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Metformin ameliorates the status epilepticus- induced hippocampal pathology through possible mTOR modulation

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Abstract

The initial precipitating injury such as SE progresses to chronic epilepsy through multiple epileptogenic processes. Early epileptogenic events are generally characterized by neuroinflammation, neurodegeneration and abnormal neurogenesis in the hippocampus. Metformin has exhibited anti-inflammatory and neuroprotective properties in numerous studies. The current study attempts to investigate the effect of metformin on seizure-induced inflammation and neuronal degeneration, and the involvement of the mTOR pathway. Status epilepticus (SE) was induced in male Wistar rats with systemic administration of Lithium (127 mg/kg) and Pilocarpine (30 mg/kg). In test rats, Metformin 100 mg/kg or 200 mg/kg was administered orally for 7 days, followed by SE induction. Results indicate that metformin did not alter the SE profile significantly which was evident by the behavioural scoring and electroencephalogram (EEG) recordings. However, metformin 200 mg/kg attenuated the SE-induced glial activation (p < 0.01), up regulated mRNA levels of proinflammatory cytokines (p < 0.001) and chemokines (p < 0.001) and enhanced BBB permeability (p < 0.05). In addition, metformin ameliorated the insult-induced region-specific neuronal damage (p < 0.01) and restored the hippocampal neuronal density. Metformin significantly inhibited phosphorylated S6 ribosomal protein (phospho-S6rp) (p < 0.05), thus demonstrating that the beneficial effects might be partly mediated by the mTOR pathway. The study thus reiterates that mTOR signalling is one of the mechanisms involved in inflammation and neurodegeneration in early epileptogenesis following SE.

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Abbreviations

mTOR:

Mammalian target of rapamycin

SE:

Status epilepticus

BBB:

Blood–brain barrier

FJB:

Fluorojade B

Li-Pi:

Lithium pilocarpine

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Acknowledgements

This work was supported by the Department of Biotechnology (DBT), India. Research fellowship was provided by the Council of Scientific & Industrial Research (CSIR), India.

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  1. Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India

    Sree Lalitha Bojja, Shashi Anand & Ranjana W. Minz

  2. Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India

    Bikash Medhi & Rupa Joshi

  3. Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India

    Alka Bhatia

  4. Department of Pharmacology, Manipal College of Pharmaceutical Sciences, MAHE, Manipal, Karnataka, 576104, India

    Sree Lalitha Bojja

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Bojja, S.L., Medhi, B., Anand, S. et al. Metformin ameliorates the status epilepticus- induced hippocampal pathology through possible mTOR modulation. Inflammopharmacol 29, 137–151 (2021). https://doi.org/10.1007/s10787-020-00782-8

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