The neurotoxic effect of long-term use of high-dose Pregabalin and the role of alpha tocopherol in amelioration: implica
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ORIGINAL ARTICLE
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 Sarah Hamed N. Taha 1 & Hala Saied Zaghloul 1 & Abla Abd El Rahman Ali 1 & Iman Fawzy Gaballah 1 & Laila Ahmed Rashed 2 & Basma Emad Aboulhoda 3 Received: 1 January 2020 / Accepted: 17 April 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
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. Keywords Pregabalin . Alpha tocopherol . Cerebral cortex . Oxidative stress . Neurotransmitters
Introduction Pregabalin [(S)-3-(aminomethyl)-5-methylhexanoic acid], one of the newest anti-epileptic drugs, is a novel lipophilic gamma-aminobutyric acid (GABA) analogue designed to diffuse across the blood brain barrier to act as a central neuromodulating agent via selectively binding to the * Basma Emad Aboulhoda [email protected] 1
Department of Forensic Medicine & Clinical Toxicology, Faculty of Medicine, Cairo University, Cairo, Egypt
2
Department of Medical Biochemistry & Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt
3
Department of Anatomy and Embryology, Faculty of Medicine, Cairo University, Cairo, Egypt
alpha 2 delta subunits of pre-synaptic
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