title: L-type calcium channel blocker ameliorates diabetic encephalopathy by modulating dysregulated calcium homeostasis.
abstract: Diabetic encephalopathy is a complication of diabetes characterized by impaired cognitive functions. The objective of the present study was to examine the beneficial effect of the calcium channel blocker, nimodipine, on diabetes-induced cognitive deficits and altered calcium homeostasis in the cerebral cortex. Diabetes was induced in mice by intraperitoneal injection of streptozotocin (40 mg/kg body wt) for 5 days. Nimodipine (10 mg/kg body weight) was administered intraperitoneally to the animals every 48 hr for 8 weeks. A significant impairment in spatial learning and memory was observed in diabetic animals, which was reversed by nimodipine treatment. Diabetic animals showed increased CaV1.2 mRNA and protein expression, which might be responsible for enhanced synaptosomal calcium uptake. Nimodipine treatment was found to lower CaV1.2 mRNA, protein expression, and calcium uptake. Mitochondrial Ca(2+) uptake was reduced in diabetic brains, which was reversed with nimodipine treatment. Plasma membrane and sarcoplasmic reticulum Ca(2+) -ATPase activity was found to be significantly decreased in diabetic animals, whereas nimodipine supplementation restored the activity of both Ca(2+) -ATPases nearly to control values. Nimodipine treatment was shown to normalize intracellular free Ca(2+) levels in diabetic animals. Nimodipine was shown to attenuate increased calpain activity measured in terms of hydrolysis of fluorogenic substrate and αII-spectrin degradation. Nimodipine supplementation also reduced reactive oxygen species production and lipid peroxidation in diabetic animals. The data suggests that L-type calcium channel blocker is beneficial in preventing cognitive deficits associated with diabetic encephalopathy through modulation of dysregulated calcium homeostasis.
authors.affiliation: Department of Biochemistry, Panjab University, Chandigarh, India.
authors.forename: Kirti
authors.initials: K
authors.lastname: Singhal
authors.forename: Rajat
authors.initials: R
authors.lastname: Sandhir
mesh_terms: D000818:Animals; D001786:Blood Glucose; D001921:Brain / Q000187:drug effects / Q000648:ultrastructure; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D004268:DNA-Binding Proteins; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D006706:Homeostasis / Q000187:drug effects*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008565:Membrane Proteins; D051379:Mice; D009553:Nimodipine / Q000627:therapeutic use*; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species / Q000378:metabolism; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D001786:Blood Glucose; C410225:CHERP protein, human; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D004268:DNA-Binding Proteins; C419385:L-type calcium channel alpha(1C); D008565:Membrane Proteins; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; D009553:Nimodipine; D002154:Calpain; D000252:Calcium-Transporting ATPases; D002118:Calcium
keywords: L-type calcium channel blocker; calcium; calpain; diabetic encephalopathy; nimodipine