Inhibition of Chk2 promotes neuroprotection, axon regeneration, and functional recovery after CNS injury

Sci. Adv., 2022 · DOI: 10.1126/sciadv.abq2611 · Published: September 14, 2022

Simple Explanation

DNA damage, specifically double-strand breaks (DSBs), can lead to neural dysfunction and apoptosis in various neurological conditions. The study found that targeting the ATM-Chk2 pathway, which regulates the response to DSBs, can slow neural decline. Inhibiting Chk2, a key protein in this pathway, promotes functional recovery after acute central nervous system (CNS) injury in rats. This suggests that focusing on nonhomologous end-joining (NHEJ) repair, rather than homologous recombination repair (HRR), is crucial for neuroprotection. The drug prexasertib, a Chk1/Chk2 inhibitor previously tested in cancer trials, shows significant neuroprotective effects. This makes it a potential treatment to encourage functional recovery following spinal cord or optic nerve injury, possibly becoming the first restorative treatment for SCI.

Study Duration

6 Weeks

Participants

Rats (n=6-18 per group), Drosophila

Evidence Level

Level II; Experimental Study (in-vivo and in-vitro)

Key Findings

1
Knockdown of ATM and Chk2 is neuroprotective in Drosophila models of chronic neurodegeneration, suggesting that suppressing the ATM-Chk2 pathway can help preserve neuronal function.
2
Inhibition of Chk2, but not Chk1, promotes dorsal root ganglion neuron (DRGN) survival and neurite outgrowth in in vitro models of spinal cord injury, indicating Chk2 as a key target molecule for neuroprotection.
3
In vivo experiments showed that Chk2 inhibition promotes axon regeneration/plasticity and functional recovery after spinal cord injury in rats, leading to improvements in electrophysiological, sensory, and locomotor function.

Research Summary

This study demonstrates that Chk2 is a promising therapeutic target for preventing functional decline in both acute and chronic neurological diseases. Targeting Chk2 suppresses neurodegeneration in Drosophila models and promotes significant recovery in rats after spinal cord and optic nerve injuries. The accumulation of DNA double-strand breaks (DSBs) is common in neurological diseases, leading to chronic activation of the DNA damage response (DDR). Neurons often fail to fully repair these DSBs, resulting in neural dysfunction and apoptosis, making the DDR pathway a key target for therapeutic intervention. Prexasertib, a clinically relevant Chk1/Chk2 inhibitor, shows significant potential as a repurposing candidate for treating spinal cord injuries. It promotes neuroprotection, axon regeneration, and marked restoration of lost function after CNS injury, addressing a major unmet clinical need.

Practical Implications

Therapeutic Target Identification

Chk2 is identified as a novel therapeutic target for neuroprotection and functional recovery after CNS injury.

Drug Repurposing Potential

Prexasertib, a clinically tested Chk1/Chk2 inhibitor, can be repurposed for treating spinal cord and optic nerve injuries.

Clinical Relevance

The study demonstrates that delayed treatment (up to 24 hours post-injury) with Chk2 inhibitors is effective, aligning with clinical timelines for patient stabilization.

Study Limitations

1
The study primarily focuses on the ATM-Chk2 pathway, and further research is needed to fully understand the interplay between ATM-Chk2 and ATR-Chk1 pathways.
2
The in vivo experiments were conducted in rat models, and further studies are necessary to validate these findings in human clinical trials.
3
The long-term effects and potential side effects of Chk2 inhibition in the CNS need to be thoroughly investigated before clinical application.

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