title: Cerebrolysin protects PC12 cells from CoCl2-induced hypoxia employing GSK3β signaling.
abstract: Cerebrolysin (EVER Neuro Pharma GmbH, Austria) is a peptidergic drug indicated for clinical use in stroke, traumatic brain injury and dementia. The therapeutic effect of Cerebrolysin is thought to ensure from its neurotrophic activity, which shares some properties with naturally occurring neurotrophic factors. However, the exact mechanism of action of Cerebrolysin is yet to be fully deciphered. This study aimed to investigate the neuroprotective effect of Cerebrolysin in a widely used in vitro model of hypoxia-induced neuronal cytotoxicity, namely cobalt chloride (CoCl2)-treatment of PC12 cells. CoCl2-cytotoxicity was indicated by a reduced cell-diameter, cell shrinkage, increased pro-apoptotic Caspase-activities and a decreased metabolic activity. Cerebrolysin maintained the cell-diameter of CoCl2-treated naïve PC12 cells, decreased the activation of Caspase 3/7 in CoCl2-stressed naïve PC12 cells and restored the cells' metabolic activity in CoCl2-impaired naïve and differentiated PC12 cells. Cerebrolysin treatment also decreased the levels of superoxide observed after exposure to CoCl2. Investigating the mechanism of action, we could demonstrate that Cerebrolysin application to CoCl2-stressed PC12 cells increased the phosphorylation of GSK3β, resulting in the inhibition of GSK3β. This might become clinically relevant for Alzheimer's disease, since GSK3β activity has been linked to the production of amyloid beta. Taken together, Cerebrolysin was found to have neuroprotective effects in CoCl2-induced cytotoxicity in PC12 cells.
authors.affiliation: EVER Neuro Pharma GmbH, Unterach, Austria.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Hartwig
authors.affiliation: EVER Neuro Pharma GmbH, Unterach, Austria.
authors.forename: Viktoria
authors.initials: V
authors.lastname: Fackler
authors.affiliation: Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Heidi
authors.initials: H
authors.lastname: Jaksch-Bogensperger
authors.affiliation: EVER Neuro Pharma GmbH, Unterach, Austria. Electronic address: stefan.winter@everpharma.com.
authors.forename: Stefan
authors.initials: S
authors.lastname: Winter
authors.affiliation: Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Tanja
authors.initials: T
authors.lastname: Furtner
authors.affiliation: Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University, Salzburg, Austria; Institute of Experimental Neuroregeneration, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Couillard-Despres
authors.affiliation: EVER Neuro Pharma GmbH, Unterach, Austria.
authors.forename: Dieter
authors.initials: D
authors.lastname: Meier
authors.affiliation: EVER Neuro Pharma GmbH, Unterach, Austria.
authors.forename: Herbert
authors.initials: H
authors.lastname: Moessler
authors.affiliation: Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University, Salzburg, Austria. Electronic address: ludwig.aigner@pmu.ac.at.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Aigner
mesh_terms: D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003035:Cobalt / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D020932:Nerve Growth Factor / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
chemical_list: D000596:Amino Acids; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; C006952:cerebrolysin; D003035:Cobalt; D020932:Nerve Growth Factor; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D020169:Caspases; C018021:cobaltous chloride
keywords: Cell death; Neuroprotection; Neurotrophic factors