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Downregulating Cdk5 reverses hippocampal neuron ferroptosis by regulating the AMP-activated protein kinase pathway
1Department of Neurology, The First People's Hospital of Zhenjiang, Jiangsu, China.
Abstract:
Aberrant activation of microglia plays a crucial role in neuronal injury after ischemic stroke. Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine-directed kinase that plays a significant role in neuronal damage. We investigated the role of Cdk5 in microglial activation and neuronal ferroptosis in cellular and animal models of hypoxic-ischemic neuronal injury. Treatment with the Cdk5 inhibitor (S)-roscovitine (Ros) and/or an AMPK pathway activator metformin (Met) were investigated in a middle cerebral artery occlusion/reperfusion (MCAO/R) model in C57BL/6J mice. The results showed that Ros and Met improved neurological functions, brain edema, mitigated "M1" polarization of microglia, and inhibited neuronal ferroptosis. The combination of Ros and Met had additive effects on the MCAO/R mice. Ros and Met suppressed the expression of Cdk5 and inhibited NF-κB pathway activation, whereas the AMPK inhibitor Compound C (CC) reversed the neuroprotective and anti-inflammatory effects of Ros and Met. In vitro assays revealed that Ros and Met inhibited the proinflammatory reactions of BV2 microglia and the damage and ferroptosis of HT22 cells after OGD/R stimulation; these effects were also reversed by CC. These results indicate that targeting Cdk5 and AMPK mitigated microglia-mediated neuroinflammation and reduced neuronal ferroptosis in ischemic stroke models.
Insights
Targeting Cyclin-dependent kinase 5 (Cdk5) with (S)-roscovitine and activating AMPK with metformin reduced microglial activation and neuronal ferroptosis, improving outcomes in ischemic stroke models.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Microglial activation contributes significantly to neuronal damage following ischemic stroke.
- Cyclin-dependent kinase 5 (Cdk5) is implicated in neuronal injury mechanisms.
- Neuronal ferroptosis is a key pathological process in hypoxic-ischemic brain injury.
Purpose of the Study:
- To investigate the role of Cdk5 in microglial activation and neuronal ferroptosis in hypoxic-ischemic injury models.
- To evaluate the therapeutic potential of a Cdk5 inhibitor ((S)-roscovitine) and an AMPK activator (metformin) in ischemic stroke.
Main Methods:
- Utilized cellular (BV2 microglia, HT22 cells) and animal (middle cerebral artery occlusion/reperfusion - MCAO/R) models of hypoxic-ischemic neuronal injury.
- Administered (S)-roscovitine (Ros) and metformin (Met), alone and in combination.
- Assessed neurological function, brain edema, microglial polarization, neuronal ferroptosis, Cdk5 expression, NF-κB pathway activation, and AMPK pathway activity.
Main Results:
- Both Ros and Met treatment improved neurological deficits and reduced brain edema in MCAO/R mice.
- Treatments mitigated M1 microglial polarization and inhibited neuronal ferroptosis.
- Combined Ros and Met showed additive therapeutic effects, suppressed Cdk5 expression, and inhibited the NF-κB pathway; these effects were reversed by the AMPK inhibitor Compound C (CC).
Conclusions:
- Targeting Cdk5 with (S)-roscovitine and activating AMPK with metformin demonstrates neuroprotective effects in ischemic stroke models.
- These interventions mitigate microglia-mediated neuroinflammation and reduce neuronal ferroptosis.
- The findings suggest a potential therapeutic strategy for ischemic stroke by modulating Cdk5 and AMPK pathways.
