# Targeting NLRP3 Inflammasome and Metabolic Dysregulation by Electroacupuncture: A Novel Therapeutic Strategy for Methamphetamine Withdrawal-Induced Depression

## TL;DR

Electroacupuncture reduces depression caused by methamphetamine withdrawal in rats by targeting the NLRP3 inflammasome and restoring brain barrier and metabolism.

## Contribution

This study first reports that electroacupuncture alleviates METH-withdrawal depression by targeting the NLRP3 inflammasome pathway.

## Key findings

- Electroacupuncture significantly restores BBB integrity and reduces neuroinflammation in METH-withdrawn rats.
- Electroacupuncture reverses transcriptomic and metabolic changes linked to NLRP3 inflammasome and brain function.
- Nigericin, an NLRP3 activator, abolishes electroacupuncture's antidepressant effects, confirming pathway dependence.

## Abstract

This study demonstrates that electroacupuncture (EA) produces robust antidepressant effects in a rat model of methamphetamine (METH) withdrawal. Behavioral tests showed that EA applied at GV20, PC6, and HT7 significantly reduced immobility in the forced swim test and enhanced exploratory activity in the open field test. Mechanistically, EA repaired blood–brain barrier (BBB) disruption, as shown by reduced hippocampal water content, decreased Evans Blue leakage, and restored expression of tight-junction proteins (Occludin, Claudin-5, ZO-1). EA also inhibited neuronal apoptosis, suppressed microglial activation, and lowered pro-inflammatory cytokines IL-6 and TNF-α. Multi-omics analyses revealed that EA reversed METH-induced alterations in 32 differentially expressed genes related to the NLRP3 inflammasome pathway (Nlrp3, Pycard, Il1b) and BBB function, while metabolomic profiling identified 13 key metabolites involved in glutamate metabolism, TCA cycle, and tryptophan pathways. Crucially, the therapeutic benefits of EA were abolished by intracerebroventricular administration of the NLRP3 activator nigericin, confirming the essential role of NLRP3 inflammasome inhibition in EA’s mechanism of action. In summary, EA represents a promising non-pharmacological approach for treating METH withdrawal-induced depression by coordinating BBB protection, suppression of neuroinflammation, and metabolic network regulation.

Molecular mechanism of EA-mediated regulation of the NLRP3 inflammasome pathway and BBB function in METH withdrawal-induced depression.Created in BioRender.

1. This study first reports that electroacupuncture alleviates METH-withdrawal depression by targeting the NLRP3 inflammasome pathway.

2. This study found that electroacupuncture significantly restores BBB integrity and reduces neuroinflammation in METH-withdrawn rats.

3. This study identified key transcriptomic changes (e.g., Nlrp3, Il1b) and metabolic alterations (glutamate, TCA, tryptophan) reversed by electroacupuncture.

4. This study demonstrated that the NLRP3 activator nigericin abolishes electroacupuncture’s therapeutic benefits, confirming pathway dependence.

5. This study provides a new theoretical basis for non-pharmacological intervention in substance withdrawal-induced depression.