Subchronic Treatment of Donepezil Rescues Impaired Social, Hyperactive, and Stereotypic Behavior in Valproic Acid-Induced Animal Model of Autism

Abstract

Autism spectrum disorder (ASD) is a group of pervasive developmental disorders with core symptoms such as sociability deficit, language impairment, and repetitive/restricted behaviors. Although worldwide prevalence of ASD has been increased continuously, therapeutic agents to ameliorate the core symptoms especially social deficits, are very limited. In this study, we investigated therapeutic potential of donepezil for ASD using valproic acid-induced autistic animal model (VPA animal model). We found that prenatal exposure of valproic acid (VPA) induced dysregulation of cholinergic neuronal development, most notably the up-regulation of acetylcholinesterase (AChE) in the prefrontal cortex of affected rat and mouse offspring. Similarly, differentiating cortical neural progenitor cell in culture treated with VPA showed increased expression of AChE in vitro. Chromatin precipitation experiments revealed that acetylation of histone H3 bound to AChE promoter region was increased by VPA. In addition, other histone deacetyalse inhibitors (HDACIs) such as trichostatin A and sodium butyrate also increased the expression of AChE in differentiating neural progenitor cells suggesting the essential role of HDACIs in the regulation of AChE expression. For behavioral analysis, we injected PBS or donepezil (0.3 mg/kg) intraperitoneally to control and VPA mice once daily from postnatal day 14 all throughout the experiment. Subchronic treatment of donepezil improved sociability and prevented repetitive behavior and hyperactivity of VPA-treated mice offspring. Taken together, these results provide evidence that dysregulation of ACh system represented by the up-regulation of AChE may serve as an effective pharmacological therapeutic target against autistic behaviors in VPA animal model of ASD, which should be subjected for further investigation to verify the clinical relevance.

The α7 nicotinic acetylcholine receptor: A mediator of pathogenesis and therapeutic target in autism spectrum disorders and Down syndrome

“…ICR offspring were injected once oncedaily with donepezil (0.3 mg/kg) from postnatal day 14 (P14) to P40; behavioral testing was performed during this injection period. Western Blot analysis of the prefrontal cortex of the valproic acid-treated rat and mouse offspring showed significantly diminished immunoreactive protein content of choline acetyltransferase (ChAT) and significantly increased immunoreactive protein content of acetylcholinesterase (AChE) [38]; these data are consistent with a cholinergic deficiency in prefrontal cortex. The authors presented data showing that the histone H3 protein in the promoter region of the gene coding AChE (i.e., Ache) was hyperacetylated in the prefrontal cortex of valproic acid-treated rat offspring, which could promote its transcription and ultimate expression.…”

“…Interestingly, donepezil did not affect repetitive behaviors, such as repetitive self-grooming and bedding-digging duration, suggesting that the circuitry underlying these repetitive behaviors differs from the circuitry underlying sociability and cognitive flexibility [20]. M a n u s c r i p t 21 Prenatal exposure of rodents to valproic acid leads to the development of autistic-like behaviors in these offspring, including impaired sociability and increased repetitive behavior [38].…”

“…Cholinergic abnormalities and the effect of treatment with donepezil on target behaviors relevant to ASD were studied in this 'valproic acid-induced animal model of autism' [38]. The model was created by subcutaneously injecting valproic acid into pregnant Sprague-Dawley rats (400 mg/kg) and ICR mice (300 mg/kg) on embryonic day 12 (E12) and E10, respectively; controls were the offspring of vehicle-injected pregnant dams.…”

“…As noted above, the effects of subchronic systemic treatment of valproate-treated ICR mouse offspring from P14 and throughout the period of behavioral testing with daily intraperitoneal injections of donepezil (0.3 mg/kg) on a variety of modeled autistic-like behaviors were explored [38]. Donepezil increased the amount of time the prenatally valproate-treated offspring spent in repetitive behaviors in the valproate-treated offspring may differ.…”

Immunological Dysfunction in Autism Spectrum Disorder: A Potential Target for Therapy

“…Studies to investigate this possibility must be carried out, and the effectiveness of therapies previously tested on humans or in animal models should be evaluated. Drugs with anti-inflammatory potential such as donepezil, resveratrol, and fingolimod have demonstrated positive findings in animal models of ASD [248][249][250][251][252][253][254][255], pointing to promising therapeutic potential, so we would encourage further research to be undertaken.…”