [Revised: 12/23/2023] [Accepted: 01/21/2024] [Indexed: 04/04/2024]
Abstract
INTRODUCTION In this study, we aimed to investigate the inflammatory factors, oxidative stress, and histopathological consequences of the brain-gut axis in male and female rats prenatally exposed to VPA. METHODS Pregnant Wistar rats were randomly divided into two groups. The animals received saline, and valproic acid (VPA) (600 mg/kg, i.p.) on embryonic day 12.5 (E12.5). All offspring were weaned on postnatal day 21, and the experiments were done in male and female rats on day 60. The brain and intestine tissues were extracted to assess histopathology, inflammation, and oxidative stress. RESULTS An increase of interleukin-1β (IL-1β) and interleukin-6 (IL-6) and a decrease of interleukin-10 (IL-10) were observed in the two sexes and two tissues of the autistic rats. In the VPA-exposed animals, malondialdehyde (MDA) and protein carbonyl (PC) increased in the brain of both sexes and the intestines of only the males. The total antioxidant capacity (TAC), superoxide dismutase (SOD), and catalase (CAT) significantly decreased in both tissues of male and female autistic groups. Histopathological evaluation showed that the %apoptosis of the cortex in the autistic male and female groups was more than in controls whereas this parameter in the CA1 and CA3 was significant only in the male rats. In the intestine, histopathologic changes were seen only in the male autistic animals. CONCLUSION The inflammatory and antioxidant factors were in line in the brain-gut axis in male and female rats prenatally exposed to VPA. Histopathological consequences were more significant in the VPA-exposed male animals.
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Affiliation(s)
- Zahra Salari
- Gastroenterology and Hepatology Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | | | - Sara Sheibani Tezerji
- Department of Behavioural and Molecular Neurobiology, Regensburg Center for Neuroscience, University of Regensburg, Regensburg, Germany
| | - Nazanin Sabet
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Ali Saeidpour Parizi
- Gastroenterology and Hepatology Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammad Khaksari
- Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | - Vahid Sheibani
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
- Department of Physiology and Pharmacology, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Elham Jafari
- Pathology and Stem Cells Research Center, Department of Pathology, Afzalipour School of Medicine, Kerman University of Medical Science, Kerman, Iran
| | - Sara Shafieipour
- Gastroenterology and Hepatology Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Hamideh Bashiri
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
- Department of Physiology and Pharmacology, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
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Pang H, Zheng K, Wang W, Zheng M, Liu Y, Yin H, Zhang D. Cefotaxime Exposure-Caused Oxidative Stress, Intestinal Damage and Gut Microbial Disruption in Artemia sinica. Microorganisms 2024; 12:675. [PMID: 38674619 PMCID: PMC11052325 DOI: 10.3390/microorganisms12040675] [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: 02/23/2024] [Revised: 03/17/2024] [Accepted: 03/25/2024] [Indexed: 04/28/2024] Open
Abstract
Cefotaxime (CTX) is an easily detectable antibiotic pollutant in the water environment, but little is known about its toxic effects on aquatic invertebrates, especially on the intestine. Here, we determined the oxidative stress conditions of A. sinica under CTX exposure with five concentrations (0, 0.001, 0.01, 0.1 and 1 mg/L) for 14 days. After that, we focused on changes in intestinal tissue morphology and gut microbiota in A. sinica caused by CTX exposure at 0.01 mg/L. We found malondialdehyde (MDA) was elevated in CTX treatment groups, suggesting the obvious antibiotic-induced oxidative stress. We also found CTX exposure at 0.01 mg/L decreased the villus height and muscularis thickness in gut tissue. The 16S rRNA gene analysis indicated that CTX exposure reshaped the gut microbiota diversity and community composition. Proteobacteria, Actinobacteriota and Bacteroidota were the most widely represented phyla in A. sinica gut. The exposure to CTX led to the absence of Verrucomicrobia in dominant phyla and an increase in Bacteroidota abundance. At the genus level, eleven genera with an abundance greater than 0.1% exhibited statistically significant differences among groups. Furthermore, changes in gut microbiota composition were accompanied by modifications in gut microbiota functions, with an up-regulation in amino acid and drug metabolism functions and a down-regulation in xenobiotic biodegradation and lipid metabolism-related functions under CTX exposure. Overall, our study enhances our understanding of the intestinal damage and microbiota disorder caused by the cefotaxime pollutant in aquatic invertebrates, which would provide guidance for healthy aquaculture.
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Affiliation(s)
- Huizhong Pang
- The International Centre for Precision Environmental Health and Governance, College of Life Sciences, Hebei University, Baoding 071002, China; (H.P.); (K.Z.); (W.W.); (M.Z.)
| | - Kaixuan Zheng
- The International Centre for Precision Environmental Health and Governance, College of Life Sciences, Hebei University, Baoding 071002, China; (H.P.); (K.Z.); (W.W.); (M.Z.)
| | - Wenbo Wang
- The International Centre for Precision Environmental Health and Governance, College of Life Sciences, Hebei University, Baoding 071002, China; (H.P.); (K.Z.); (W.W.); (M.Z.)
| | - Mingjuan Zheng
- The International Centre for Precision Environmental Health and Governance, College of Life Sciences, Hebei University, Baoding 071002, China; (H.P.); (K.Z.); (W.W.); (M.Z.)
| | - Yudan Liu
- The International Centre for Precision Environmental Health and Governance, College of Life Sciences, Hebei University, Baoding 071002, China; (H.P.); (K.Z.); (W.W.); (M.Z.)
| | - Hong Yin
- The International Centre for Precision Environmental Health and Governance, College of Life Sciences, Hebei University, Baoding 071002, China; (H.P.); (K.Z.); (W.W.); (M.Z.)
