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Published on: June 22, 2013
Increase of p25 associated with cortical neuronal death induced by hypoxia
Tianwen Huang1, Lijun Fang2, Zhiying Lin1
1Department of Neurology, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, Fuzhou, 350001, China.
Abstract:
The mechanisms of neuronal damage in hypoxic cerebral cortex are complicated. Recent studies indicated that deregulation of Cdk5 was involved in neuronal death induced by hypoxia (1% O2). However, the pathological effect of Cdk5 is not fully elucidated. Therefore, in order to decipher the effect of Cdk5 on cellular death in hypoxic condition, the Cdk5 and its activator p35/p25 were investigated in cortical neurons at 10 DIV (Days In Vitro). Upon exposure to hypoxia, the cortical neurons showed a time-dependent increase of neuronal death compared to normoxia-treated control neurons. In correlation to the increase of neuronal death under hypoxia, the level of p25, a truncated form of p35, also increased in a time-dependent manner. Importantly, inhibition of Cdk5 kinase activity by roscovitine protected neurons from death under hypoxic stress. In contrast, ectopic upregulation of Cdk5 kinase activity in neurons expressing p25 led to an increase of neuronal death in comparison to control neurons expressing GFP. It suggests that ectopic increase of Cdk5 kinase activity through conversion of p35 to p25 is involved in the process of neuronal death induced by hypoxia.
Insights
Hypoxia causes neuronal death by increasing p25, which activates cyclin-dependent kinase 5 (Cdk5). Inhibiting Cdk5 protects neurons, suggesting its role in hypoxic brain injury.
Area of Science:
- Neuroscience
- Cellular Biology
- Biochemistry
Background:
- Neuronal damage mechanisms in hypoxic cerebral cortex are complex.
- Cyclin-dependent kinase 5 (Cdk5) deregulation is implicated in hypoxia-induced neuronal death.
- The precise pathological role of Cdk5 in this context requires further elucidation.
Purpose of the Study:
- To investigate the effect of Cdk5 and its activators (p35/p25) on cellular death in cortical neurons under hypoxic conditions.
- To determine the role of p35 to p25 conversion in hypoxia-induced neuronal death.
Main Methods:
- Cortical neurons at 10 Days In Vitro (DIV) were exposed to hypoxia (1% O2).
- Time-dependent changes in neuronal death, p25 levels, and Cdk5 kinase activity were assessed.
- Pharmacological inhibition of Cdk5 using roscovitine was employed.
- Ectopic expression of p25 in neurons was used to study its effect on Cdk5 activity and neuronal survival.
Main Results:
- Hypoxia exposure led to a time-dependent increase in cortical neuronal death.
- The level of p25, a truncated form of p35, increased concurrently with neuronal death under hypoxia.
- Inhibition of Cdk5 kinase activity with roscovitine conferred neuroprotection against hypoxic stress.
- Ectopic upregulation of Cdk5 kinase activity via p25 expression increased neuronal death.
Conclusions:
- The conversion of p35 to p25 and the subsequent increase in Cdk5 kinase activity are involved in hypoxia-induced neuronal death.
- Targeting Cdk5 activity may offer a therapeutic strategy for mitigating neuronal damage during hypoxic events.
