Possible therapeutic effect of MOTS-C in valproic acid induced autism model in rats: Role of tetrahidrobiopterine and brain-derived neurotrophic factor

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction and repetitive behaviors. Currently, treatment searches for ASD continue. Oxidative stress (OS) is suggested as significant in ASD pathophysiology. Exercise has been shown to reduce brain OS, alleviate ASD symptoms, and increase levels of tetrahydrobiopterin (BH4) and brain-derived neurotrophic factor (BDNF) via AMPK activation, both of which also reduce brain OS. MOTS-c, a mitochondria-derived peptide that reportedly does not cross the blood-brain barrier (BBB), also acts via AMPK. Considering challenges in exercise adherence in ASD, our study hypothesizes that MOTS-c, which is exercise-mimetic, may alleviate ASD symptoms by reducing OS in the brain through BH4 and BDNF, which can cross the BBB. Thus, we investigated the potential therapeutic effects of MOTS-c in a rat model of autism induced by valproic acid (VPA). Adult Sprague-Dawley rats were mated, and a 500 mg/kg i.p. VPA or saline was administered on E12. The 64 male and female offspring were divided into eight groups (Female-Control, Female-VPA, Female-MOTS-c, Female-VPA+MOTS-c, Male-Control, Male-VPA, Male-MOTS-c, Male-VPA+MOTS-c). From P21 to P46, they received 0.5 mg/kg/day MOTS-c or saline. Following behavioral tests between P42-P46, animals were sacrificed. Histological and biochemical analyses were conducted on plasma and brain samples. VPA groups exhibited decreased sociability, increased repetitive behavior and anxiety, reduced Purkinje cell numbers in the cerebellum; neuronal damage, increased malondialdehyde levels, decreased total glutathione levels, and superoxide dismutase activity in the prefrontal cortex (PFC). In the VPA+MOTS-c groups, these changes were reversed (except for anxiety symptoms and neuronal damage in the PFC). The lack of differences in plasma BH4 and BDNF levels suggests that MOTS-c's positive effects are independent of them. MOTS-c may ameliorate autism-like behaviors through neuroprotective and antioxidant effects mediated by different molecule(s).