- Key Laboratory of Zoological Systematics and Application of Hebei Province, College of Life Sciences, Hebei University, Baoding 071002, China
| | - Daochuan Zhang
- The International Centre for Precision Environmental Health and Governance, College of Life Sciences, Hebei University, Baoding 071002, China; (H.P.); (K.Z.); (W.W.); (M.Z.)
- Key Laboratory of Zoological Systematics and Application of Hebei Province, College of Life Sciences, Hebei University, Baoding 071002, China
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Hung LY, Margolis KG. Autism spectrum disorders and the gastrointestinal tract: insights into mechanisms and clinical relevance. Nat Rev Gastroenterol Hepatol 2024; 21:142-163. [PMID: 38114585 DOI: 10.1038/s41575-023-00857-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/11/2023] [Indexed: 12/21/2023]
Abstract
Autism spectrum disorders (ASDs) are recognized as central neurodevelopmental disorders diagnosed by impairments in social interactions, communication and repetitive behaviours. The recognition of ASD as a central nervous system (CNS)-mediated neurobehavioural disorder has led most of the research in ASD to be focused on the CNS. However, gastrointestinal function is also likely to be affected owing to the neural mechanistic nature of ASD and the nervous system in the gastrointestinal tract (enteric nervous system). Thus, it is unsurprising that gastrointestinal disorders, particularly constipation, diarrhoea and abdominal pain, are highly comorbid in individuals with ASD. Gastrointestinal problems have also been repeatedly associated with increased severity of the core symptoms diagnostic of ASD and other centrally mediated comorbid conditions, including psychiatric issues, irritability, rigid-compulsive behaviours and aggression. Despite the high prevalence of gastrointestinal dysfunction in ASD and its associated behavioural comorbidities, the specific links between these two conditions have not been clearly delineated, and current data linking ASD to gastrointestinal dysfunction have not been extensively reviewed. This Review outlines the established and emerging clinical and preclinical evidence that emphasizes the gut as a novel mechanistic and potential therapeutic target for individuals with ASD.
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Affiliation(s)
- Lin Y Hung
- Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY, USA
| | - Kara Gross Margolis
- Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY, USA.
- Department of Cell Biology, NYU Grossman School of Medicine and Langone Medical Center, New York, NY, USA.
- Department of Pediatrics, NYU Grossman School of Medicine and Langone Medical Center, New York, NY, USA.
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Zhang N, Wang ST, Yao L. Inhalation of Cananga odorata essential oil relieves anxiety behaviors in autism-like rats via regulation of serotonin and dopamine metabolism. JOURNAL OF INTEGRATIVE MEDICINE 2023; 21:205-214. [PMID: 36792414 DOI: 10.1016/j.joim.2023.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 01/01/2023] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Anxiety is one of the most common symptoms associated with autistic spectrum disorder. The essential oil of Cananga odorata (Lam.) Hook. f. & Thomson, usually known as ylang-ylang oil (YYO), is often used in aromatherapy as a mood-regulating agent, sedative, or hypotensive agent. In the present study, the effects and mechanisms of YYO in alleviating anxiety, social and cognitive behaviors in autism-like rats were investigated. METHODS The prenatal valproic acid (VPA) model was used to induce autism-like behaviors in offspring rats. The effectiveness of prenatal sodium valproate treatment (600 mg/kg) on offspring was shown by postnatal growth observation, and negative geotaxis, olfactory discrimination and Morris water maze (MWM) tests. Then three treatment groups were formed with varying exposure to atomized YYO to explore the effects of YYO on the anxiety, social and cognitive behaviors of the autistic-like offspring through the elevated plus-maze test, three-chamber social test, and MWM test. Finally, the monoamine neurotransmitters, including serotonin, dopamine and their metabolites, in the hippocampus and prefrontal cortex (PFC) of the rats were measured using a high-performance liquid chromatography. RESULTS Offspring of VPA exposure rats showed autism-like behaviors. In the VPA offspring, medium-dose YYO exposure significantly elevated the time and entries into the open arms in the elevated plus-maze test, while low-dose YYO exposure significantly enhanced the social interaction time with the stranger rat in session 1 of the three-chamber social test. VPA offspring treated with YYO exposure used less time to reach the platform in the navigation test of the MWM test. YYO exposure significantly elevated the metabolism of serotonin and dopamine in the PFC of VPA offspring. CONCLUSION YYO exposure showed the effects in alleviating anxiety and improving cognitive and social abilities in the offspring of VPA exposure rats. The role of YYO was related to the regulation of the metabolism of serotonin and dopamine. Please cite this article as: Zhang N, Wang ST, Yao L. Inhalation of Cananga odorata essential oil relieves anxiety behaviors in autism-like rats via regulation of serotonin and dopamine metabolism. J Integr Med. 2023; Epub ahead of print.
