Investigation of the role of agmatine and PI3K/Akt/mTOR signaling pathway in experimental model of autism spectrum disorder

Aims

Although the prevalence of Autism Spectrum Disorder (ASD) continues to increase worldwide, its neurobiology remains incompletely understood and no specific pharmacological treatment has yet been established. Among the proposed mechanisms, PI3K/Akt/mTOR intracellular signaling pathway has drawn increasing attention in recent years.The PI3K/Akt/mTOR intracellular signaling pathway is a fundamental signaling mechanism involved in biological processes such as cell growth, differentiation, survival, protein synthesis, and metabolism. Upregulation of the PI3K/AKT/mTOR signaling pathway is responsible for many neurological dysfunctions, including ASD. In this study, we investigated the role of PI3K/Akt/mTOR intracellular signaling pathway in the ASD model created with VPA and the effect of agmatine (AGM) treatment a compound known for its anti-inflammatory and neuromodulator properties, in a valproic acid (VPA)-induced experimental model of ASD.

Methods

An ASD model was established in pregnant Sprague Dawley rats by administering a single subcutaneous dose of VPA (400 mg/kg) on embryonic day 12.5. On postnatal day 21, offspring were divided into four groups (n=12): control, ASD, ASD+AGM50 ((single dose 400 mg/kg VPA; s.c. + 50 mg/kg AGM; i.p. for 15 days from postnatal day 30 intraperitoneally). In behavioral assessments, open field, sucrose splash, new object recognition, social interaction and three chamber test (TCT) were used at postnatal 46th day. PI3K, Akt and mTOR gene expressions were evaluated in the prefrontal cortex of animals decapitated after behavioral tests.

Results

Compared to the control group in the ASD group; it was found that total activity and repetitive grooming behavior increased in OFT, attantion/learning and memory performance decreased in the novel object recognition test, socialization behavior decreased in social interaction test, and sociability preference decreased in TCT. On the other hand, agmatine has been shown to reduce increased activity, alleviate repetitive behaviors, alleviate cognitive rigidity, increased visual learning and memory, and significantly increase socialization behavior and sociability preference. Molecular analyzes showed that in ASD group PI3K, Akt, mTOR gene expressions are increased significantly and treatment with AGM significantly decreased the increased PI3K, Akt, mTOR gene expressions in ASD.

Conclusions

AGM, an endogenous polyamine, has been shown to play a role in the regulation of numerous functions due to its widespread distribution in the mammalian brain and periphery, and it is also an atypical neurotransmitter and neuromodulator. In the light of the findings of the study, it was thought that the AGM, administered exogenously, has an effect on characteristic symptoms in ASD models, and that at least some of these effects may be through the PI3K/Akt/mTOR pathway. It has been evaluated that molecules effective on AGM synthesis and metabolism in the future may provide new treatment approaches, based on the fact that the treatment performed due to the external application of AGM, which is an endogenous molecule, improves the behavioral and molecular parameters of ASD.

References

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