Neuroprotection by the novel calcium antagonist PCA50938, nimodipine and flunarizine, in gerbil global brain ischemia

Zapater, Pedro; Moreno, Joaquín Melgarejo; Horga, J.F.

doi:10.1016/s0006-8993(97)00838-x

Cited by 37 publications

(16 citation statements)

References 17 publications

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“…Intracellular calcium accumulation plays a pivotal role in the development of ischemic neuronal death. A reduction of ischemic damage after administration of nimodipine was repeatedly observed in experimental focal and global cerebral ischemia [17,41,51,64,70,73]. The neuroprotective mechanism of nimodipine is attributed to the reduction of increased cytosolic Ca 2+ concentration as an important trigger in the development of necrotic ischemic cell death.…”

Section: Discussionmentioning

confidence: 96%

Treatment with nimodipine or mannitol reduces programmed cell death and infarct size following focal cerebral ischemia

et al. 2000

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The present study was conducted to evaluate the effects of nimodipine and mannitol on infarct size and on the amount of apoptosis after transient focal cerebral ischemia. Focal cerebral ischemia was induced in male Sprague-Dawley rats (weight 300-380 g) by transient occlusion of the right middle cerebral artery (MCAO) using an intraluminal thread model. All animals underwent ischemia for 2 h, followed by 24 h of reperfusion. Group I (n=16) was untreated. Group II (n=16) received 15% mannitol (1 g/kg as bolus) and group III (n=9) received 15 microg/kg/h nimodipine intravenously beginning 15 min prior to MCAO. Twenty-four hours after reperfusion, the brain was taken and sectioned in coronal slices. The slices were stained with H&E and with the transferase dUTP nick-end labeling (TUNEL) technique. Histopathological analysis revealed a significant (P<0.05) decrease in infarct size in the striatum with both drugs: mannitol (group II) 25.4+/-5.9% and nimodipine (group III) 21.5+/-11.0% versus control (group I) 34.9+/-7.0% and in the cortex 2.7+/-2.0% (group II) and 6.3+/-2.4% (group III) versus control 14.4+/-9.0% (group I). The number of apoptotic cells was statistically lower in the therapy groups (group III 9.6, group II 25.8) versus control (group I 57.9) (Mann-Whitney-Wilcoxon U-test Z>1.96, P<0.05). This study indicates that mannitol and nimodipine provide neuroprotection by preventing both the necrotic and apoptotic components of cell death after transient focal cerebral ischemia and may be effective as neuroprotective drugs for cerebrovascular surgery.

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Section: Discussionmentioning

confidence: 96%

Treatment with nimodipine or mannitol reduces programmed cell death and infarct size following focal cerebral ischemia

et al. 2000

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“…L-type calcium channel blockers have also been shown to be neuroprotective in subarachnoid hemorrhage (SAH) and to a lesser degree in intracerebral hemorrhage (ICH) [39]. Clinically, nimodipine is used as a vasodilator for the treatment of vasospasm in aneurysmal SAH [40].…”

Section: Discussionmentioning

confidence: 99%

Voltage-gated Calcium Channels Provide an Alternate Route for Iron Uptake in Neuronal Cell Cultures

et al. 2007

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Recent studies suggest that iron enters cardiomyocytes via the L-type voltage-gated calcium channel (VGCC). The neuronal VGCC may also provide iron entry. As with calcium, extraneous iron is associated with the pathology and progression of neurodegenerative diseases such as Parkinson's and Alzheimer's disease. VGCCs, ubiquitously expressed, may be an important route of excessive entry for both iron and calcium, contributing to cell toxicity or death. We evaluated the uptake of (45)Ca(2+) and (55)Fe(2+) into NGF-treated rat PC12, and murine N-2alpha cells. Iron not only competed with calcium for entry into these cells, but iron uptake (similar to calcium uptake) was inhibited by nimodipine, a specific L-type VGCC blocker, and enhanced by FPL 64176, an L-VGCC activator, in a dose-dependent manner. Taken together, these data suggest that voltage-gated calcium channels are an alternate route for iron entry into neuronal cells under conditions that promote cellular iron overload toxicity.

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“…L-type calcium channel antagonists, specifically nimodipine, are used clinically as vasodilators for the treatment of secondary arterial vasospasm after aneurysmal subarachnoid hemorrhage and intracerebral hemorrhage [44]. During vascular hemorrhages heme is deposited into the extracellular space [7] at near millimolar concentrations [45], and free iron levels within the cerebral spinal fluid are significantly elevated and not cleared for at least 28 days [46].…”

Section: Discussionmentioning

confidence: 99%

Differential Effect of Nimodipine in Attenuating Iron-Induced Toxicity in Brain- and Blood–Brain Barrier-Associated Cell Types

et al. 2011

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Metal homeostasis is increasingly being evaluated as a therapeutic target in stroke and neurodegenerative diseases. Metal dysregulation has been shown to lead to protein aggregation, plaque formation and neuronal death. In 2007, we first reported that voltage-gated calcium channels act as a facile conduit for the entry of free ferrous (Fe(2+)) ions into neurons. Herein, we evaluate differential iron toxicity to central nervous system cells and assess the ability of the typical L-type voltage-gated calcium channel blocker nimodipine to attenuate iron-induced toxicity. The data demonstrate that iron sulfate induces a dose-dependent decrease in cell viability in rat brain endothelial cells (RBE4; LC(50) = 150 μM), neuronal cells (Neuro-2α neuroblastoma; LC(50) = 400 μM), and in astrocytes (DI TNC1; LC(50) = 1.1 mM). Pre-treatment with nimodipine prior to iron sulfate exposure provided a significant (P < 0.05) increase in viable cell numbers for RBE4 (2.5-fold), Neuro2-α (~2-fold), and nearly abolished toxicity in primary neurons. Astrocytes were highly resistant to iron toxicity compared to the other cell types tested and nimodipine had no (P > 0.05) protective effect in these cells. The data demonstrate variable susceptibility to iron overload conditions in different cell types of the brain and suggest that typical L-type voltage-gated calcium channel blockers (here represented by nimodipine), may serve as protective agents in conditions involving iron overload, particularly in cell types highly susceptible to iron toxicity.

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Neuroprotection by the novel calcium antagonist PCA50938, nimodipine and flunarizine, in gerbil global brain ischemia

Cited by 37 publications

References 17 publications

Treatment with nimodipine or mannitol reduces programmed cell death and infarct size following focal cerebral ischemia

Treatment with nimodipine or mannitol reduces programmed cell death and infarct size following focal cerebral ischemia

Voltage-gated Calcium Channels Provide an Alternate Route for Iron Uptake in Neuronal Cell Cultures

Differential Effect of Nimodipine in Attenuating Iron-Induced Toxicity in Brain- and Blood–Brain Barrier-Associated Cell Types

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