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Affiliation(s)
- Nan Zhang
- School of Design, Shanghai Jiao Tong University, Shanghai 200000, China
| | - Shu-Ting Wang
- School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200000, China
| | - Lei Yao
- School of Design, Shanghai Jiao Tong University, Shanghai 200000, China.
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Serra D, Henriques JF, Sousa FJ, Laranjo M, Resende R, Ferreira-Marques M, de Freitas V, Silva G, Peça J, Dinis TCP, Almeida LM. Attenuation of Autism-like Behaviors by an Anthocyanin-Rich Extract from Portuguese Blueberries via Microbiota-Gut-Brain Axis Modulation in a Valproic Acid Mouse Model. Int J Mol Sci 2022; 23:9259. [PMID: 36012528 PMCID: PMC9409076 DOI: 10.3390/ijms23169259] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 08/13/2022] [Accepted: 08/15/2022] [Indexed: 12/14/2022] Open
Abstract
Autism Spectrum Disorders (ASDs) are a group of neurodevelopmental pathologies whose current treatment is neither curative nor effective. Anthocyanins are naturally occurring compounds abundant in blueberries and in other red fruits which have been shown to be successful in the treatment of several neurological diseases, at least in in vitro and in vivo disease models. The aim of the present work was to study the ability of an anthocyanin-rich extract (ARE) obtained from Portuguese blueberries to alleviate autism-like symptoms in a valproic acid (VPA) mouse model of ASD and to get insights into the underlying molecular mechanisms of such benefits. Therefore, pregnant BALB/c females were treated subcutaneously with a single dose of VPA (500 mg/kg) or saline on gestational day 12.5. Male offspring mice were orally treated with the ARE from Portuguese blueberries (30 mg/kg/day) or the vehicle for three weeks, and further subjected to behavioral tests and biochemical analysis. Our data suggested that the ARE treatment alleviated autism-like behaviors in in utero VPA-exposed mice and, at the same time, decreased both neuroinflammation and gut inflammation, modulated the gut microbiota composition, increased serotonin levels in cerebral prefrontal cortex and gut, and reduced the synaptic dysfunction verified in autistic mice. Overall, our work suggests that anthocyanins extracted from Portuguese blueberries could constitute an effective strategy to ameliorate typical autistic behaviors through modulation of the microbiota-gut-brain axis.
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Affiliation(s)
- Diana Serra
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-531 Coimbra, Portugal
- Faculty of Pharmacy, University of Coimbra, 3004-531 Coimbra, Portugal
- CIVG—Vasco da Gama Research Center, EUVG—Vasco da Gama University School, 3020-210 Coimbra, Portugal
| | - Joana F. Henriques
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-531 Coimbra, Portugal
- Faculty of Pharmacy, University of Coimbra, 3004-531 Coimbra, Portugal
| | - Fábio J. Sousa
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-531 Coimbra, Portugal
| | - Mariana Laranjo
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-531 Coimbra, Portugal
- PhD Program in Experimental Biology and Biomedicine (PDBEB), Institute for Interdisciplinary Research, University of Coimbra, 3004-531 Coimbra, Portugal
| | - Rosa Resende
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-531 Coimbra, Portugal
| | - Marisa Ferreira-Marques
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-531 Coimbra, Portugal
| | - Victor de Freitas
- REQUIMTE/LAQV—Research Unit, Faculty of Science, Porto University, 4099-002 Porto, Portugal
| | - Gabriela Silva
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-531 Coimbra, Portugal
- Faculty of Pharmacy, University of Coimbra, 3004-531 Coimbra, Portugal
| | - João Peça
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-531 Coimbra, Portugal
- Department of Life Science, Faculty of Science and Technology, University of Coimbra, 3004-531 Coimbra, Portugal
| | - Teresa C. P. Dinis
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-531 Coimbra, Portugal
- Faculty of Pharmacy, University of Coimbra, 3004-531 Coimbra, Portugal
| | - Leonor M. Almeida
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-531 Coimbra, Portugal
- Faculty of Pharmacy, University of Coimbra, 3004-531 Coimbra, Portugal
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Perspective: Chicken Models for Studying the Ontogenetic Origin of Neuropsychiatric Disorders. Biomedicines 2022; 10:biomedicines10051155. [PMID: 35625892 PMCID: PMC9138209 DOI: 10.3390/biomedicines10051155] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 05/13/2022] [Accepted: 05/15/2022] [Indexed: 12/29/2022] Open
Abstract
Nutrients and xenobiotics cross the blood–placenta barrier, potentially depositing in the fetal brain. The prenatal exposure affects the neuroendocrine and microbial development. The mechanism underlying maternal risk factors reprograming the microbiota–gut–brain axis with long-term effects on psychosocial behaviors in offspring is not clear. In humans, it is not possible to assess the nutrient or xenobiotic deposition in the fetal brain and gastrointestinal system for ethical reasons. Moreover, the maternal–fetal microbe transfer during gestation, natural labor, and breast-feeding constitutes the initial gut microbiome in the progeny, which is inevitable in the most widely utilized rodent models. The social predisposition in precocial birds, including chickens, provides the possibility to test behavioral responses shortly after being hatched. Hence, chickens are advantageous in investigating the ontogenetic origin of behaviors. Chicken embryos are suitable for deposition assessment and mechanistic study due to the accessibility, self-contained development, uniform genetic background, robust microbiota, and easy in vivo experimental manipulation compared to humans and rodents. Therefore, chicken embryos can be used as an alternative to the rodent models in assessing the fetal exposure effect on neurogenesis and investigating the mechanism underlying the ontogenetic origin of neuropsychiatric disorders.
