Abstract 29: Neuroprotective Potential of Nitroglycerin (GTN) in Ischemic Stroke: Insights Into Glucose Metabolism and ER Stress Inhibition Through NO-CGMP-PKG Signaling

Abstract

Background: While Nitroglycerin (GTN) is predominantly recognized as a vasodilator for ischemic heart disease, its potential neuroprotective properties in acute ischemic stroke (AIS) remain under exploration. This investigation sought to discover the therapeutic advantages of GTN post-recanalization in AIS and underlying mechanisms. Methods: Adult male Sprague Dawley rats were categorized into sham, MCAO with or without GTN treatment, and MCAO treated with both GTN and KT5823, an inhibitor of cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG). AIS was induced by MCAO for 2 hours followed by 6 or 24 hours of reperfusion (tMCAO). A 28-hour MCAO without reperfusion was defined as the permanent MCAO group (pMCAO). The study assessed infarct volumes, neurological impairments, glucose metabolism metrics (lactate and ROS levels), nitric oxide (NO) and cGMP levels (via ELISA). mRNA and protein expressions of hyperglycolysis (GLUT1, GLUT3, PFK, LDH), gluconeogenesis (PCK1, PCK2), ER stress (BIP, PERK, EIF2α, ATF4, CHOP) as well as signaling molecules (PKG, AMPK), were measured with RT-PCR and Western blotting. Apoptotic cell death was evaluated using TUNEL. Results: GTN significantly reduced cerebral infarct volumes, neurological deficits, apoptotic cell death, lactate and ROS levels and decreased the expression of NO and cGMP levels and key glucose metabolism and ER stress-related genes and proteins, including GLUT1, GLUT3, PFK1, LDH, PCK1, PCK2, BIP, PERK, EIF2α, ATF4, CHOP and phosphorylated AMPK, while boosting PKG expression only in tMCAO. The coadministration of GTN and KT5823 reversed the observed GTN benefits. Conclusion: Our findings illuminate that GTN showcases neuroprotective properties in tMCAO (but not pMCAO) by enhancing glucose metabolism (hyperglycolysis and gluconeogenesis), controlling ER stress, and working through the NO-CGMP-PKG signaling cascade to inhibit AMPK phosphorylation.