Ischemic Stroke Injury Is Mediated by Aberrant Cdk5

Abstract

Ischemic stroke is one of the leading causes of morbidity and mortality. Treatment options are limited and only a minority of patients receive acute interventions. Understanding the mechanisms that mediate neuronal injury and death may identify targets for neuroprotective treatments. Here we show that the aberrant activity of the protein kinase Cdk5 is a principal cause of neuronal death in rodents during stroke. Ischemia induced either by embolic middle cerebral artery occlusion (MCAO) in vivo or by oxygen and glucose deprivation in brain slices caused calpain-dependent conversion of the Cdk5-activating cofactor p35 to p25. Inhibition of aberrant Cdk5 during ischemia protected dopamine neurotransmission, maintained field potentials, and blocked excitotoxicity. Furthermore, pharmacological inhibition or conditional knock-out (CKO) of Cdk5 prevented neuronal death in response to ischemia. Moreover, Cdk5 CKO dramatically reduced infarctions following MCAO. Thus, targeting aberrant Cdk5 activity may serve as an effective treatment for stroke.

Calpains and neuronal damage in the ischemic brain: The swiss knife in synaptic injury

“…Accumulation of p25, translocation of the complex p25/Cdk5 to the nucleus and aberrant activation of Cdk5 have been shown to have an important role in excitotoxic and ischemic neuronal death(Amini et al, 2013;Meyer et al, 2014;O'Hare et al, 2005).…”

A novel phosphorylation site of N-methyl- d -aspartate receptor GluN2B at S1284 is regulated by Cdk5 in neuronal ischemia

“…One the other hand, there is considerable evidence demonstrating the both NMDARs and Cdk5 are involved in neuropathological processes, such as stroke (Menn et al, 2010;Meyer et al, 2014;Wang et al, 2003). Therefore, we examined whether ischemic insult brought about any changes in the pS1284 level.…”

HO-1 Signaling Activation by Pterostilbene Treatment Attenuates Mitochondrial Oxidative Damage Induced by Cerebral Ischemia Reperfusion Injury

“…GSTs are best known for their ability to catalyze the conjugation of the reduced form of glutathione (GSH) to xenobiotic substrates for detoxification [44]. GST Pi 1 (GSTP1), the most abundant member of the GST family, has been identified as a negative regulator of cyclin-dependent kinase-5 (Cdk5), which promotes neuronal death and increases infarctions following middle cerebral artery occlusion (MCAO) [45]. Notably, mitochondrial GSTs display both glutathione transferase and peroxidase activities that detoxify harmful products through GSH conjugation or GSH-mediated peroxide reduction [46].…”