Butanol Extract of Tinospora cordifolia Ameliorates Cognitive Deficits Associated with Glutamate-Induced Excitotoxicity: A Mechanistic Study Using Hippocampal Neurons
Overstimulation of glutamate receptors leads to development of excitotoxicity, which is implicated as final destructive pathway in neurodegenerative diseases. Development of alternative therapeutic strategies effective against glutamate-induced excitotoxicity is much in demand. Herbal drug development is emerging as a major research area for the treatment of various debilitating diseases due to multimodal action and least side effects of herbal products. The current study was aimed to investigate neuroprotective potential of butanol extract of Tinospora cordifolia (B-TCE) against glutamate-induced excitotoxicity using primary hippocampal neurons as in vitro and Wistar strain albino rats as in vivo model systems. Molecular and behavioral parameters were studied to elucidate the underlying mechanism of beneficial effects of B-TCE. B-TCE treatment was also effective in prevention of anxiety, cognition, and motor-coordination deficits induced by glutamate. B-TCE pre-treatment protected the hippocampal neurons from glutamate-induced neurodegeneration and impaired plasticity. At molecular level, B-TCE was observed to attenuate overactivation of glutamate receptors. B-TCE promoted upregulation of ERK and AKT pathways of synaptic plasticity and cell survival in the hippocampus region of brain. This study provides first evidence of neuroprotective potential of B-TCE against glutamate-induced excitotoxicity in hippocampus region and suggests that B-TCE may act as a potential candidate for neuroprotective therapeutic approaches. A single compound ‘tinosporicide’ was further isolated from B-TCE, which was found to be effective at 800× lower concentration against glutamate-induced neurodegeneration under in vitro conditions.
KeywordsHippocampus Tinospora cordifolia Synaptic plasticity Glutamate Excitotoxicity Tinosporicide
AS, SK, and PB are thankful to Department of Science and Technology (DST), New Delhi, India for their Research Fellowship. HS is thankful to UGC, India for his research fellowship. Infrastructure provided by University grants commission (UGC), India under UPE and CPEPA schemes and DBT under DISC scheme is highly acknowledged. Dr. Bikram Singh (Institute of Himalyan Bioresource Technology), Dr. Amrita K. Cheema, Ms. Kirandeep Gill (Georgetown University, USA), and Dr. Shreyans Jain (IIT-BHU, Varanasi) are deeply acknowledged for their kind support to characterize the compound. Ms. Muskan Gupta, Dr. Taranjeet Kaur, and Dr. Shaffi Manchanda are acknowledged for their technical help during experimental study.
AS and GK designed the study. AS conducted the experiments and analyzed data. SK, PB, and HS performed behavioral studies and analyzed the behavioral data. Manuscript was written by AS and GK. Funding to carry out the reported work was provided by GK. All the authors reviewed and approved the final manuscript.
This work was funded by Department of Biotechnology (DBT), GOI to Prof. Gurcharan Kaur [BT/PR12200/MED/30/1439/2014]. The funding agencies had no role in design of study, data collection and interpretation, manuscript preparation, and decision to publish the study.
Compliance with Ethical Standards
Conflict of interest
Authors declare no conflict of interest.
All procedures performed in studies involving animals were in accordance with the ethical standards of the Institutional Animal Ethical Committee, Guru Nanak Dev University, Amritsar registered to “Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), GOI” (Registration no. 226/CPCSEA) (permission number 226/CPCSEA/2017/01).
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