Novel role of peroxisome proliferator activated receptor-α in valproic acid rat model of autism: Mechanistic study of risperidone and metformin monotherapy versus combination

Autism spectrum disorder (ASD) is a neurodevelopmental disorder of heterogenous etiology exhibiting a challenge in understanding its exact neuro-pathophysiology. Recently, peroxisome proliferator activated receptor (PPAR)-α activation was found to play a fundamental role in neuroprotection and impro...

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Published in:Progress in neuro-psychopharmacology & biological psychiatry 2022-06, Vol.116, p.110522-110522, Article 110522
Main Authors: Elnahas, Esraa M., Abuelezz, Sally A., Mohamad, Magda I., Nabil, Mai M., Abdelraouf, Sahar M., Bahaa, Nevine, Hassan, Ghada A.M., Aboul-Fotouh, Sawsan
Format: Article
Language:English
Subjects:
Animals
Apoptosis
ASD
Astrocytes and Tauopathy
Autism Spectrum Disorder - chemically induced
Autism Spectrum Disorder - drug therapy
Autism Spectrum Disorder - metabolism
Autistic Disorder - chemically induced
Behavior, Animal
Disease Models, Animal
Female
Male
Metformin - adverse effects
Metformin and risperidone
Peroxisome Proliferator-Activated Receptors - adverse effects
PPAR-α
Pregnancy
Prenatal Exposure Delayed Effects
Rats
Rats, Wistar
Risperidone - pharmacology
Risperidone - therapeutic use
Tauopathies
Valproic Acid - pharmacology
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Summary:Autism spectrum disorder (ASD) is a neurodevelopmental disorder of heterogenous etiology exhibiting a challenge in understanding its exact neuro-pathophysiology. Recently, peroxisome proliferator activated receptor (PPAR)-α activation was found to play a fundamental role in neuroprotection and improving autistic-like-behaviors in experimental animal models of ASD through alleviating neuroinflammation, oxidative-stress, astrocyte reactivity, tauopathy in addition to its favorable role in metabolic regulation, thus attracting attention as a possible target in treatment of ASD. This study aimed to investigate the role of PPAR-α, astrocytic dysfunction and tauopathy in ASD and detect the possible neuroprotective effects of metformin (MET), through PPAR-α activation, and risperidone (RIS) either monotherapy or in combination in alleviating autistic-like-changes at behavioral and neurobiological levels in male Wistar rats. Pregnant female Wistar rats received valproic-acid (VPA) to induce autistic-like-behavioral and neurobiological alterations in their offspring. Chronic intra-peritoneal MET (100 mg/kg/day) and RIS (1 mg/kg/day) either monotherapy or in combination started from postnatal day (PND) 24 till PND61 (38 days). Prenatal VPA exposure simulated the autistic core behaviors associated with neurochemical and histopathological neurodevelopmental degenerative changes. Both MET and RIS either monotherapy or in combination were able to reverse these changes. The effect of MET was comparable to RIS. Moreover, MET was able to alleviate the RIS induced weight gain and improve cognitive functions highlighting its promising adjunctive role in alleviating ASD pathophysiology. Our study highlighted the favorable effects of MET and RIS both in monotherapy and in combination in alleviating the autistic-like-changes and proposed PPAR-α activation along with restoring astrocytes homeostasis as promising targets in novel therapeutic strategies in ASD. •Prenatal VPA induced autistic-like behaviors and neurobiological changes.•The autistic-like changes were associated with decreased PPAR-α expression.•Metformin and/or risperidone alleviated these autistic-like-changes.•Metformin was comparable to risperidone effect in alleviating these changes.•Metformin alleviated risperidone-induced weight gain and boosted cognitive function.
ISSN:0278-5846
1878-4216
DOI:10.1016/j.pnpbp.2022.110522