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Nath A, Chakrabarti P, Sen S, Barui A. Reactive Oxygen Species in Modulating Intestinal Stem Cell Dynamics and Function. Stem Cell Rev Rep 2022; 18:2328-2350. [DOI: 10.1007/s12015-022-10377-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/13/2022] [Indexed: 10/18/2022]
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Vitamin A deficiency exacerbates autism-like behaviors and abnormalities of the enteric nervous system in a valproic acid-induced rat model of autism. Neurotoxicology 2020; 79:184-190. [DOI: 10.1016/j.neuro.2020.06.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 06/03/2020] [Accepted: 06/05/2020] [Indexed: 02/06/2023]
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Lefter R, Ciobica A, Antioch I, Ababei DC, Hritcu L, Luca AC. Oxytocin Differentiated Effects According to the Administration Route in a Prenatal Valproic Acid-Induced Rat Model of Autism. ACTA ACUST UNITED AC 2020; 56:medicina56060267. [PMID: 32485966 PMCID: PMC7353871 DOI: 10.3390/medicina56060267] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 05/14/2020] [Accepted: 05/25/2020] [Indexed: 12/31/2022]
Abstract
Background and objectives: The hormone oxytocin (OXT) has already been reported in both human and animal studies for its promising therapeutic potential in autism spectrum disorder (ASD), but the comparative effectiveness of various administration routes, whether central or peripheral has been insufficiently studied. In the present study, we examined the effects of intranasal (IN) vs. intraperitoneal (IP) oxytocin in a valproic-acid (VPA) autistic rat model, focusing on cognitive and mood behavioral disturbances, gastrointestinal transit and central oxidative stress status. Materials and Methods: VPA prenatally-exposed rats (500 mg/kg; age 90 days) in small groups of 5 (n = 20 total) were given OXT by IP injection (10 mg/kg) for 8 days consecutively or by an adapted IN pipetting protocol (12 IU/kg, 20 μL/day) for 4 consecutive days. Behavioral tests were performed during the last three days of OXT treatment, and OXT was administrated 20 minutes before each behavioral testing for each rat. Biochemical determination of oxidative stress markers in the temporal area included superoxide dismutase (SOD), glutathione peroxidase (GPx) and malondialdehyde (MDA). A brief quantitative assessment of fecal discharge over a period of 24 hours was performed at the end of the OXT treatment to determine differences in intestinal transit. Results: OXT improved behavioral and oxidative stress status in both routes of administration, but IN treatment had significantly better outcome in improving short-term memory, alleviating depressive manifestations and mitigating lipid peroxidation in the temporal lobes. Significant correlations were also found between behavioral parameters and oxidative stress status in rats after OXT administration. The quantitative evaluation of the gastrointestinal (GI) transit indicated lower fecal pellet counts in the VPA group and homogenous average values for the control and both OXT treated groups. Conclusions: The data from the present study suggest OXT IN administration to be more efficient than IP injections in alleviating autistic cognitive and mood dysfunctions in a VPA-induced rat model. OXT effects on the cognitive and mood behavior of autistic rats may be associated with its effects on oxidative stress. Additionally, present results provide preliminary evidence that OXT may have a balancing effect on gastrointestinal motility.
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Affiliation(s)
- Radu Lefter
- Center of Biomedical Research, Romanian Academy, B dul Carol I, No 8, 700505 Iasi, Romania;
| | - Alin Ciobica
- Department of Research, Faculty of Biology, Alexandru Ioan Cuza University, B dul Carol I, No 11, 700506 Iasi, Romania;
- Correspondence: (A.C.); (L.H.)
| | - Iulia Antioch
- Department of Research, Faculty of Biology, Alexandru Ioan Cuza University, B dul Carol I, No 11, 700506 Iasi, Romania;
| | - Daniela Carmen Ababei
- “Grigore T.Popa” University of Medicine and Pharmacy, 16, Universitatii Street, 700115 Iasi, Romania; (D.C.A.); (A.-C.L.)
| | - Luminita Hritcu
- Faculty of Veterinary Medicine, University of Agricultural Sciencies and Veterinary Medicine “Ion Ionescu de la Brad” of Iasi, 3rd Mihail Sadoveanu Alley, 700490 Iasi, Romania
- Correspondence: (A.C.); (L.H.)
| | - Alina-Costina Luca
- “Grigore T.Popa” University of Medicine and Pharmacy, 16, Universitatii Street, 700115 Iasi, Romania; (D.C.A.); (A.-C.L.)
