Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Dec;34(6):650-661.
doi: 10.1111/fcp.12567. Epub 2020 Jun 16.

Novel potential of metformin on valproic acid-induced autism spectrum disorder in rats: involvement of antioxidant defence system

Ismail O Ishola  1 , Aishat O Balogun  1 , Olufunmilayo O Adeyemi  1
Affiliations

Novel potential of metformin on valproic acid-induced autism spectrum disorder in rats: involvement of antioxidant defence system

Ismail O Ishola et al. Fundam Clin Pharmacol. 2020 Dec.

Abstract

Prenatal exposure to valproic acid (VPA) has been shown to increase the risk of autism in children. This study examined the effect of metformin on VPA-induced autism spectrum disorders in rats. Pregnant albino rats administered VPA (500 mg/kg, i.p.) or normal saline (10 mL/kg, i.p.; vehicle-control) on gestational day 12.5. The pups were given metformin (5, 50 or 500 mg/kg, p.o.) or vehicle (10 mL/kg, p.o.) daily from postnatal day (PND) 21-50. Social behaviour, spatial learning/reference memory, repetitive behaviour and anxiety were assessed using the three-chamber social assay, Morris water maze (MWM), Y maze and elevated plus maze tests (EPM), respectively. On PND 51, the animals were euthanized and brains removed for biochemical assay. In utero VPA exposure caused significant reduction in sociability index, social novelty preference index in three-chambered apparatus and spatial learning and reference memory deficits in the MWM task as well as increase in repetitive/anxiety-like behaviour in Y maze and EPM tests, respectively, which were ameliorated by post-treatment with metformin in a dose-dependent manner. Moreover, prenatal VPA increased malondialdehyde (MDA) and nitrite levels as well as deficits in antioxidant enzymes activities in the hippocampus and prefrontal cortex (PFC) which were attenuated by metformin administration. Similarly, VPA-induced increase in acetylcholinesterase activity in the hippocampus and PFC were attenuated by postnatal treatment with metformin. Findings from this study showed that postnatal administration of metformin prevented valproic acid-induced autistic-like behaviour. Hence, metformin could be a potential adjunct in the management of autism spectrum disorders.

Keywords: Y maze; anxiety; oxidative stress; social interaction deficits; three-chambered social apparatus; valproic acid-induced autism.

PubMed Disclaimer

References

REFERENCES

    1. Jones E.J.H., Gliga T., Bedford R., Charman T., Johnson M.H. Developmental pathways to autism: a review of prospective studies of infants at risk. Neurosci. Biobehav. Rev. (2014) 39 1-33.
    1. Lamb J.A., Moore J., Bailey A., Monaco A.P. Autism: recent molecular genetic advances. Hum. Mol. Genet. (2000) 9 861-868.
    1. Nicolini C., Fahnestock M. The valproic acid-induced rodent model of autism. Exp. Neurol. (2018) 299(Pt A) 217-227.
    1. Christensen J., Grønborg T.K., Sørensen M.J. et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA (2013) 309 1696-1703.
    1. Kim K.C., Kim P., Go H.S. et al. The critical period of valproate exposure to induce autistic symptoms in Sprague-Dawley rats. Toxicol. Lett. (2011) 201 137-142.