title: Targeting CDK5 post-stroke provides long-term neuroprotection and rescues synaptic plasticity.
abstract: Post-stroke cognitive impairment is a major cause of long-term neurological disability. The prevalence of post-stroke cognitive deficits varies between 20% and 80% depending on brain region, country, and diagnostic criteria. The biochemical mechanisms underlying post-stroke cognitive impairment are not known in detail. Cyclin-dependent kinase 5 is involved in neurodegeneration, and its dysregulation contributes to cognitive disorders and dementia. Here, we administered cyclin-dependent kinase 5-targeting gene therapy to the right hippocampus of ischemic rats after transient right middle cerebral artery occlusion. Cyclin-dependent kinase 5 RNA interference prevented the impairment of reversal learning four months after ischemia as well as neuronal loss, tauopathy, and microglial hyperreactivity. Additionally, cyclin-dependent kinase 5 silencing increased the expression of brain-derived neurotrophic factor in the hippocampus. Furthermore, deficits in hippocampal long-term potentiation produced by excitotoxic stimulation were rescued by pharmacological blockade of cyclin-dependent kinase 5. This recovery was blocked by inhibition of the TRKB receptor. In summary, these findings demonstrate the beneficial impact of cyclin-dependent kinase 5 reduction in preventing long-term post-ischemic neurodegeneration and cognitive impairment as well as the role of brain-derived neurotrophic factor/TRKB in the maintenance of normal synaptic plasticity.
authors.affiliation: 1 Cellular and Molecular Neurobiology Area, Group of Neuroscience of Antioquia, School of Medicine, SIU, University of Antioquia UdeA, Medellín, Colombia.
authors.forename: Johanna A
authors.initials: JA
authors.lastname: Gutiérrez-Vargas
authors.affiliation: 2 The Robert F. Furchgott Center for Neural and Behavioral Science, Departments of Neurology and Physiology/Pharmacology, SUNY Downstate Medical Center, Brooklyn, NY, USA.
authors.forename: Herman
authors.initials: H
authors.lastname: Moreno
authors.affiliation: 1 Cellular and Molecular Neurobiology Area, Group of Neuroscience of Antioquia, School of Medicine, SIU, University of Antioquia UdeA, Medellín, Colombia.
authors.forename: Gloria P
authors.initials: GP
authors.lastname: Cardona-Gómez
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D060825:Cognitive Dysfunction / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors* / Q000235:genetics; D004195:Disease Models, Animal; D055724:Electrophysiological Phenomena; D055785:Gene Knockdown Techniques; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D017208:Rats, Wistar; D012193:Reversal Learning / Q000502:physiology; D045442:Rotarod Performance Test; D020521:Stroke / Q000150:complications / Q000378:metabolism* / Q000473:pathology
chemical_list: D034741:RNA, Small Interfering; D051360:Cyclin-Dependent Kinase 5; C495907:Cdk5 protein, rat
keywords: BDNF; CDK5 RNAi; cognitive impairment; long-term post-ischemia; neuronal plasticity; neuroprotection