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

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.

The comparative effectiveness of metformin and risperidone in a rat model of valproic acid-induced autism, Potential role for enhanced autophagy

“…Improved sociability of our adolescent rats treated with either risperidone or metformin was confirmed by the obviously higher preference to spend time with the novel rat rather than with the object (non-social stimulus). Our results correlate with previous studies (Hara et al 2017 ; Wang et al 2018 ; Ishola et al 2020 ; Román et al 2021 ; Deng et al 2022b ; Elnahas et al 2022 )…”

“…Mechanisms by which metformin ameliorates the characteristic ASD behavioral phenotypes remains an interesting question. Down rearrangement of mTOR/mTORC1 signaling in the cerebral cortex (Wang et al 2018 ) or cerebellum (Liu et al 2022 ), down-regulation of the pro-inflammatory cytokines (NF-κB, IL-17A, and IL-6) in the hippocampus (Deng et al 2022b ), reestablishment of oxide-antioxidant balance and enhancement of cortical and hippocampal cholinergic activity (Ishola et al 2020 ), selective abundance of some gut microbiota and/or enhanced serotonin production in the colon (Deng et al 2022a ); were all suggested in preclinical models treated with metformin. In similar context, the favorable behavioral effects of risperidone in ASD were explained by its ability to suppress neuroinflammation (Elnahas et al 2022 ), restore redox balance and regulate serotonergic and dopaminergic transmission in the prefrontal cortex and hippocampus (Hara et al 2017 ).…”

“…Litters born up to the 17:00 h in any given day were considered in their zero postnatal day, P0. All pups were allowed to grow till weaning, P21, when male offspring were separated and grouped as follows: control group (n=6) born to mothers injected with saline and treated with vehicle (0.5% v/v methylcellulose); VPA-untreated group (n=8) born to mothers injected with VPA and treated with vehicle (0.5% v/v methylcellulose); VPA-risperidone group (n=8), born to mothers injected with VPA and treated with oral risperidone (0.5 mg/kg/day suspended in 0.5% v/v methylcellulose) (Zhu et al, 2014); VPA-metformin group (n=8) born to mothers injected with VPA and treated with oral metformin (200 mg/kg/day suspended in 0.5% v/v methylcellulose) (Ishola et al 2020 ). Vehicle and drug suspensions were administered by gavage once a day using a volume of 5 ml/kg.…”

Behavioral effects of environmental enrichment on male and female wistar rats with early life stress experiences

“…Many reports describe the effect of early stressors on this response ( Couto et al, 2012 ; Diehl et al, 2012 ). These studies usually use severe stressors, such as anticonvulsant drugs ( Ishola et al, 2020 ), amphetamine ( Holubová et al, 2018 ), ultrasound exposure ( Abramova et al, 2020 ), maternally induced diabetes ( Huerta-Cervantes et al, 2020 ), gamma exposure ( Pipová Kokošová et al, 2020 ), or chronic changes in maternal diet during gestation ( Bengoetxea et al, 2017 ). Such procedures cause serious cellular alterations in many brain regions, including the hippocampus, and the results found in the MWM may reflect these structural alterations.…”

Influence of the Aryl Hydrocarbon Receptor Activating Environmental Pollutants on Autism Spectrum Disorder

“…The study suggested that neonatal metformin treatment is capable of averting some of the classic behavioral symptoms commonly observed in patients with ASD. In addition, a recent study conducted on rats to examine the effect of metformin on valproic acid-induced autism-like behaviors has demonstrated that postnatal treatment with metformin improved the sociability index, spatial learning, and reference memory deficits through the attenuation of malondialdehyde and nitrite levels, AChE activity, and antioxidant enzymes activities in the rat hippocampus and prefrontal cortex [159]. In humans, the clinical studies on the beneficial effects of metformin are controversial.…”