TFP5 peptide, derived from CDK5-activating cofactor p35, provides neuroprotection in early-stage of adult ischemic stroke

Sci Rep. 2017 Jan 3;7:40013. doi: 10.1038/srep40013.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Astrocytes / drug effects
  • Astrocytes / pathology
  • Blood-Brain Barrier / drug effects
  • Brain / pathology
  • Cyclin-Dependent Kinase 5 / metabolism
  • Disease Models, Animal
  • Infarction, Middle Cerebral Artery / complications
  • Male
  • Matrix Metalloproteinase 9 / blood
  • Neurons / drug effects
  • Neurons / metabolism
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use*
  • Peptides / pharmacology
  • Peptides / therapeutic use*
  • Protein Subunits / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Stroke / drug therapy*
  • Stroke / etiology
  • Stroke / pathology
  • Stroke / prevention & control

Substances

  • Neuroprotective Agents
  • Peptides
  • Protein Subunits
  • Receptors, N-Methyl-D-Aspartate
  • TFP5 peptide
  • Cyclin-Dependent Kinase 5
  • Matrix Metalloproteinase 9