Beneficial effects of pioglitazone, a selective peroxisome proliferator‐activated receptor‐γ agonist in prenatal valproic acid‐induced behavioral and biochemical autistic like features in Wistar rats

Abstract

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder in children. It is diagnosis by two main behavioral phenotypes i.e. social‐communication impairments and repetitive behavior. ASD is complex disorder with unsolved etiology due to multiple genes involvement, epigenetic mechanism and environmental factors. Valproic acid (VPA), a teratogen is known to induce characteristic features related to ASD in rodents. Numerous studies suggest the potential therapeutic effects of peroxisome proliferator‐activated receptor‐gamma (PPAR‐γ) in different brain disorders. This research evaluates the utility of selective agonist of PPAR‐γ, pioglitazone in prenatal VPA induced experimental ASD symptomatology in Wistar rats. The prenatal administration of VPA has induced social impairment, repetitive behavior, hyperlocomotion, anxiety and low exploratory activity in rats. Also, prenatal VPA‐treated rats have shown higher levels of oxidative stress (increased in thiobarbituric acid reactive species, and decreased in reduced glutathione level) and inflammation (increased in interleukin‐6, tumor necrosis factor‐alpha and decreased in interleukin‐10) in the cerebellum, brainstem and prefrontal cortex. Treatment with pioglitazone significantly attenuated the prenatal VPA‐induced social impairment, repetitive behavior, hyperactivity, anxiety and low exploratory activity. Furthermore, pioglitazone also reduced the prenatal VPA‐induced oxidative stress and neuroinflammation in aforementioned brain regions. Hence, it may be concluded that pioglitazone may provide neurobehavioral and biochemical benefits in prenatal VPA‐induced autistic phenotypes in rats.

Novel potential of metformin on valproic acid‐induced autism spectrum disorder in rats: involvement of antioxidant defence system

“…It is well known that VPA induced ASD possibly through chromatin remodelling by inhibition of HDAC activity [11], inhibition of GABA transaminase [12] or via the b-catenin-Ras-ERK-p21 pathway [13]. Interestingly, metformin has been shown to modulate HDAC activity [39], attenuates ERK signalling by activating AMPK pathway [40] and rescues multiple pathological phenotypes of fragile X syndrome in Drosophila [41].…”

“…Several lines of evidences have shown that mitochondrial dysfunction and oxidative stress play significant role in ASD. Interestingly, autistic brains showed significant decrease in antioxidant enzymes activities, mitochondrial electron transport chainKyoto, Kyoto, Japan and ATP levels as well as increased levels of reactive oxygen species (ROS) and carbonyl proteins in comparison with normal unaffected control [11][12][13].…”

Is There a Future for PPARs in the Treatment of Neuropsychiatric Disorders?

“…In preclinical studies, administering pioglitazone decreases inflammation and oxidative stress, thus reverting the ASD-like behavior [114]. The ASD-like behavioral deficits can be induced in rats with a postnatal treatment with propionic acid, which increases inflammation and oxidative stress [51].…”

PPARγ and Cognitive Performance

“…In the brain, ASD is characterized by depletion of brain GSH (Glutathione), oxidative stress, and inflammation paralleled by neuroanatomical defects. The observations in humans have also been confirmed in animal models of disease, such as valproic-treated rats or propionic-treated rats [135,136].…”