Abstract
Effective pharmacological neuroprotection is one of the most desired aims in modern medicine. We postulated that a combination of two clinically used drugs—nimodipine (L-Type voltage-gated calcium channel blocker) and amiloride (acid-sensing ion channel inhibitor)—might act synergistically in an experimental model of ischaemia, targeting the intracellular rise in calcium as a pathway in neuronal cell death. We used organotypic hippocampal slices of mice pups and a well-established regimen of oxygen-glucose deprivation (OGD) to assess a possible neuroprotective effect. Neither nimodipine (at 10 or 20 µM) alone or in combination with amiloride (at 100 µM) showed any amelioration. Dissolved at 2.0 Vol.% dimethyl-sulfoxide (DMSO), the combination of both components even increased cell damage (p = 0.0001), an effect not observed with amiloride alone. We conclude that neither amiloride nor nimodipine do offer neuroprotection in an in vitro ischaemia model. On a technical note, the use of DMSO should be carefully evaluated in neuroprotective experiments, since it possibly alters cell damage.
Highlights
Despite years of research pharmacological neuroprotection remains challenging
Beside calcium influx via glutamate receptor overactivation, calcium influx may occur via voltage-gated calcium channels (VGCC) located within neuronal membranes
We investigated the possible neuroprotective effect of two clinically used drugs, which both block calcium channels: The L-type calcium channel inhibitor nimodipine and the acid-sensing ion channel (ASIC1a) blocker amiloride
Summary
Neuronal cell death represents the smallest common denominator occurring within the pathophysiological cascade of acute cerebrovascular or traumatic brain diseases. The pathomechanisms of neuronal cell death are yet to be fully understood, one of the first and most frequently investigated events is the elevation of intracellular calcium concentration. Elevated intracellular calcium represents a central part within the early phenomenon of excitotoxicity as well as all the pathways resulting in or from these raised ion concentrations [3,4,5,6,7]. Various drugs blocking the excitotoxicity-induced calcium influx have failed to show effective neuroprotection in the first place or failed in overcoming the translational roadblock from in vivo or animal in vitro experiments to actual clinical application (e.g., trials of glutamate-receptor antagonists) [8,9]. VGCCs are expressed by vascular smooth muscle cells responsible for intracellular calcium rise and vasoconstriction when activated
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