Dapsone prolong delayed excitotoxic neuronal cell death by interacting with proapoptotic/survival signaling proteins

• Published in: Journal of stroke and cerebrovascular diseases Vol. 29; no. 8; p. 104848
• Main Authors: Mahale, Ashutosh, Kumar, Rakesh, Sarode, Lopmudra P., Gakare, Sukanya, Prakash, Anand, Ugale, Rajesh R.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.08.2020
• Subjects: Cell survival proteins; Dapsone; Glutamate excitotoxicity; Ischemic reperfusion injury; MCAO; Proapoptotic protiens; Stroke; MCAO; Stroke; Dapsone; Proapoptotic protiens; Cell survival proteins; Ischemic reperfusion injury; Glutamate excitotoxicity
• ISSN: 1052-3057; 1532-8511
• DOI: 10.1016/j.jstrokecerebrovasdis.2020.104848

Dapsone prevents ischemic injury, inhibits apoptosis and shows functional improvement post-ischemia. However, its effect on proapoptotic or survival proteins in delayed ischemia remains unclear. Male adult Wistar rats were subjected to middle cerebral artery occlusion (MCAO) for 90 min followed by 24 h of ischemic reperfusion (I/R). Dapsone [9.375 or 12.5 mg/kg, intraperitoneally (IP)] was administered at 3, 6 and 12 h of I/R followed by behavioural assessment, brain infarction, histological alteration and cell viability study. Further, dapsone (25 and 50 µM) was added at 3, 6 and 12 h after L-glutamate (100 µM) in primary cortical culture (DIV 14) and cell viability, cytotoxicity, apoptosis was observed. Proteins expression were observed using immunocytochemistry. All experiments were performed after 24 h of I/R (In-Vivo) and 24 h of recovery post glutamate insult (In-Vitro). Reduced brain infarction, improved neurobehavioural functions in addition to reduction in abnormal morphological structures of ischemic brain and improvement in cell viability was observed with treatment of dapsone (12.5 mg/kg) administered upto 6 h. Similarly, dapsone (25, 50 µM) increased cell survival post glutamate insult in cortical culture (In-vitro). Further, dapsone treatment at delayed hours (6 h) reduced apoptotic nuclei and proapoptotic proteins JNK, PTEN, Calpain, Caspase 3 expression along with activation of prosurvival protein BDNF expression post-glutamate insult. Our results suggest that dapsone has the potential to limit the neuronal damage post-glutamate insult in delayed hours (6 h) through repressing proapoptotic proteins JNK, PTEN, Calpain, Caspase-3 of cerebral ischemia along with activation of pro-survival protein BDNF.