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13
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Wang J, Zheng B, Zhou D, Xing J, Li H, Li J, Zhang Z, Zhang B, Li P. Supplementation of Diet With Different n-3/n-6 PUFA Ratios Ameliorates Autistic Behavior, Reduces Serotonin, and Improves Intestinal Barrier Impairments in a Valproic Acid Rat Model of Autism. Front Psychiatry 2020; 11:552345. [PMID: 33033482 PMCID: PMC7509584 DOI: 10.3389/fpsyt.2020.552345] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 08/24/2020] [Indexed: 12/29/2022] Open
Abstract
The implication of different dietary n-3/n-6 polyunsaturated fatty acids (PUFAs) ratios has been investigated in some neurodevelopmental disorders (including autism and depression). However, the mechanisms underlying the effects of different PUFAs ratios on the autism are still poorly understood. In the present study, a valproic acid (VPA) rat model of autism was used to study the effects of diet with different n-3/n-6 PUFA ratios on the autism, and the underlying mechanisms explored. Our results showed that rats with prenatal administration of VPA took less response time to sniff three odorants in the olfactory habituation/dishabituation tests, had lower frequency of pinning and following patterns, and had decreased hippocampal 5-hydroxytryptamine (5-HT), increased serum 5-HT and downregulated expression of tight junction protein (occludin and claudin-1) in the colon. However, supplementation of n-3/n-6 PUFAs (1:5) in the VPA treated rats ameliorated the autistic behaviors, increased hippocampal 5-HT and tight junction expression in the colon, and decreased serum 5-HT. In conclusion, dietary supplementation of n-3/n-6 PUFAs (1:5) significantly improves VPA-induced autism-like behaviors in rats, which may be, at least partially, related to the increased hippocampal 5-HT. Furthermore, this diet can increase the expression of tight junction proteins to improve intestinal barrier impairment.
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Affiliation(s)
- Jinpeng Wang
- Department of Cardiology, The Second Hospital of Jilin University, Changchun, China
| | - Baihong Zheng
- Department of Pediatrics, The Second Hospital of Jilin University, Changchun, China
| | - Dan Zhou
- Department of Pediatrics, The Second Hospital of Jilin University, Changchun, China
| | - Jie Xing
- Department of Developmental Pediatrics, The Second Hospital of Jilin University, Changchun, China
| | - Honghua Li
- Department of Developmental and Behavioral Pediatrics, The First Hospital of Jilin University, Changchun, China
| | - Jiayu Li
- Department of Physiology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Zehui Zhang
- Department of Developmental and Behavioral Pediatrics, The First Hospital of Jilin University, Changchun, China
| | - Beilin Zhang
- Department of Physiology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Ping Li
- Department of Developmental Pediatrics, The Second Hospital of Jilin University, Changchun, China
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14
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Serra D, Almeida LM, Dinis TCP. Polyphenols as food bioactive compounds in the context of Autism Spectrum Disorders: A critical mini-review. Neurosci Biobehav Rev 2019; 102:290-298. [PMID: 31085194 DOI: 10.1016/j.neubiorev.2019.05.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 03/18/2019] [Accepted: 05/10/2019] [Indexed: 12/15/2022]
Abstract
Dietary polyphenols are bioactive compounds with potential in preventing and treating several chronic disorders, mainly due to their ability to modulate key pro-inflammatory and pro-oxidant signalling pathways. Although some studies have expressed concern about their efficacy in vivo, accumulating evidence has suggested that these compounds may achieve large concentrations in the gastrointestinal tract, which may be important in the context of intestinal and of neurological disorders, via modulation of the "gut-brain axis". Autism Spectrum disorders (ASD) are a group of lifelong neurodevelopmental disorders in which many patients suffer from gastrointestinal impairments. Thus, in the scope of these disorders, a growing number of studies have been focused on the microbiota-gut-brain axis. In this mini-review, we present gathered data on gut-to-brain communication in the scope of ASD and we address the advantages of polyphenols in the treatment of these disorders, presenting the more recent preclinical and clinical data on this issue. According to most studies, dietary polyphenols can be a promising strategy for the alleviation of ASD symptoms.
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Affiliation(s)
- Diana Serra
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.
| | - Leonor M Almeida
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
| | - Teresa C P Dinis
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
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15
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Golubeva AV, Joyce SA, Moloney G, Burokas A, Sherwin E, Arboleya S, Flynn I, Khochanskiy D, Moya-Pérez A, Peterson V, Rea K, Murphy K, Makarova O, Buravkov S, Hyland NP, Stanton C, Clarke G, Gahan CGM, Dinan TG, Cryan JF. Microbiota-related Changes in Bile Acid & Tryptophan Metabolism are Associated with Gastrointestinal Dysfunction in a Mouse Model of Autism. EBioMedicine 2017; 24:166-178. [PMID: 28965876 PMCID: PMC5652137 DOI: 10.1016/j.ebiom.2017.09.020] [Citation(s) in RCA: 245] [Impact Index Per Article: 30.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Revised: 09/01/2017] [Accepted: 09/15/2017] [Indexed: 01/24/2023] Open
Abstract
Autism spectrum disorder (ASD) is one of the most prevalent neurodevelopmental conditions worldwide. There is growing awareness that ASD is highly comorbid with gastrointestinal distress and altered intestinal microbiome, and that host-microbiome interactions may contribute to the disease symptoms. However, the paucity of knowledge on gut-brain axis signaling in autism constitutes an obstacle to the development of precision microbiota-based therapeutics in ASD. To this end, we explored the interactions between intestinal microbiota, gut physiology and social behavior in a BTBR T+Itpr3tf/J mouse model of ASD. Here we show that a reduction in the relative abundance of very particular bacterial taxa in the BTBR gut - namely, bile-metabolizing Bifidobacterium and Blautia species, - is associated with deficient bile acid and tryptophan metabolism in the intestine, marked gastrointestinal dysfunction, as well as impaired social interactions in BTBR mice. Together these data support the concept of targeted manipulation of the gut microbiota for reversing gastrointestinal and behavioral symptomatology in ASD, and offer specific plausible targets in this endeavor.
