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Benzamide protects delayed neuronal death and behavioural impairment in a mouse model of global cerebral ischemia
D Kumaran1, M Udayabanu, R Unnikrishnan Nair
1Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi 110007, India.
Abstract:
The present study is aimed at evaluating the functional and neuroprotective effect of benzamide, a poly-(ADP-ribose) polymerase (PARP) inhibitor on delayed neuronal death (DND) in hippocampus CA1 region and memory impairment following global cerebral ischemia (GCI) in a mouse model. GCI was induced by bilateral common carotid artery occlusion (BCAo) for 20 min followed by reperfusion for 9 days. Postischemic continuous treatment with benzamide (160 mg/kg b w i.p. for 9 days) significantly reversed the GCI-induced anterograde memory impairment in passive avoidance step through and elevated plus maze tasks. The observed memory impairment in vehicle treated ischemia group was found to be well correlated with DND and downregulation of cholinergic muscarinic receptor-1 expression, which was possibly mediated by inflammation and apoptosis, as revealed from inducible nitric oxide synthase (iNOS) expression and number of TUNEL positive neurons in hippocampus CA1 region. It is clear from the present experiment that benzamide treatment significantly decreases the iNOS expression and number of apoptotic neurons and thereby improves the neuronal survival and memory during GCI. Our present findings provide compelling evidence that multiple doses of benzamide treatment is a promising therapeutic approach for cerebrovascular and neurodegenerative diseases, which deserves further clinical evaluation.
Insights
Benzamide, a PARP inhibitor, protects against delayed neuronal death and memory loss after global cerebral ischemia in mice. This neuroprotective effect improves neuronal survival and memory, showing therapeutic potential for brain injury and neurodegenerative diseases.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Global cerebral ischemia (GCI) can cause delayed neuronal death (DND) and memory impairment.
- Poly-(ADP-ribose) polymerase (PARP) activation is implicated in neuronal death following ischemia.
Purpose of the Study:
- To evaluate the neuroprotective and functional effects of benzamide, a PARP inhibitor, on DND and memory deficits after GCI in a mouse model.
- To investigate the mechanisms underlying benzamide's effects, including inflammation and apoptosis.
Main Methods:
- GCI was induced in mice via bilateral common carotid artery occlusion followed by reperfusion.
- Mice received continuous postischemic treatment with benzamide (160 mg/kg) or vehicle for 9 days.
- Memory function was assessed using passive avoidance and elevated plus maze tasks.
- Hippocampus CA1 region was analyzed for neuronal death, inducible nitric oxide synthase (iNOS) expression, and TUNEL-positive cells.
Main Results:
- Benzamide treatment significantly reversed GCI-induced memory impairment.
- Memory deficits in the vehicle group correlated with DND, inflammation (iNOS expression), and apoptosis (TUNEL-positive neurons).
- Benzamide treatment decreased iNOS expression and the number of apoptotic neurons, improving neuronal survival.
Conclusions:
- Benzamide demonstrates significant neuroprotective effects against DND and memory impairment following GCI.
- Benzamide's mechanism involves reducing inflammation and apoptosis, thereby enhancing neuronal survival.
- Benzamide is a promising therapeutic candidate for cerebrovascular and neurodegenerative diseases, warranting further clinical investigation.
