Clinical Therapeutic Strategies to Ameliorate the Mitochondrial ETC Complexes Dysfunctions in Autism: First Time from India

Autism is a prototypical form of pervasive developmental disorder (PDD), characterized by complex behavioural impairments detectable as early as 18-36 months of age with severe abnormalities in communications, social awareness and skills, and the presence of restrictive and stereotyped patterns of behaviors, interests, and activities. In addition to these core symptoms, there are few other behavior disturbances which are commonly seen in the autistic individuals, such as anxiety, depression, sleeping and eating disturbances, attention issues, temper tantrums, motor disabilities and aggression or self-injury. Propionic acid (PPA) on oral and intraventricular injection of PPA in rodents mimics the behavioural and biochemical abnormalities observed in autism patients. Increased PPA levels may interfere with overall cellular metabolism in tricarboxylic acid cycle where it interferes with the conversion of succinyl co-A to succinate for generation of FADH2 in electron transport chain complex II further impairs the ATP synthesis. Extracellular signals regulate various intracellular neuroprotective functions through secondary messenger's cyclic AMP (cAMP) that subsequently activate target enzymes Protein kinase A (PKA) & activate cyclic AMP responsive element binding protein (CREB) which regulate and protects various toxic damage in brain. Forskolin (FSK) (also called Coleonol) Coleus forskohlii Briq. (Lamiaceae), major pharmacological mechanism of action is linked to its direct action on adenyl cyclase (AC) enzyme which results in the increase intracellular cAMP/PKA/CREB pathway further responsible for various neuroprotective mechanisms. It is first time designed to investigate the protective and therapeutic potency of FSK in AC/cAMP/PKA mediated CREB activation in intraventricular PPA induced autism in rats.