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17 November 2016 : Animal Research

Garcinol Upregulates GABAA and GAD65 Expression, Modulates BDNF-TrkB Pathway to Reduce Seizures in Pentylenetetrazole (PTZ)-Induced Epilepsy

Fang HaoABCDEF, Li-Hua JiaABCDEF, Xiao-Wan LiBCDF, Ying-Rui ZhangBDF, Xue-Wu LiuABDEF

DOI: 10.12659/MSM.897579

Med Sci Monit 2016; 22:4415-4425

Abstract

BACKGROUND: Epilepsy is the most predominant neurological disorder characterized by recurrent seizures. Despite treatment with antiepileptic drugs, epilepsy still is a challenge to treat, due to the associated adverse effects of the drugs. Previous investigations have shown critical roles of BDNF-TrkB signalling and expression of glutamic acid decarboxylase 65 (GAD65) and GABAA in the brain during epilepsy. Thus, drugs that could modulate BDNF-TrkB signal and expression of GAD65 and GABAA could aid in therapy. Recent experimental data have focussed on plant-derived compounds in treatments. Garcinol (camboginol), is a polyisoprenylated benzophenone derived from the fruit of Garcinia indica. We investigated the effects of garcinol in pentylenetetrazole (PTZ)-induced epileptic models.

MATERIAL AND METHODS: Seizure scores were measured in epilepsy kindled mice. Neuronal degeneration and apoptosis were assessed by Nissl staining, TUNEL assay, and Fluoro-Jade B staining. Immunohistochemistry was performed to evaluate cleaved caspase-3 expressions. Expression of BDNF, TrkB, GABAA, GAD65, Bad, Bcl-2, Bcl-xL, and Bax were determined by western blots.

RESULTS: Significantly reduced seizure scores and mortality rates were observed with pretreatment with garcinol. Elevated expression of apoptotic proteins and caspase-3 in kindled mice were effectively downregulated by garcinol. Epileptogenic mice presented increased BDNF and TrkB with considerably decreased GABAA and GAD65 expression. Garcinol significantly enhanced GABAA and GAD65 while it suppressed BDNF and TrkB. Garcinol enhanced the performance of mice in Morris water maze tests.

CONCLUSIONS: Garcinol exerts neuroprotective effects via supressing apoptosis and modulating BDNF-TrkB signalling and GAD65/GABAA expressions and also enhanced cognition and memory of the mice.

Keywords: Apoptosis - drug effects, Anticonvulsants - pharmacology, Animals, Brain-Derived Neurotrophic Factor - metabolism, Epilepsy - metabolism, Glutamate Decarboxylase - metabolism, Memory - drug effects, Mice, Mice, Inbred C57BL, Neuroprotective Agents - metabolism, Pentylenetetrazole, Receptor, trkB - metabolism, Receptors, GABA-A - metabolism, Signal Transduction - physiology, Terpenes - pharmacology, Up-Regulation - drug effects

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750