Therapeutic Effects of MOTS-c in the Valproic Acid-Induced Autism Model in Rats: Role of Tetrahydrobiopterin and Brain-Derived Neurotrophic Factor. | Pepdox
Therapeutic Effects of MOTS-c in the Valproic Acid-Induced Autism Model in Rats: Role of Tetrahydrobiopterin and Brain-Derived Neurotrophic Factor.
Rat valproic acid (VPA) autism model study examining whether MOTS-c replicates exercise-like neuroprotective effects through AMPK activation, demonstrating that MOTS-c increased tetrahydrobiopterin (BH4) and BDNF levels, reduced oxidative stress, and improved social behavior and repetitive behavior scores. Suggests MOTS-c may address ASD pathophysiology through antioxidant and neurotrophic mechanisms. Provides the first evidence for MOTS-c's potential in autism spectrum disorder—establishing that mitochondrial peptide-mediated AMPK activation replicates exercise-associated improvements in ASD-relevant behavioral and neurochemical endpoints.
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction and repetitive behaviors, with currently limited therapeutic options. Oxidative stress is suggested as significant in ASD pathophysiology, making antioxidant strategies a promising therapeutic direction. Exercise reduces oxidative stress, alleviates ASD symptoms, and increases tetrahydrobiopterin (BH4) and brain-derived neurotrophic factor (BDNF) levels through AMP-activated protein kinase (AMPK) activation. MOTS-c, a mitochondrial-derived peptide acting through AMPK, mimics the effects of exercise but reportedly does not cross the blood-brain barrier (BBB). Considering the challenges in exercise adherence in ASD, our study hypothesizes that MOTS-c could increase circulating BH4 and BDNF, both of which are BBB-permeable, and alleviate oxidative stress and ASD symptoms. To evaluate this hypothesis, we investigated the effects of MOTS-c in the valproic acid-induced rat model of autism. Pregnant Sprague-Dawley rats received intraperitoneal 500 mg/kg valproic acid or saline on embryonic day 12. Female and male offspring were treated with 0.5 mg/kg/day MOTS-c or saline intraperitoneally from postnatal days 21 to 46. Following behavioral testing, animals were sacrificed, and histological and biochemical analyses were performed. Valproic acid exposure led to impaired sociability, repetitive behaviors, anxiety, cerebellar Purkinje cell loss, and increased oxidative stress and neuronal damage in the prefrontal cortex. These alterations were reversed by MOTS-c, except for anxiety and neocortical damage. No significant changes in plasma BH4 or BDNF levels were detected. Through its neuroprotective and antioxidant effects independent of BH4 and BDNF, MOTS-c may alleviate autism-like behaviors, suggesting its potential as a therapeutic candidate for ASD.