The neurotoxic effect of long-term use of high-dose Pregabalin and the role of alpha tocopherol in amelioration: implication of MAPK signaling with oxidative stress and apoptosis

Abstract

Pregabalin abuse has become an emerging concern; thus, the current study has been designed to study the neurotoxic hazards of prolonged high-dose of pregabalin (akin to that abused by addicts) and to evaluate the effect of alpha tocopherol as a possible ameliorating agent. The current study evaluated the brain neurotransmitters; dopamine, glutamate, and norepinephrine. The study also assessed the expression of the apoptosis-related markers Bax, Bcl2, and caspase 3. Western-blotted analysis of the three major mitogen-activated protein kinases (MAPKs), the c-JUN N-terminal kinase (JNK), the p38 MAPK, and the extracellular signal-regulated kinase (ERK), has also been performed. The study also evaluated oxidative stress via assessment of the cortical tissue levels of reduced glutathione and malondialdehyde and the activity of superoxide dismutase. Histopathological examination and histomorphometric evaluation of the darkly degenerated cortical neurons have also been performed. Pregabalin in high doses (150 mg/kg/day and 300 mg/kg/day) disrupted the ERK/JNK/p38-MAPK signaling, reversed the bax/bcl2 ratio, and induced oxidative stress. It also diminished the release of dopamine, glutamate, and norepinephrine and increased the count of degenerated neurons. Alpha tocopherol treatment significantly attenuated the deleterious effects induced by pregabalin. The role of alpha tocopherol in ameliorating the oxidative stress injury, and apoptosis induced by pregabalin, along with its role in normalizing neurotransmitters, modulating the ERK/JNK/p38-MAPK signaling pathways and improving the histopathological cortical changes, offers alpha tocopherol as a promising adjunctive therapy in patients undergoing prolonged pregabalin therapy as those suffering from prolonged seizures and neuropathies.

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S.H.T. performed the experimental work, wrote, and revised the manuscript. H.S.Z. shared in designing the protocol of the work with interpretation of data. A.A.A. developed the research idea, supervised the experiment execution, and revised the manuscript. I.F.G. wrote and revised the manuscript. L.A. R. performed the biochemical analysis, wrote, and revised the manuscript. B.E.A. performed the histopathological analysis with data interpretation, wrote, and revised the manuscript.

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Correspondence to Basma Emad Aboulhoda.

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The study complies with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH Publications No. 8023, revised 1978) and is approved by the Ethical Committee, Faculty of Medicine, Cairo University and Cairo University Institutional Animal Care and Use Committee (CU- IACUC).

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Taha, S.H.N., Zaghloul, H.S., Ali, A.A.E.R. et al. The neurotoxic effect of long-term use of high-dose Pregabalin and the role of alpha tocopherol in amelioration: implication of MAPK signaling with oxidative stress and apoptosis. Naunyn-Schmiedeberg's Arch Pharmacol 393, 1635–1648 (2020). https://doi.org/10.1007/s00210-020-01875-5

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Keywords

  • Pregabalin
  • Alpha tocopherol
  • Cerebral cortex
  • Oxidative stress
  • Neurotransmitters