Karen Nguyen

 Introduction. Strokes are a leading cause in death and neurological disability, resulting from sudden disturbances in blood supply.^1-4 Stroke incidence more than doubles every decade after age 55 and causes post-stroke cognitive impairment (PSCI) in over 65% of stroke survivors.^4-6 Cyclin-dependent kinase 5 (CDK5) is typically regulated by cofactor p35, but complexes with protein p25 in stroke events. This results in CDK5 hyperactivation, consequently leading to neuronal death and cognitive deterioration.^2,7,8 However, because the pathogenesis for PSCI in particular is not clearly understood, there are no established treatments. This highlights the urgency in developing an effective therapy for PSCI, which can be potentially found via CDK5 downregulation.^2,4 Methods. Effects on CDK5 activity, calpain activation, p25 levels, and brain-derived neurotrophic factor (BDNF) levels were assessed in ischemic rats treated with CDK5 RNA interference sequences (CDK5miR) administered via adeno-associated viral particles. Evaluations were done at 1- and 4-months post-ischemia via assays, western blotting, immunohistochemistry (IHC), and immunofluorescence.^2,7 CDK5miR-treated ischemic mice were also assessed via immunofluorescence and field excitatory post-synaptic potential (fEPSP) measurements for effects on spine morphogenesis and long-term potentiation (LTP).⁸ Lastly, TFP5, a p35-derived peptide, was used as a therapeutic application for CDK5 downregulation in ischemic rats. These rats were assessed via infarct size analysis, ELISA, western blotting, TUNEL and IHC staining, and measurements of biotinylated IgG, Iba1, and serum matrix metallopeptidase (MMP9).⁹ Results. CDK5miR-treated ischemic rats had reduced CDK5 activity, calpain activation, and p25 protein levels at both 1- and 4-months post-ischemia.^2,7 CDK5miR treatment also induced neuronal BDNF production, activating the plasticity pathway involving BDNF and phosphorylated CREB.^2,7,8 Increases in the total number and length of average dendritic protrusions were observed. There was also a notable decrease in the LTP induction threshold, thereby resulting in increased LTP as shown by the increased amplitude of fEPSPs.⁸ Lastly, TFP5 was shown to reduce the infarct size and apoptosis of brain cells in ischemic rats as shown via examination of brain slices and a reduction of TUNEL-positive cells. A decrease in biotinylated IgG, Iba1, and MMP9 with TFP5 treatment was also noted.⁹ Conclusions. Studies have found that CDK5 silencing may play an important role in the treatment of PSCI shown by the decrease in CDK5 and p25 levels, activated plasticity pathways, reduction of brain neuronal death, and increased LTP. TFP5 may be a potential avenue for this CDK5 downregulation with results signifying an anti-neuroinflammatory effect and blood-brain barrier protection.

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