title: CDK5 knockdown prevents hippocampal degeneration and cognitive dysfunction produced by cerebral ischemia.
abstract: Acute ischemic stroke is a cerebrovascular accident and it is the most common cause of physical disabilities around the globe. Patients may present with repeated ictuses, experiencing mental consequences, such as depression and cognitive disorders. Cyclin-dependent kinase 5 (CDK5) is a kinase that is involved in neurotransmission and plasticity, but its dysregulation contributes to cognitive disorders and dementia. Gene therapy targeting CDK5 was administered to the right hippocampus of ischemic rats during transient cerebral middle artery occlusion. Physiologic parameters (blood pressure, pH, pO2, and pCO2) were measured. The CDK5 downregulation resulted in neurologic and motor improvement during the first week after ischemia. Cyclin-dependent kinase 5 RNA interference (RNAi) prevented dysfunctions in learning, memory, and reversal learning at 1 month after ischemia. These observations were supported by the prevention of neuronal loss, the reduction of microtubule-associated protein 2 (MAP2) immunoreactivity, and a decrease in astroglial and microglia hyperreactivities and tauopathy. Additionally, CDK5 silencing led to an increase in the expression of brain-derived neurotrophic factor (BDNF), its Tropomyosin Receptor kinase B (TRKB) receptor, and activation of cyclic AMP response element-binding protein (CREB) and extracellular signal-regulated kinase (ERK), which are important targets in neuronal plasticity. Together, our findings suggest that gene therapy based on CDK5 silencing prevents cerebral ischemia-induced neurodegeneration and motor and cognitive deficits.
authors.affiliation: Cellular and Molecular Neurobiology Area, Group of Neuroscience of Antioquia, School of Medicine, SIU, University of Antioquia UdeA, Medellín, Colombia.
authors.forename: Johana A
authors.initials: JA
authors.lastname: Gutiérrez-Vargas
authors.affiliation: Behavioral Neurophysiology Laboratory, School of Medicine, Universidad Nacional de Colombia, Bogotá, Colombia.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Múnera
authors.affiliation: 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; D001794:Blood Pressure; D001923:Brain Chemistry / Q000235:genetics; D002545:Brain Ischemia / Q000150:complications* / Q000473:pathology / Q000523:psychology; D002245:Carbon Dioxide / Q000097:blood; D003072:Cognition Disorders / Q000209:etiology* / Q000517:prevention & control*; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics* / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006624:Hippocampus / Q000473:pathology*; D006863:Hydrogen-Ion Concentration; D007859:Learning Disabilities / Q000209:etiology / Q000517:prevention & control / Q000523:psychology; D008297:Male; D018782:Maze Learning; D008569:Memory Disorders / Q000209:etiology / Q000517:prevention & control / Q000523:psychology; D009069:Movement Disorders / Q000209:etiology / Q000517:prevention & control / Q000523:psychology; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D010100:Oxygen / Q000097:blood; D034622:RNA Interference; D051381:Rats; D012193:Reversal Learning / Q000187:drug effects; D020521:Stroke / Q000150:complications* / Q000473:pathology / Q000523:psychology
chemical_list: D002245:Carbon Dioxide; D051360:Cyclin-Dependent Kinase 5; C495907:Cdk5 protein, rat; D010100:Oxygen