The effect of ketogenic diet in an animal model of autism induced by prenatal exposure to valproic acid

Abstract

Objectives: Autism spectrum disorder (ASD) is characterized by impairments in social interaction and communication, and by restricted repetitive behaviors and interests. Its etiology is still unknown, but different environmental factors during pregnancy, such as exposure to valproic acid (VPA), are associated with high incidence of ASD in children. In this context, prenatal exposure to VPA in rodents has been used as a reliable model of ASD. Ketogenic diet (KD) is an alternative therapeutic option for refractory epilepsy; however, the effects of this approach in ASD-like behavior need to be evaluated. We conducted a behavioral assessment of the effects of KD in the VPA model of autism.

Methods: Pregnant animals received a single-intraperitoneal injection of 600 mg/kg VPA, and their offspring were separated into four groups: (1) control group with standard diet (C-SD), (2) control group with ketogenic diet (C-KD), (3) VPA group with standard diet (VPA-SD), and (4) VPA group with ketogenic diet (VPA-KD).

Results: When compared with the control group, VPA animals presented increased social impairment, repetitive behavior and higher nociceptive threshold. Interestingly, the VPA group fed with KD presented improvements in social behavior. These mice displayed higher scores in sociability index and social novelty index when compared with the SD-fed VPA mice.

Discussion: VPA mice chronically exposed to a KD presented behavioral improvements; however, the mechanism by which KD improves ASD-like features needs to be further investigated. In conclusion, the present study reinforces the potential use of KD as a treatment for the core deficits of ASD.

Keywords:

• Autistic disorder
• Ketogenic diet
• Valproic acid

Acknowledgments

This study received financial support from FIPE-HCPA (Fundo de Incentivo à Pesquisa/Hospital de Clínicas de Porto Alegre) and research grants from FAPERGS/HCPA (Fundo de Amparo à Pesquisa do Rio Grande do Sul/Hospital de Clínicas de Porto Alegre), CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) and CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico).

Disclaimer statements

Contributors All authors contributed equally.

Funding FIPE-HCPA (Fundo de Incentivo à Pesquisa), FAPERGS-HCPA (Fundação de Amparo à Pesquisa do Estado do Rio Grande, do Sul-Hospital de Clínicas de Porto Alegre), CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior), CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico)

Conflict of interest The authors declare that there is no conflict of interest.

Ethics approval The experiments were conducted according to the Guide for the Care and Use of Laboratory Animals, and the project was approved by the Animal Research Ethics Committee at the Hospital de Clínicas de Porto Alegre (HCPA), (protocol number 13-0037).