Nimodipine-Dependent Protection of Schwann Cells, Astrocytes and Neuronal Cells from Osmotic, Oxidative and Heat Stress Is Associated with the Activation of AKT and CREB

Abstract

Clinical and experimental data assumed a neuroprotective effect of the calcium channel blocker nimodipine. However, it has not been proven which neuronal or glial cell types are affected by nimodipine and which mechanisms underlie these neuroprotective effects. Therefore, the aim of this study was to investigate the influence of nimodipine treatment on the in vitro neurotoxicity of different cell types in various stress models and to identify the associated molecular mechanisms. Therefore, cell lines from Schwann cells, neuronal cells and astrocytes were pretreated for 24 h with nimodipine and incubated under stress conditions such as osmotic, oxidative and heat stress. The cytotoxicity was measured via the lactate dehydrogenase (LDH) activity of cell culture supernatant. As a result, the nimodipine treatment led to a statistically significantly reduced cytotoxicity in Schwann cells and neurons during osmotic (p ≤ 0.01), oxidative (p ≤ 0.001) and heat stress (p ≤ 0.05), when compared to the vehicle. The cytotoxicity of astrocytes was nimodipine-dependently reduced during osmotic (p ≤ 0.01), oxidative (p ≤ 0.001) and heat stress (not significant). Moreover, a decreased caspase activity as well as an increased proteinkinase B (AKT) and cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation could be observed after the nimodipine treatment under different stress conditions. These results demonstrate a cell type-independent neuroprotective effect of the prophylactic nimodipine treatment, which is associated with the prevention of stress-dependent apoptosis through the activation of CREB and AKT signaling pathways and the reduction of caspase 3 activity.

Ion Channels as New Attractive Targets to Improve Re-Myelination Processes in the Brain

“…When nimodipine was administered preventively at the time point of disease induction, EAE severity and demyelination decreased [ 67 ]. Recently, nimodipine has been reported to have positive effects on Schwann cells, astrocytes and neurons, being associated to increased phosphorylation of either protein kinase B and the cyclic adenosine monophosphate response element-binding protein (CREB) [ 68 , 148 ]. It is known that axonal Ca 2+ overload activates the Ca 2+ -dependent protease calpain, leading to disruption of the cytoskeleton and to other structural and functional alterations of the axon [ 149 ].…”

Electrospun Fiber Scaffolds for Engineering Glial Cell Behavior to Promote Neural Regeneration

“…Additionally, the sustained release of fingolimod reduced the Schwann cell expression of mature, promyelinating markers [ 157 ]. Following injury or in a disease state, the PNS can be subjected to various forms of stress that can lead to increased Schwann cell death [ 158 ]. However, small-molecule drugs can also be incorporated into electrospun fibers to aid in protecting cells from various forms of stress [ 159 ].…”

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].…”