Nimodipine Exerts Time-Dependent Neuroprotective Effect after Excitotoxical Damage in Organotypic Slice Cultures

Abstract

During injuries in the central nervous system, intrinsic protective processes become activated. However, cellular reactions, especially those of glia cells, are frequently unsatisfactory, and further exogenous protective mechanisms are necessary. Nimodipine, a lipophilic L-type calcium channel blocking agent is clinically used in the treatment of aneurysmal subarachnoid haemorrhage with neuroprotective effects in different models. Direct effects of nimodipine on neurons amongst others were observed in the hippocampus as well as its influence on both microglia and astrocytes. Earlier studies proposed that nimodipine protective actions occur not only via calcium channel-mediated vasodilatation but also via further time-dependent mechanisms. In this study, the effect of nimodipine application was investigated in different time frames on neuronal damage in excitotoxically lesioned organotypic hippocampal slice cultures. Nimodipine, but not nifedipine if pre-incubated for 4 h or co-applied with NMDA, was protective, indicating time dependency. Since blood vessels play no significant role in our model, intrinsic brain cell-dependent mechanisms seems to strongly be involved. We also examined the effect of nimodipine and nifedipine on microglia survival. Nimodipine seem to be a promising agent to reduce secondary damage and reduce excitotoxic damage.

Nimodipine Protects Vascular and Cognitive Function in an Animal Model of Cerebral Small Vessel Disease

“… 44 It is therefore noteworthy that apart from reducing blood pressure, nimodipine is directly protective to neurons, 16 and anti-inflammatory effects in reducing astrocyte and microglial activation, 16 with protective effects on pericytes and oligodendrocytes. 16 , 45 Even in vitro, where effects on blood flow are not involved, nimodipine still shows cell type–independent suppression of stress-dependent apoptosis, 46 and protection of tissue slices 47 and the neurovascular unit. 48 In summary, it is likely that the mechanisms underlying the neuroprotective effects of nimodipine are multifactorial.…”

“…Interestingly, it appears that nimodipine has particular benefits that are not necessarily shared by other dihydropyridine calcium channel–blocking agents. 47 Thus, the protective effects of nimodipine are not adequately reproduced by nifedipine in slice cultures, 49 or by nicardipine in a systematic review. 50 Indeed, although nimodipine is used to improve outcome in subarachnoid hemorrhage on the basis that it avoids delayed vasoconstriction, the actual mechanism of action is now being re-evaluated since other interventions that successfully target angiographic vasospasm have not improved outcomes.…”

Neuroprotection: Rescue from Neuronal Death in the Brain 2.0

“…Nimodipine is a lipophilic L-type calcium channel blocker and a potent cerebral vasodilator. Hohmann et al [ 6 ] investigated the neuroprotective effect of nimodipine on excitotoxic injuries in organotypic hippocampal slice cultures (OHSCs) and found that nimodipine reduced the impact of the injury in OHSCs when they were co-applied with NMDA, indicating the neuroprotective effect on excitotoxic injuries in the hippocampus.…”