CDK5 Knockdown Prevents Hippocampal Degeneration and Cognitive Dysfunction Produced by Cerebral Ischemia

• Published in: Journal of cerebral blood flow and metabolism Vol. 35; no. 12; pp. 1937 - 1949
• Main Authors: Gutiérrez-Vargas, Johana A, Múnera, Alejandro, Cardona-Gómez, Gloria P
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.12.2015; Sage Publications Ltd; Nature Publishing Group
• Subjects: Animals; Blood Pressure; Brain Chemistry - genetics; Brain Ischemia - complications; Brain Ischemia - pathology; Brain Ischemia - psychology; Carbon Dioxide - blood; Cognition Disorders - etiology; Cognition Disorders - prevention & control; Cyclin-Dependent Kinase 5 - genetics; Cyclin-Dependent Kinase 5 - metabolism; Gene Knockdown Techniques; Hippocampus - pathology; Hydrogen-Ion Concentration; Learning Disorders - etiology; Learning Disorders - prevention & control; Learning Disorders - psychology; Male; Maze Learning; Memory Disorders - etiology; Memory Disorders - prevention & control; Memory Disorders - psychology; Movement Disorders - etiology; Movement Disorders - prevention & control; Movement Disorders - psychology; Nerve Degeneration - genetics; Nerve Degeneration - pathology; Nerve Degeneration - prevention & control; Original; Oxygen - blood; Rats; Reversal Learning - drug effects; RNA Interference; Stroke - complications; Stroke - pathology; Stroke - psychology; gene therapy; cerebral ischemia; neuroprotection; cognitive disorder; CDK5 RNAi
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1038/jcbfm.2015.150

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.