title: Nimodipine enhances neurite outgrowth in dopaminergic brain slice co-cultures.
abstract: Calcium ions (Ca(2+)) play important roles in neuroplasticity and the regeneration of nerves. Intracellular Ca(2+) concentrations are regulated by Ca(2+) channels, among them L-type voltage-gated Ca(2+) channels, which are inhibited by dihydropyridines like nimodipine. The purpose of this study was to investigate the effect of nimodipine on neurite growth during development and regeneration. As an appropriate model to study neurite growth, we chose organotypic brain slice co-cultures of the mesocortical dopaminergic projection system, consisting of the ventral tegmental area/substantia nigra and the prefrontal cortex from neonatal rat brains. Quantification of the density of the newly built neurites in the border region (region between the two cultivated slices) of the co-cultures revealed a growth promoting effect of nimodipine at concentrations of 0.1μM and 1μM that was even more pronounced than the effect of the growth factor NGF. This beneficial effect was absent when 10μM nimodipine were applied. Toxicological tests revealed that the application of nimodipine at this higher concentration slightly induced caspase 3 activation in the cortical part of the co-cultures, but did neither affect the amount of lactate dehydrogenase release or propidium iodide uptake nor the ratio of bax/bcl-2. Furthermore, the expression levels of different genes were quantified after nimodipine treatment. The expression of Ca(2+) binding proteins, immediate early genes, glial fibrillary acidic protein, and myelin components did not change significantly after treatment, indicating that the regulation of their expression is not primarily involved in the observed nimodipine mediated neurite growth. In summary, this study revealed for the first time a neurite growth promoting effect of nimodipine in the mesocortical dopaminergic projection system that is highly dependent on the applied concentrations.
authors.affiliation: Translational Centre for Regenerative Medicine (TRM), University of Leipzig, Philipp-Rosenthal-Straße 55, 04103 Leipzig, Germany; Rudolf Boehm Institute of Pharmacology and Toxicology, University of Leipzig, Härtelstr. 16-18, 04107 Leipzig, Germany. Electronic address: katja.sygnecka@trm.uni-leipzig.de.
authors.forename: Katja
authors.initials: K
authors.lastname: Sygnecka
authors.affiliation: Translational Centre for Regenerative Medicine (TRM), University of Leipzig, Philipp-Rosenthal-Straße 55, 04103 Leipzig, Germany; Rudolf Boehm Institute of Pharmacology and Toxicology, University of Leipzig, Härtelstr. 16-18, 04107 Leipzig, Germany. Electronic address: claudia.heine@trm.uni-leipzig.de.
authors.forename: Claudia
authors.initials: C
authors.lastname: Heine
authors.affiliation: Institute for Medical Informatics and Biometry, Dresden University of Technology, Fetscherstraße 74, 01307 Dresden, Germany. Electronic address: nico.scherf@tu-dresden.de.
authors.forename: Nico
authors.initials: N
authors.lastname: Scherf
authors.affiliation: Interdisciplinary Centre for Bioinformatics, University of Leipzig, Härtelstr. 16-18, 04107 Leipzig, Germany. Electronic address: mario@bioinf.uni-leipzig.de.
authors.forename: Mario
authors.initials: M
authors.lastname: Fasold
authors.affiliation: Interdisciplinary Centre for Bioinformatics, University of Leipzig, Härtelstr. 16-18, 04107 Leipzig, Germany. Electronic address: binder@izbi.uni-leipzig.de.
authors.forename: Hans
authors.initials: H
authors.lastname: Binder
authors.affiliation: Translational Centre for Regenerative Medicine (TRM), University of Leipzig, Philipp-Rosenthal-Straße 55, 04103 Leipzig, Germany; Department of Neurosurgery, University of Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle/Saale, Germany. Electronic address: christian.scheller@medizin.uni-halle.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Scheller
authors.affiliation: Rudolf Boehm Institute of Pharmacology and Toxicology, University of Leipzig, Härtelstr. 16-18, 04107 Leipzig, Germany. Electronic address: heike.franke@medizin.uni-leipzig.de.
authors.forename: Heike
authors.initials: H
authors.lastname: Franke
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D000431:Ethanol / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D018698:Glutamic Acid / Q000494:pharmacology; D017874:Immediate-Early Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016501:Neurites / Q000187:drug effects*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D009553:Nimodipine / Q000494:pharmacology*; D009924:Organ Culture Techniques; D051381:Rats; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D002121:Calcium Channel Blockers; D017077:Culture Media, Conditioned; D017874:Immediate-Early Proteins; D009419:Nerve Tissue Proteins; D000431:Ethanol; D018698:Glutamic Acid; D009553:Nimodipine; D020932:Nerve Growth Factor; D007770:L-Lactate Dehydrogenase; D053148:Caspase 3; D004298:Dopamine
keywords: Calcium channel blockade; Development; Neurite growth; Nimodipine; Organotypic slice co-culture; Regeneration