# Electroacupuncture alleviates blood-brain barrier disruption and neuroinflammation via astrocytic MC4R in a mouse model of multiple sclerosis

## TL;DR

Electroacupuncture helps reduce brain inflammation and protect the blood-brain barrier in a mouse model of multiple sclerosis by targeting astrocytic MC4R.

## Contribution

This study identifies astrocytic MC4R as a novel mediator of electroacupuncture's neuroprotective effects in multiple sclerosis.

## Key findings

- EA at ST36 upregulated α-MSH and MC4R in spinal astrocytes, reducing BBB disruption and neuroinflammation.
- MC4R agonists mimicked EA's effects, while antagonists weakened them, confirming MC4R's role in EA's mechanism.
- EA's neuroprotection was mediated through MC4R inhibition of MAPK and NF-κB signaling pathways.

## Abstract

Astrocytes are key regulators of neuroinflammation in multiple sclerosis (MS). Electroacupuncture (EA), a safe and cost-effective adjuvant therapy, has shown benefits in neurodegenerative diseases, but its astrocyte-related mechanisms remain unclear. Here, we demonstrated that EA at ST36 alleviated blood-brain barrier (BBB) disruption and neuroinflammation during the peak period of experimental autoimmune encephalomyelitis (EAE). Additionally, EA at ST36 upregulated the expression of α-melanocyte-stimulating hormone (α-MSH) and its receptor melanocortin-4 receptor (MC4R) in spinal astrocytes. Pharmacological studies showed that MC4R agonist RO27-3225 mimicked the therapeutic effects of EA, whereas MC4R antagonist TCMCB07 weakened EA-mediated BBB protection and neuroinflammation suppression. Moreover, astrocyte-specific silencing of MC4R via adeno-associated virus (AAV) weakened EA-mediated BBB protection and neuroinflammation suppression. RNA-sequencing (RNA-seq) and western blot (WB) revealed that EA exerts neuroprotective effects by activating MC4R to inhibit MAPK and NF-κB signaling pathways. Moreover, in MC4R-overexpressing astrocytes, α-MSH and RO27-3225 reduced inflammation responses, while TCMCB07 reversed the effects by MAPK/NF-κB signaling pathways. Collectively, our findings identify astrocytic MC4R as a critical mediator of EA-driven neuroprotection by suppressing MAPK/NF-κB signaling, providing mechanistic insight and a promising therapeutic target for EAE and other neuroinflammatory disorders.

The online version contains supplementary material available at 10.1186/s12974-025-03667-1.