Abstract
Cyclin-dependent kinase 5 (CDK5) is a multifaceted protein shown to play important roles in the central nervous system. Abundant evidence indicates that CDK5 hyperactivities associated with neuronal apoptosis and death following ischemic stroke. CDK5 activity increases when its cofactor p35 cleaves into p25 during ischemia. Theoretically, inhibition of CDK5/p25 activity or reduction of p25 would be neuroprotective. TFP5, a modified 24-aa peptide (Lys254-Ala277) derived from p35, was found to effectively inhibit CDK5 hyperactivity and improve the outcomes of Alzheimer’s disease and Parkinson’s disease in vivo. Here, we showed that intraperitoneal injection of TFP5 significantly decreased the size of ischemia in early-stage of adult ischemic stroke rats. Relative to controls, rats treated with TFP5 displayed reduced excitotoxicity, neuroinflammation, apoptosis, astrocytes damage, and blood-brain barrier disruption. Our findings suggested that TFP5 might serve as a potential therapeutic candidate for acute adult ischemic stroke.
Highlights
Multiple mechanisms of ischemic stroke have been described[1], and designing strategies to counter these mechanisms maybe neuroprotective
Based on the similar pathological mechanism of Cyclin-dependent kinase 5 (CDK5) hyperactivity in Alzheimer’s disease (AD), Parkinson’s disease (PD), and ischemia, as well as the specific neuroprotection provided by TFP5, we designed this study to determine the efficacy of TFP5 in adult rats with transient middle cerebral artery occlusion (MCAO) by assessing ischemic size, excitotoxicity, neuroinflammation, apoptosis, astrocyte and blood-brain barrier (BBB) status
During normal development and function of the nervous system, CDK5 and its main cofactor p35 maintain normal CDK5 activity, which is involved in a wide variety of physiological processes, including neuronal migration, Figure 5
Summary
Multiple mechanisms of ischemic stroke have been described[1], and designing strategies to counter these mechanisms maybe neuroprotective. Kinase inhibitors that target ATP binding sites in CDKs, such as roscovitine and aminothizole, have been evaluated as potential therapeutic agents[10,11,12,13]. These compounds can produce serious side effects due to their lack of specificity for CDK5. Based on the similar pathological mechanism of CDK5 hyperactivity in AD, PD, and ischemia, as well as the specific neuroprotection provided by TFP5, we designed this study to determine the efficacy of TFP5 in adult rats with transient middle cerebral artery occlusion (MCAO) by assessing ischemic size, excitotoxicity, neuroinflammation, apoptosis, astrocyte and blood-brain barrier (BBB) status. We postulated that TFP5 is neuroprotective for adult ischemic stroke
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