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

• Published in: Progress in neuro-psychopharmacology & biological psychiatry Vol. 116; p. 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: Journal Article
• Language: English
• Published: England Elsevier Inc 08-06-2022
• 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; ASD; Metformin and risperidone; Astrocytes and Tauopathy; PPAR-α; Apoptosis
• ISSN: 0278-5846; 1878-4216
• DOI: 10.1016/j.pnpbp.2022.110522

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.