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.

A Novel Role for the Calcium Sensing Receptor in Rat Diabetic Encephalopathy

“…Studies of streptozotocin (STZ)-induced diabetes in rats have demonstrated neurobehavioral deficits using the Morris water maze, which is associated with impaired hippocampal long-term potentiation [4]. The multifaceted pathogenesis of diabetic encephalopathy is not yet completely understood, but classical factors such as an imbalance in Ca 2+ homeostasis [5] may contribute to the pathology of diabetic encephalopathy. In the CNS, Ca 2+ acts as a second messenger and is known to be associated with almost every cellular event, including ion channel function, cellular proliferation and migration, neurotransmitter secretion, axon pathfinding, and dendritic outgrowth.…”

Substantiated therapy of pre-dementia cognitive impairment with calcium-channel blockers

“…Недавнее исследование показало способность нимодипина не просто улучшать мозговое кровообращение пациентов после субарахноидального кровоизлияния, но и восстанавливать ишемически поврежденные нейроны и когнитивные функции [30]. Данные других исследований [31,32] свидетельствуют о том, что блокатор кальциевых каналов L-типа нимодипин полезен для предотвращения когнитивных нарушений, связанных с диабетической энцефалопатией, посредством модуляции нарушенного гомеостаза кальция. Предварительные исследования показывают, что нимодипин может также улучшать кальций-зависимые формы синаптической пластичности в гиппокампе крыс с диабетом и его введение животным с диабетом снижает выработку активных форм кислорода и перекисное окисление липидов [32].…”

The Plasma Membrane Calcium ATPasesand Their Role as Major New Players in Human Disease

“…For example, basolateral membrane vesicles isolated from syncytiotrophoblast of insulin-dependent diabetic patients display increased PMCA activity (359), while reduced PMCA activity or expression has been identified in parotid and submandibular salivary glands, kidney, and brain synaptosomes of streptozotocin-induced diabetic rats (260,347,421).…”