Altaf N Alabdali, Abir Ben Bacha, Mona Alonazi, Sameera Abuaish, Ahmad Almotairi, Laila Al-Ayadhi, Afaf K El-Ansary
{"title":"Impact of GABA and nutritional supplements on neurochemical biomarkers in autism: a PPA rodent model study.","authors":"Altaf N Alabdali, Abir Ben Bacha, Mona Alonazi, Sameera Abuaish, Ahmad Almotairi, Laila Al-Ayadhi, Afaf K El-Ansary","doi":"10.3389/fnmol.2025.1553438","DOIUrl":null,"url":null,"abstract":"<p><strong>Background/objectives: </strong>Autism spectrum disorder (ASD) is associated with excitatory-inhibitory imbalance and oxidative stress. GABA, an inhibitory neurotransmitter, and related nutritional therapies are promising in restoring these imbalances. GABAergic deficits and glutamate excitotoxicity are two essential signaling pathways that could be addressed to treat autism, thus medications targeting these pathways are critical for treating behavioral symptoms. In a rat model of autism produced by propionic acid (PPA), this study assessed the effects of GABA supplementation and combined nutritional therapy (probiotics, vitamin D3) and <i>β</i>-lactam as an activator of glutamate transporter.</p><p><strong>Methods: </strong>Sixty rats were randomly assigned into six groups: Group I (Control), Group II (PPA-treated), Group III (Control-GABA), Group IV (Control-Combination), Group V (PPA-GABA), and Group VI (PPA-Combination). Social behavior was evaluated using the three-chamber test. Selected biochemical variables related to oxidative stress (GST, Catalase, Lipid peroxides, GSH and Vitamin C), GABA and glutamate signaling (EAAT2, KCC2, NKCC1, GABA, VD3, Glutamate and GABRA5) were measured in the brain homogenates of the six groups. The hippocampus was examined histopathologically to assess cellular integrity.</p><p><strong>Results: </strong>The obtained data revealed that PPA treatment caused significant oxidative stress and neurotransmitter imbalances, characterized by reduced GABA and elevated glutamate levels. GABA supplementation alone produced moderate benefits in biochemical and behavioral markers, but combined therapy considerably restored GABA levels, reduced oxidative stress, and enhanced social interaction behaviors. Histopathology revealed that combination therapy mitigated neurodegenerative changes induced by PPA, preserving hippocampal cellular structure.</p><p><strong>Conclusion: </strong>This study demonstrated that combined therapy (GABA, probiotics, vitamin D3, and <i>β</i>-lactam) were more effective than GABA alone in enhancing neurochemical balance and lowering oxidative stress in a PPA-induced mouse model of autism, indicating promise for treating symptoms.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1553438"},"PeriodicalIF":3.5000,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11959029/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Frontiers in Molecular Neuroscience","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.3389/fnmol.2025.1553438","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
Background/objectives: Autism spectrum disorder (ASD) is associated with excitatory-inhibitory imbalance and oxidative stress. GABA, an inhibitory neurotransmitter, and related nutritional therapies are promising in restoring these imbalances. GABAergic deficits and glutamate excitotoxicity are two essential signaling pathways that could be addressed to treat autism, thus medications targeting these pathways are critical for treating behavioral symptoms. In a rat model of autism produced by propionic acid (PPA), this study assessed the effects of GABA supplementation and combined nutritional therapy (probiotics, vitamin D3) and β-lactam as an activator of glutamate transporter.
Methods: Sixty rats were randomly assigned into six groups: Group I (Control), Group II (PPA-treated), Group III (Control-GABA), Group IV (Control-Combination), Group V (PPA-GABA), and Group VI (PPA-Combination). Social behavior was evaluated using the three-chamber test. Selected biochemical variables related to oxidative stress (GST, Catalase, Lipid peroxides, GSH and Vitamin C), GABA and glutamate signaling (EAAT2, KCC2, NKCC1, GABA, VD3, Glutamate and GABRA5) were measured in the brain homogenates of the six groups. The hippocampus was examined histopathologically to assess cellular integrity.
Results: The obtained data revealed that PPA treatment caused significant oxidative stress and neurotransmitter imbalances, characterized by reduced GABA and elevated glutamate levels. GABA supplementation alone produced moderate benefits in biochemical and behavioral markers, but combined therapy considerably restored GABA levels, reduced oxidative stress, and enhanced social interaction behaviors. Histopathology revealed that combination therapy mitigated neurodegenerative changes induced by PPA, preserving hippocampal cellular structure.
Conclusion: This study demonstrated that combined therapy (GABA, probiotics, vitamin D3, and β-lactam) were more effective than GABA alone in enhancing neurochemical balance and lowering oxidative stress in a PPA-induced mouse model of autism, indicating promise for treating symptoms.
期刊介绍：
Frontiers in Molecular Neuroscience is a first-tier electronic journal devoted to identifying key molecules, as well as their functions and interactions, that underlie the structure, design and function of the brain across all levels. The scope of our journal encompasses synaptic and cellular proteins, coding and non-coding RNA, and molecular mechanisms regulating cellular and dendritic RNA translation. In recent years, a plethora of new cellular and synaptic players have been identified from reduced systems, such as neuronal cultures, but the relevance of these molecules in terms of cellular and synaptic function and plasticity in the living brain and its circuits has not been validated. The effects of spine growth and density observed using gene products identified from in vitro work are frequently not reproduced in vivo. Our journal is particularly interested in studies on genetically engineered model organisms (C. elegans, Drosophila, mouse), in which alterations in key molecules underlying cellular and synaptic function and plasticity produce defined anatomical, physiological and behavioral changes. In the mouse, genetic alterations limited to particular neural circuits (olfactory bulb, motor cortex, cortical layers, hippocampal subfields, cerebellum), preferably regulated in time and on demand, are of special interest, as they sidestep potential compensatory developmental effects.
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