Neuroprotective Effects of Diazoxide and Its Antagonism by Glibenclamide in Pyramidal Neurons of Rat Hippocampus Subjected to Ischemia-Reperfusion-Induced Injury

• Published in: International journal of neuroscience Vol. 119; no. 9; pp. 1346 - 1361
• Main Authors: Zarch, Anoushiravan Vakili, Toroudi, Hamidreza Pazoki, Soleimani, Mansooreh, Bakhtiarian, Azam, Katebi, Majid, Djahanguiri, Bijan
• Format: Journal Article
• Language: English
• Published: England Informa UK Ltd 2009; Taylor & Francis
• Subjects: Animals; bcl-2-Associated X Protein - genetics; Blotting, Western; Cell Death - drug effects; diazoxide; Diazoxide - antagonists & inhibitors; Diazoxide - pharmacology; Diuretics - pharmacology; Gene Expression - drug effects; Genes, bcl-2 - drug effects; glibenclamide; Glyburide - pharmacology; hippocampus; Hippocampus - cytology; Hippocampus - drug effects; Hypoglycemic Agents - pharmacology; ischemia reperfusion injury; KATP Channels - agonists; Male; Microscopy, Electron; Mitochondria - drug effects; Mitochondria - ultrastructure; neuroprotection; Neuroprotective Agents; Pyramidal Cells - drug effects; rat; Rats; Rats, Wistar; Reperfusion Injury - pathology; Reperfusion Injury - prevention & control
• ISSN: 0020-7454; 1563-5279; 1543-5245
• DOI: 10.1080/00207450802338721

Mitochondrial ATP-sensitive potassium channel opener, diazoxide, is shown to have protective effect on the heart and brain following ischemia-reperfusion-induced injury (IR/II). However, the detailed effect of diazoxide and its antagonist on neuronal death, mitochondrial changes, and apoptosis in cerebral IR/II has not fully studied. IR/II was induced in rats by the 4-vessel occlusion model. Neuronal cell death and mitochondrial changes in CA1-CA4 pyramidal cells of the hippocampus were studied by light and electron microscopy, respectively. Apoptosis was assessed by measuring the amount of protein expressed by Bax and Bcl-2 genes. In light microscopy studies, the number of total and normal cells were increased only following 18 mg/kg of diazoxide. Lower doses (2 and 6 mg/kg) failed to change the cell numbers. All three doses of glibenclamide (1, 5, and 25 mg/kg) decreased the number of total and normal cell populations. In electron microscopy studies, different doses of diazoxide and glibenclamide prevented and aggravated the IR-induced morphological changes, respectively. Western blot analysis showed that diazoxide and glibenclamide inhibited and enhanced Bax protein expression respectively. Regarding Bcl-2 expression, only diazoxide showed a significant enhancement of gene expression. In conclusion, the results show that diazoxide can exhibit neuroprotective effects against IR/II in hippocampal regions, possibly through the opening of mitochondrial ATP-sensitive K+ channels.