Oxidative damage and mitochondrial dysfunction in valproic acid-exposed autism model rats

抄録

[Background and Objectives] Autism spectrum disorders (ASD) are a neurodevelopmental disease represented by social communication deficits and learning disability. Oxidative stress and mitochondrial dysfunction are implicated in ASD brain pathology. It is well known that prenatal exposure to anticonvulsant valproic acid (VPA) increases the risk of postnatal ASD (1). We here addressed a question whether oxidative stress and mitochondrial dysfunction are involved in autism-like behaviors in prenatally VPA-exposed rats (VPA rats).

[Methods] Pregnant rats were treated with oral administration of VPA (600 mg/kg) at E12.5, and male pups after birth were used for postnatal analyses. (i) Behavioral tasks were carried out at 5-6 weeks of age to assess social and learning abilities. (ii) At 8 weeks of age, oxidative stress and mitochondrial function were assessed in the hippocampus of VPA rats. (iii) Some VPA rats were subjected to chronic administration (3 to 8 weeks of age) with orally 5-aminolevulinic acid (ALA; 30 mg/kg), a precursor of protoporphyrin IX, or intranasally oxytocin (OXT; 12 µg/kg), a neurohormone involved in ASD etiology.

[Results] (i) Social and learning abilities were impaired in VPA rats, assessed by social interaction, Y maze, and novel object recognition tasks. (ii) Immunohistochemical analyses revealed elevated lipid peroxidation in the hippocampus of VPA rats, suggesting oxidatively damaged. Moreover, enzymatic activities of both complex I and II of mitochondrial electron transport chain were decreased, whereas the complex IV activity was conversely elevated in the hippocampus of VPA rats. ATP levels in the hippocampus were also decreased in VPA rats. (iii) Autism-like behaviors observed in VPA rats were improved by both oral ALA and intranasal OXT administration.

[Conclusions] Taken together, oral ALA administration rescues oxidative stress and mitochondrial energetic disturbance in the brain, thereby ameliorating autism-like behaviors in VPA rats, like OXT. The authors declare no conflicts of interest.

[Reference] 1. Huang JY, Fukunaga K, Han F et al., CNS Neurosci & Therap. 2016. 22:845-853.