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Affiliation(s)
- Anna V Golubeva
- APC Microbiome Institute, University College Cork, Cork, Ireland
| | - Susan A Joyce
- APC Microbiome Institute, University College Cork, Cork, Ireland; School of Biochemistry & Cell Biology, University College Cork, Cork, Ireland
| | - Gerard Moloney
- Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland
| | | | - Eoin Sherwin
- APC Microbiome Institute, University College Cork, Cork, Ireland
| | - Silvia Arboleya
- APC Microbiome Institute, University College Cork, Cork, Ireland; Teagasc Food Research Centre, Moorepark Fermoy, County Cork, Ireland
| | - Ian Flynn
- Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland
| | | | | | | | - Kieran Rea
- APC Microbiome Institute, University College Cork, Cork, Ireland
| | - Kiera Murphy
- Teagasc Food Research Centre, Moorepark Fermoy, County Cork, Ireland
| | - Olga Makarova
- Research Institute of Human Morphology, Moscow, Russia; Lomonosov Moscow State University, Moscow, Russia
| | - Sergey Buravkov
- Research Institute of Human Morphology, Moscow, Russia; Lomonosov Moscow State University, Moscow, Russia
| | - Niall P Hyland
- APC Microbiome Institute, University College Cork, Cork, Ireland; Department of Pharmacology & Therapeutics, University College Cork, Cork, Ireland
| | - Catherine Stanton
- APC Microbiome Institute, University College Cork, Cork, Ireland; Teagasc Food Research Centre, Moorepark Fermoy, County Cork, Ireland; Department of Psychiatry & Neurobehavioural Sciences, University College Cork, Cork, Ireland
| | - Gerard Clarke
- APC Microbiome Institute, University College Cork, Cork, Ireland; Department of Psychiatry & Neurobehavioural Sciences, University College Cork, Cork, Ireland
| | - Cormac G M Gahan
- APC Microbiome Institute, University College Cork, Cork, Ireland; School of Microbiology, University College Cork, Cork, Ireland
| | - Timothy G Dinan
- APC Microbiome Institute, University College Cork, Cork, Ireland; Department of Psychiatry & Neurobehavioural Sciences, University College Cork, Cork, Ireland
| | - John F Cryan
- APC Microbiome Institute, University College Cork, Cork, Ireland; Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland.
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16
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Lim JS, Lim MY, Choi Y, Ko G. Modeling environmental risk factors of autism in mice induces IBD-related gut microbial dysbiosis and hyperserotonemia. Mol Brain 2017; 10:14. [PMID: 28427452 PMCID: PMC5399341 DOI: 10.1186/s13041-017-0292-0] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Accepted: 04/04/2017] [Indexed: 02/07/2023] Open
Abstract
Autism spectrum disorder (ASD) is a range of neurodevelopmental conditions that are sharply increasing in prevalence worldwide. Intriguingly, ASD is often accompanied by an array of systemic aberrations including (1) increased serotonin, (2) various modes of gastrointestinal disorders, and (3) inflammatory bowel disease (IBD), albeit the underlying cause for such comorbidities remains uncertain. Also, accumulating number of studies report that the gut microbial composition is significantly altered in children with ASD or patients with IBD. Surprisingly, when we analyzed the gut microbiota of poly I:C and VPA-induced mouse models of ASD, we found a distinct pattern of microbial dysbiosis that highly recapitulated those reported in clinical cases of ASD and IBD. Moreover, we report that such microbial dysbiosis led to notable perturbations in microbial metabolic pathways that are known to negatively affect the host, especially with regards to the pathogenesis of ASD and IBD. Lastly, we found that serum level of serotonin is significantly increased in both poly I:C and VPA mice, and that it correlates with increases of a bacterial genus and a metabolic pathway that are implicated in stimulation of host serotonin production. Our results using animal model identify prenatal environmental risk factors of autism as possible causative agents of IBD-related gut microbial dysbiosis in ASD, and suggest a multifaceted role of gut microbiota in the systemic pathogenesis of ASD and hyperserotonemia.
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Affiliation(s)
- Joon Seo Lim
- Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Seoul, Republic of Korea.,Institute of Health and Environment, Seoul National University, Seoul, Republic of Korea
| | - Mi Young Lim
- Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Seoul, Republic of Korea.,Institute of Health and Environment, Seoul National University, Seoul, Republic of Korea.,Research Group of Gut Microbiome, Korea Food Research Institute, Seongnam, Gyeonggi-do, Republic of Korea
| | - Yongbin Choi
- Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Seoul, Republic of Korea
| | - GwangPyo Ko
- Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Seoul, Republic of Korea. .,Center for Human and Environmental Microbiome, Seoul National University, Seoul, Republic of Korea. .,N-Bio, Seoul National University, Seoul, Republic of Korea. .,KoBioLabs, Inc., 1-Gwanak-ro, Gwanak-gu, Bldg 220, Rm 630, Seoul, 151-746, Republic of Korea.
