3,4-Dimethoxychalcone, a caloric restriction mimetic, enhances TFEB-mediated autophagy and alleviates pyroptosis and necroptosis after spinal cord injury

Theranostics, 2023 · DOI: 10.7150/thno.78370 · Published: January 1, 2023

Simple Explanation

Spinal cord injury (SCI) often leads to permanent paralysis and various motor, sensory and autonomic nervous system dysfunctions, which seriously affect quality of life and life expectancy. 3,4-DC promotes functional recovery by upregulating TFEB-mediated autophagy and inhibiting pyroptosis and necroptosis after SCI, which may have potential clinical application value. Caloric restriction mimetics (CRMs) were designed to simulate the favourable effects of CR without decreasing food consumption. CRMs are natural or synthetic compounds that mimic calorie restriction by reducing protein acetylation to induce protective autophagy

Study Duration

Not specified

Participants

276 female C57BL/6J mice

Evidence Level

Not specified

Key Findings

1
3,4-DC reduced glial scar area and motor neuron death and improved functional recovery after SCI.
2
3,4-DC inhibited pyroptosis and necroptosis by enhancing autophagy.
3
3,4-DC enhances autophagy by promoting TFEB activity. A decrease in the TFEB level abolished the protective effect of 3,4-DC.

Research Summary

This study investigated the neuroprotective potency of 3,4-DC as a candidate CRMs in a traumatic SCI model, finding that 3,4-DC mainly promoted functional recovery after SCI by regulating autophagy, pyroptosis and necroptosis. The study found that 3,4-DC treatment promoted neuronal autophagy. Furthermore, inhibition of autophagy by 3MA partially reversed pyroptosis activity and functional recovery after 3,4-DC treatment. 3,4-DC promotes TFEB nuclear translocation through the AMPK–TRPML1–calcineurin signalling pathway, thereby enhancing autophagy in SCI, leading to the inhibition of pyroptosis and necroptosis in the injured spinal cord and helping to restore function after SCI.

Practical Implications

Potential Therapeutic Target

CRMs like 3,4-DC could be further explored as a therapeutic approach for SCI.

Underlying Mechanisms

The study provides insights into the mechanisms by which 3,4-DC enhances autophagy and reduces pyroptosis and necroptosis.

Clinical Application

The findings support the potential clinical application of CRMs in the treatment of SCI, although further evaluation and optimization are needed.

Study Limitations

1
Toxicological effects and side effects of 3,4-DC need full evaluation before clinical application.
2
The timeframe in which 3,4-DC treatment promotes behavioural recovery in an SCI model must be further investigated.
3
The study primarily focused on the acute effects of CRMs and further studies are needed to assess the long-term effects on functional restoration after SCI.

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