Neuroprotective effects of diazoxide and its antagonism by glibenclamide in pyramidal neurons of rat hippocampus subjected to ischemia-reperfusion-induced injury.
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.
Zarch
Anoushiravan Vakili
AV
Department of Pharmacology, Tehran University School of Medicine 13145-784, Tehran, Iran.
Toroudi
Hamidreza Pazoki
HP
Soleimani
Mansooreh
M
Bakhtiarian
Azam
A
Katebi
Majid
M
Djahanguiri
Bijan
B
D000818:Animals; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D003981:Diazoxide / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D004232:Diuretics / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D019254:Genes, bcl-2 / Q000187:drug effects; D005905:Glyburide / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D054086:KATP Channels / Q000819:agonists; D008297:Male; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D018696:Neuroprotective Agents; D017966:Pyramidal Cells / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D051028:bcl-2-Associated X Protein / Q000235:genetics
D004232:Diuretics; D007004:Hypoglycemic Agents; D054086:KATP Channels; D018696:Neuroprotective Agents; D051028:bcl-2-Associated X Protein; D003981:Diazoxide; D005905:Glyburide