Electroacupuncture restores Shh signaling, reducing neuroinflammation and improving cognition in vascular dementia rats

Vascular dementia (VD), a common neurodegenerative disorder, is characterized by cognitive decline due to cerebrovascular damage. A key pathological feature is chronic neuroinflammation, often driven by dysfunctional microglial activation. Microglia can adopt pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes, with M2 polarization being neuroprotective. Current treatments for VD are limited, highlighting a need for novel therapeutic strategies that can modulate neuroinflammation and microglial responses. The Sonic hedgehog (Shh) signaling pathway is known to play roles in neurogenesis and neuroprotection, making it a promising target for intervention.

Researchers induced a vascular dementia (VD) model in rats and treated them with electroacupuncture (EA), with or without the Shh pathway inhibitor cyclopamine. An in vitro VD model was also created by exposing BV2 microglial cells to oxygen-glucose deprivation (OGD). Cognitive function was assessed using novel object recognition and Morris water maze tests. Histopathological changes were examined via H&E and TUNEL staining, while synaptic ultrastructure was analyzed by transmission electron microscopy. Microglial activation and polarization were evaluated using immunofluorescence, inflammatory cytokine secretion by ELISA, and protein expression by immunoblotting. Cellular viability was measured with CCK-8 assays.

VD model rats exhibited attenuated Shh signaling in brain tissues, which EA treatment effectively restored in a duration-dependent manner. This intervention observably improved cognitive performance in novel object recognition and Morris water maze tests, mitigating neuronal damage and enhancing synaptic plasticity. EA also significantly suppressed pro-inflammatory responses, as evidenced by reduced inflammatory cytokine secretion, and promoted microglial M2 polarization. These beneficial effects of EA were completely abolished by the Shh pathway inhibitor cyclopamine, indicating a critical role for Shh signaling. Furthermore, Shh overexpression in BV2 microglia attenuated OGD-induced pro-inflammatory activation and reduced its detrimental impact on neuronal cells. This suggests that Shh-driven reprogramming of microglial responses is central to EA's neuroprotective effects.

The cognitive benefits of electroacupuncture in vascular dementia are critically dependent on Shh-driven reprogramming of microglial responses.