Investigation of the Neuroprotective Impact of Nimodipine on Neuro2a Cells by Means of a Surgery-Like Stress Model

Abstract

Nimodipine is well characterized for the management of SAH (subarachnoid hemorrhage) and has been shown to promote a better outcome and less DIND (delayed ischemic neurological deficits). In rat experiments, enhanced axonal sprouting and higher survival of motoneurons was demonstrated after cutting or crushing the facial nerve by nimodipine. These results were confirmed in clinical trials following vestibular Schwannoma surgery. The mechanism of the protective competence of nimodipine is unknown. Therefore, in this study, we established an in vitro model to examine the survival of Neuro2a cells after different stress stimuli occurring during surgery with or without nimodipine. Nimodipine significantly decreased ethanol-induced cell death of cells up to approximately 9% in all tested concentrations. Heat-induced cell death was diminished by approximately 2.5% by nimodipine. Cell death induced by mechanical treatment was reduced up to 15% by nimodipine. Our findings indicate that nimodipine rescues Neuro2a cells faintly, but significantly, from ethanol-, heat- and mechanically-induced cell death to different extents in a dosage-dependent manner. This model seems suitable for further investigation of the molecular mechanisms involved in the neuroprotective signal pathways influenced by nimodipine.

Nimodipine but Not Nifedipine Promotes Expression of Fatty Acid 2-Hydroxylase in a Surgical Stress Model Based on Neuro2a Cells

“…This may be due to translational regulation processes. The upregulation of FA2H may contribute to better survival of stressed Neuro2a cells pre-treated with nimodipine—also except for osmotic stress—shown previously by our workgroup [20]. Especially in mechanical stress, which is strongly linked to surgical manipulation in patients, regulation of FA2H without nimodipine may be analogous to processes in vivo.…”

“…While optimal pre-treatment period for cell culture is 24 h [20], best pre-treatment period for patients still needs to be defined.…”

Nimodipine fosters remyelination in a mouse model of multiple sclerosis and induces microglia-specific apoptosis

“…To ensure that our in vitro dose of nimodipine was clinically relevant, we studied the literature closely and tested doses that already had been used in several CNS disease models (13,18,50,51). The dose used for cell culture had been shown to induce equivalent effects in patients (e.g., reduced stress-mediated effects after brain surgery and decreased excitotoxicity) (51). Stimulation was performed with 100 ng/mL TNF-α (PeproTech; catalog no.…”

Strategies for Neuroprotection in Multiple Sclerosis and the Role of Calcium

“…Recently, nimodipine has been reported to have positive effects on Schwann cells, astrocytes and neurons, which was associated with increased phosphorylation of proteinkinase B and the cyclic adenosine monophosphate response element-binding protein (CREB) [207][208][209]. Additionally, the pro-apoptotic protein caspase 3 and the calcium-dependent protein calpain were downregulated upon nimodipine treatment, whereas calbindin expression was upregulated, indicating that modulation of calcium homeostasis and prevention of calcium overload might be responsible for the neuroprotective properties of nimodipine [207,210].…”