Neuroprotektive Eigenschaften von niedrig dosiertem Nifedipin auf Schwann Zellen

Nifedipine is a calcium channel antagonist and is mainly used as an antihypertensive and in vasospastic angina pectoris. Recent studies have shown a neuroprotective effect of nifedipine in demyelinated nerves and on the dopaminergic substantia nigra. This suggests that nifedipine may have a neuroprotective potential similar to that of nimodipine. Therefore, the aim of this study was to analyse the mode of action of nifedipine on different cell lines, to investigate stress-induced cell death, calcium balance and the effects of nifedipine on the molecular mechanism of neuroprotection.

We investigated the effect of nifedipine on murine (SW10) and human Schwann cells (HSC) and on rat neuronal cells (RN33B). All assays were performed with nifedipine-pretreated and untreated groups, under cytotoxic and oxidative stress (20µM Cisplatin; 2% EtOH). We analysed cytotoxicity by measuring lactate dehydrogenase (LDH) activation in the cell culture supernatant and calcium assay to measure intracellular Ca2+ levels. To investigate the effect on expression and protein signalling cascades, we performed Western blots of pretreated and untreated SW10 and RN33B cells.

Nifedipine is cytotoxic at concentrations >10µM, but has a neuroprotective effect of 12% on murine and of 25% on human Schwann cells exposed to cytotoxic and oxidative stress. In stressed cells, it caused increased phosphorylation of AKT at serin residue 473 and of CREB at serin residue 133. The AKT pathway is a signalling pathway that responds to extracellular signals to promote survival and growth, and by activating AKT and CREB it suppresses apoptosis. Nifedipine did not show a neuroprotective effect on neuronal cells.

We have shown that low doses of nifedipine have a neuroprotective effect on Schwann cells. Further studies are necessary to investigate the intracellular Ca2+ concentration in Schwann and neuronal cells. In addition, the effects on human primary cell cultures and HSCs need to be analysed. Based on the preliminary results, and assuming that nifedipine is not lipophilic, it may be particularly relevant for peripheral neuropathies caused, for example, by chemotherapy. It would therefore be necessary to investigate the penetration of nifedipine into the cerebrospinal fluid and the serum concentrations of nifedipine.