AZD5438 a GSK-3a/b and CDK inhibitor is antiapoptotic modulates mitochondrial activity and protects human neurons from mitochondrial toxins

We previously reported that kenpaullone, which inhibits GSK-3a/b and CDKs inhibited CCCP mediated mitochondrial depolarisation and augments the mitochondrial network. To investigate the actions of this class of drug further, we compared the ability of kenpaullone, alsterpaullone, 1-azakenapaullone, AZD5438, AT7519 (CDK and GSK-3a/b inhibitors) and dexpramipexole and olesoxime (mitochondrial permeability transition pore inhibitors) to prevent CCCP mediated mitochondrial depolarisation and found that AZD5438 and AT7519, were the most effective. Furthermore, treatment with AZD5438 alone increased the complexity of the mitochondrial network. We also found that AZD5438 prevented the rotenone induced decrease in PGC-1alpha and TOM20 levels and that it mediated powerful anti-apoptotic effects and promoted glycolytic respiration. Importantly, experiments in human iPSC derived cortical and midbrain neurons showed AZD5438 mediated significant protective effects, preventing the neuronal cell death, and collapse in the neurite and mitochondrial network associated with rotenone treatment. These results suggest drugs that target GSK-3a/b and CDKs should be developed and assessed further as they may have significant therapeutic potential.

 

Comments:

The passage you provided discusses the effects of several drugs, including kenpaullone, alsterpaullone, 1-azakenapaullone, AZD5438, AT7519, dexpramipexole, and olesoxime, on mitochondrial function and neuroprotection. Here's a summary of the key findings:

1. **Kenpaullone**: Kenpaullone inhibits GSK-3a/b and CDKs, and it was found to inhibit CCCP-mediated mitochondrial depolarization and enhance the mitochondrial network.

2. **Comparison of Drugs**: The study compared the efficacy of various drugs, including kenpaullone, alsterpaullone, 1-azakenapaullone, AZD5438, AT7519, dexpramipexole, and olesoxime, in preventing CCCP-mediated mitochondrial depolarization.

3. **AZD5438 and AT7519**: Among the drugs tested, AZD5438 and AT7519 were the most effective in preventing CCCP-induced mitochondrial depolarization.

4. **Effect of AZD5438**: Treatment with AZD5438 alone increased the complexity of the mitochondrial network. It also prevented the decrease in PGC-1alpha and TOM20 levels induced by rotenone, a compound known to affect mitochondrial function.

5. **Anti-Apoptotic Effects**: AZD5438 demonstrated powerful anti-apoptotic effects, which means it helped protect cells from undergoing programmed cell death.

6. **Glycolytic Respiration**: AZD5438 promoted glycolytic respiration, indicating a shift in cellular energy metabolism.

7. **Protective Effects in Neurons**: Experiments conducted on human iPSC-derived cortical and midbrain neurons showed that AZD5438 had significant protective effects. It prevented neuronal cell death and maintained the integrity of neurites and the mitochondrial network when exposed to rotenone, which is known to be toxic to neurons.

8. **Therapeutic Potential**: The findings suggest that drugs targeting GSK-3a/b and CDKs, such as AZD5438 and AT7519, should be further developed and assessed for their therapeutic potential, especially in conditions where mitochondrial dysfunction and neuronal damage are implicated.

These results indicate that AZD5438, in particular, has promising neuroprotective properties and may hold potential as a therapeutic agent for conditions involving mitochondrial dysfunction and neurodegeneration. Further research and clinical trials may be needed to explore its efficacy and safety in specific medical contexts.

Related Products

Cat.No.	Product Name	Information
S2621	AZD5438	AZD5438 is a potent inhibitor of CDK1/2/9 with IC50 of 16 nM/6 nM/20 nM in cell-free assays. It is less potent to CDK5/6 and also inhibits GSK3β.

Related Targets

CDK