Neurotoxicology · 2025
Blockade of NMDA-receptors mitigates autistic and cognitive behaviors via modulation of TLR-4/NLRP3 inflammasomes and microglia/astrocyte crosstalk in rat model of autism.
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Aboul-Fotouh Sawsan, Zohny Sohir M, Hassan Ghada Am, Eissa Abeer M, Elshahawi Heba Hamed, Abdelraouf Sahar M, Ahmed Manar Yehia, Rabei Mohammed R, Hassan Fatma E, Mahmoud Ahmed Nageh, Eltantawy Eman H, Khedr Shaimaa, Ramadan Yasmin, El-Ashry Maha Khaled, Elnahas Esraa M
Аннотация
UNLABELLED: Converging evidence proposed NMDA-receptor dysfunction as a real challenge underlying excitotoxicity implicated in neurological changes of autism spectrum disorder (ASD). Nevertheless, the role of NMDA receptors in relation to toll-like receptor-4 (TLR-4), NOD-like receptor-3 (NLRP3), and microglia/astrocyte activity in autism-related neuroinflammation has not been investigated hitherto.
METHODS: The present study was designed to explore the potential role of NMDA-receptor blockade in autism by chronic memantine (MEM) treatment (20 mg/kg/d, i.p.) in male Wistar rats, prenatally exposed to valproic acid (VPA).
RESULTS: Prenatal VPA exposure exhibited autistic-like core symptoms and cognitive deficits that were accompanied by gene and protein overexpression of NMDAR-GluN1 & GluN2B subunits, TLR-4, and NF-κB in the prefrontal cortex (PFC). Additionally, VPA increased oxidative/nitrosative stress and inflammasome markers (NLRP3, procaspase-1, and caspase-1). Similarly, histopathological and immunohistochemical studies confirmed neurodegenerative changes, together with microglia/astrocyte reactivity, increased inflammatory and apoptotic markers, along with elevated Ki-67, β-amyloid expression, and the number of neurofibrillary tangles in prefrontal and cerebellar cortices. Chronic treatment with MEM ameliorated the above-mentioned behavioral, neurochemical, and histopathological abnormalities, and interestingly, these effects significantly correlated with NMDAR expression.
CONCLUSION: To the author's knowledge, this study is the first to confirm the potential modulatory effect of NMDA-receptor blockade, via memantine, on TLR-4/NLRP3 inflammasome pathway and microglia/astrocyte crosstalk, in relation to its role in mitigating the autistic behaviors and cognitive deficits in autism. These findings therefore lend further support to the hypothesis that NMDA-receptor blockade may represent a novel and promising pharmacotherapeutic strategy for ASD.
METHODS: The present study was designed to explore the potential role of NMDA-receptor blockade in autism by chronic memantine (MEM) treatment (20 mg/kg/d, i.p.) in male Wistar rats, prenatally exposed to valproic acid (VPA).
RESULTS: Prenatal VPA exposure exhibited autistic-like core symptoms and cognitive deficits that were accompanied by gene and protein overexpression of NMDAR-GluN1 & GluN2B subunits, TLR-4, and NF-κB in the prefrontal cortex (PFC). Additionally, VPA increased oxidative/nitrosative stress and inflammasome markers (NLRP3, procaspase-1, and caspase-1). Similarly, histopathological and immunohistochemical studies confirmed neurodegenerative changes, together with microglia/astrocyte reactivity, increased inflammatory and apoptotic markers, along with elevated Ki-67, β-amyloid expression, and the number of neurofibrillary tangles in prefrontal and cerebellar cortices. Chronic treatment with MEM ameliorated the above-mentioned behavioral, neurochemical, and histopathological abnormalities, and interestingly, these effects significantly correlated with NMDAR expression.
CONCLUSION: To the author's knowledge, this study is the first to confirm the potential modulatory effect of NMDA-receptor blockade, via memantine, on TLR-4/NLRP3 inflammasome pathway and microglia/astrocyte crosstalk, in relation to its role in mitigating the autistic behaviors and cognitive deficits in autism. These findings therefore lend further support to the hypothesis that NMDA-receptor blockade may represent a novel and promising pharmacotherapeutic strategy for ASD.
Предметные рубрики MeSH
AnimalsToll-Like Receptor 4MaleMicrogliaRats, WistarReceptors, N-Methyl-D-AspartateRatsMemantineNLR Family, Pyrin Domain-Containing 3 ProteinInflammasomesAutistic DisorderValproic AcidAstrocytesPregnancyFemaleDisease Models, AnimalPrenatal Exposure Delayed EffectsExcitatory Amino Acid AntagonistsCognitionBehavior, Animal