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17
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Ozturk O, Koklu S, Koklu H. RECURRENT GASTRIC POLYPOSIS IN A PATIENT USING ANTIEPILEPTIC DRUGS FOR A LONG TIME. Gastroenterol Nurs 2017; 40:152-153. [DOI: 10.1097/sga.0000000000000281] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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18
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Kumar H, Sharma B. Memantine ameliorates autistic behavior, biochemistry & blood brain barrier impairments in rats. Brain Res Bull 2016; 124:27-39. [PMID: 27034117 DOI: 10.1016/j.brainresbull.2016.03.013] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Revised: 03/19/2016] [Accepted: 03/22/2016] [Indexed: 12/15/2022]
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder, commonly characterized by altered social behavior, communication, biochemistry and pathological conditions. One percent of the worldwide population suffers from autism and males suffer more than females. NMDA receptors have the important role in neurodevelopment, neuropsychiatric and neurodegenerative disorders. This study has been designed to investigate the role of memantine, a NMDA receptor modulator, in prenatal valproic acid-induced autism in rats. Animals with prenatal valproic acid have shown the reduction in social interaction (three-chamber social behavior apparatus), spontaneous alternation (Y-Maze), exploratory activity (Hole board test), intestinal motility, serotonin levels (both in prefrontal cortex and ileum) and prefrontal cortex mitochondrial complex activity (complex I, II, IV). Furthermore, prenatal valproic acid-treated animals have shown an increase in locomotion (actophotometer), anxiety (elevated plus maze), brain oxidative stress (thiobarbituric acid reactive species, glutathione, catalase), nitrosative stress (nitrite/nitrate), inflammation (both in brain and ileum myeloperoxidase activity), calcium and blood-brain barrier permeability. Treatment with memantine has significantly attenuated prenatal valproic acid-induced reduction in social interaction, spontaneous alteration, exploratory activity intestinal motility, serotonin levels and prefrontal cortex mitochondrial complex activity. Furthermore, memantine has also attenuated the prenatal valproic acid-induced increase in locomotion, anxiety, brain oxidative and nitrosative stress, inflammation, calcium and blood-brain barrier permeability. Thus, it may be concluded that prenatal valproic acid has induced autistic behavior, biochemistry and blood-brain barrier impairment in animals, which were significantly attenuated by memantine. NMDA receptor modulators like memantine should be explored further for the therapeutic benefits in autism.
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Affiliation(s)
- Hariom Kumar
- CNS Research Lab., Department of Pharmacology, School of Pharmacy, Bharat Institute of Technology, Partapur Bypass, Meerut, Uttar Pradesh, India.
| | - Bhupesh Sharma
- Department of Pharmacology, Amity Institute of Pharmacy, Amity University, Sector-125, Noida, Uttar Pradesh, India; CNS Pharmacology, Conscience Research, Pocket F-233 B, Dilshad Garden, Delhi 110095, India.
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19
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Mabunga DFN, Gonzales ELT, Kim JW, Kim KC, Shin CY. Exploring the Validity of Valproic Acid Animal Model of Autism. Exp Neurobiol 2015; 24:285-300. [PMID: 26713077 PMCID: PMC4688329 DOI: 10.5607/en.2015.24.4.285] [Citation(s) in RCA: 167] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Revised: 12/01/2015] [Accepted: 12/02/2015] [Indexed: 02/06/2023] Open
Abstract
The valproic acid (VPA) animal model of autism spectrum disorder (ASD) is one of the most widely used animal model in the field. Like any other disease models, it can't model the totality of the features seen in autism. Then, is it valid to model autism? This model demonstrates many of the structural and behavioral features that can be observed in individuals with autism. These similarities enable the model to define relevant pathways of developmental dysregulation resulting from environmental manipulation. The uncovering of these complex pathways resulted to the growing pool of potential therapeutic candidates addressing the core symptoms of ASD. Here, we summarize the validity points of VPA that may or may not qualify it as a valid animal model of ASD.
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Affiliation(s)
- Darine Froy N Mabunga
- Department of Neuroscience, School of Medicine, and Neuroscience Research Center, SMART-IABS and KU Open Innovation Center, Konkuk University, Seoul 05029, Korea
| | - Edson Luck T Gonzales
- Department of Neuroscience, School of Medicine, and Neuroscience Research Center, SMART-IABS and KU Open Innovation Center, Konkuk University, Seoul 05029, Korea
| | - Ji-Woon Kim
- Department of Neuroscience, School of Medicine, and Neuroscience Research Center, SMART-IABS and KU Open Innovation Center, Konkuk University, Seoul 05029, Korea
| | - Ki Chan Kim
- Department of Neuroscience, School of Medicine, and Neuroscience Research Center, SMART-IABS and KU Open Innovation Center, Konkuk University, Seoul 05029, Korea
| | - Chan Young Shin
- Department of Neuroscience, School of Medicine, and Neuroscience Research Center, SMART-IABS and KU Open Innovation Center, Konkuk University, Seoul 05029, Korea. ; Department of Pharmacology, School of Medicine, Konkuk University, Seoul 05029, Korea
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20
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Minocycline ameliorates prenatal valproic acid induced autistic behaviour, biochemistry and blood brain barrier impairments in rats. Brain Res 2015; 1630:83-97. [PMID: 26551768 DOI: 10.1016/j.brainres.2015.10.052] [Citation(s) in RCA: 75] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Revised: 10/16/2015] [Accepted: 10/29/2015] [Indexed: 01/07/2023]
Abstract
Autism is a neurodevelopment disorder. One percent worldwide population suffers with autism and males suffer more than females. Microglia plays an important role in neurodevelopment, neuropsychiatric and neurodegenerative disorders. The present study has been designed to investigate the role of minocycline in prenatal valproic acid induced autism in rats. Animals with prenatal valproic acid have reduced social interaction (three chamber social behaviour apparatus), spontaneous alteration (Y-Maze), exploratory activity (Hole board test), intestinal motility, serotonin levels (both in prefrontal cortex and ileum) and prefrontal cortex mitochondrial complex activity (complexes I, II, IV). Furthermore, prenatal valproic acid treated animals have shown an increase in locomotion (actophotometer), anxiety (elevated plus maze), brain oxidative stress (thiobarbituric acid reactive species, glutathione, catalase), nitrosative stress (nitrite/nitrate), inflammation (both in brain and ileum myeloperoxidase activity), calcium and blood brain barrier permeability. Treatment with minocycline significantly attenuated prenatal valproic acid induced reduction in social interaction, spontaneous alteration, exploratory activity intestinal motility, serotonin levels and prefrontal cortex mitochondrial complex activity. Furthermore, minocycline has also attenuated prenatal valproic acid induced increase in locomotion, anxiety, brain oxidative and nitrosative stress, inflammation, calcium and blood brain barrier permeability. Thus, it may be concluded that prenatal valproic acid has induced autistic behaviour, biochemistry and blood brain barrier impairment in animals, which were significantly attenuated by minocycline. Minocycline should be explored further for its therapeutic benefits in autism.
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21
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Kumar H, Sharma BM, Sharma B. Benefits of agomelatine in behavioral, neurochemical and blood brain barrier alterations in prenatal valproic acid induced autism spectrum disorder. Neurochem Int 2015; 91:34-45. [PMID: 26498253 DOI: 10.1016/j.neuint.2015.10.007] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2015] [Revised: 10/15/2015] [Accepted: 10/16/2015] [Indexed: 01/01/2023]
Abstract
Valproic acid administration during gestational period causes behavior and biochemical deficits similar to those observed in humans with autism spectrum disorder. Although worldwide prevalence of autism spectrum disorder has been increased continuously, therapeutic agents to ameliorate the social impairment are very limited. The present study has been structured to investigate the therapeutic potential of melatonin receptor agonist, agomelatine in prenatal valproic acid (Pre-VPA) induced autism spectrum disorder in animals. Pre-VPA has produced reduction in social interaction (three chamber social behavior apparatus), spontaneous alteration (Y-Maze), exploratory activity (Hole board test), intestinal motility, serotonin levels (prefrontal cortex and ileum) and prefrontal cortex mitochondrial complex activity (complex I, II, IV). Furthermore, Pre-VPA has increased locomotor activity (actophotometer), anxiety, brain oxidative stress (thiobarbituric acid reactive species, glutathione, and catalase), nitrosative stress (nitrite/nitrate), inflammation (brain and ileum myeloperoxidase activity), calcium levels and blood brain barrier leakage in animals. Treatment with agomelatine has significantly attenuated Pre-VPA induced reduction in social interaction, spontaneous alteration, exploratory activity intestinal motility, serotonin levels and prefrontal cortex mitochondrial complex activity. Furthermore, agomelatine also attenuated Pre-VPA induced increase in locomotion, anxiety, brain oxidative stress, nitrosative stress, inflammation, calcium levels and blood brain barrier leakage. It is concluded that, Pre-VPA has induced autism spectrum disorder, which was attenuated by agomelatine. Agomelatine has shown ameliorative effect on behavioral, neurochemical and blood brain barrier alteration in Pre-VPA exposed animals. Thus melatonin receptor agonists may provide beneficial therapeutic strategy for managing autism spectrum disorder.
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Affiliation(s)
- Hariom Kumar
- CNS Research Lab, Department of Pharmacology, School of Pharmacy, Bharat Institute of Technology, Partapur Bypass, Meerut, Uttar Pradesh, India.
| | - B M Sharma
- School of Pharmacy, Bharat Institute of Technology, Partapur Bypass, Meerut, Uttar Pradesh, India.
| | - Bhupesh Sharma
- Amity Institute of Pharmacy, Amity University, Sector-125, Noida, Uttar Pradesh, India; CNS Pharmacology, Conscience Research, Pocket F-233, B, Dilshad Garden, Delhi 110095, India.
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22
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Perinatal Influences of Valproate on Brain and Behaviour: An Animal Model for Autism. Curr Top Behav Neurosci 2015; 29:363-386. [PMID: 26510739 DOI: 10.1007/7854_2015_404] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Valproic acid or valproate (VPA) is an anti-convulsant and mood stabiliser effective in treating epilepsy and bipolar disorders. Although in adults VPA is well tolerated and safe, there is convincing evidence that it has teratogenic properties, ranging from mild neurodevelopmental changes to severe congenital malformations. In particular, studies involving humans and other animals have shown that prenatal exposure to VPA can induce developmental abnormalities reminiscent of autism spectrum disorder (ASD). In this chapter, we discuss the connection between VPA and ASD, evaluate the VPA animal model of ASD, and describe the possible molecular mechanisms underlying VPA's teratogenic properties.
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