2026: Fasudil attenuates fluoride-induced neuronal synaptic damage by inhibiting microglial inflammation

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Yang W, Bu K, Ren X, Qin S, Wang S, Chu F, Lu C, Liu Z, Liu J, Zhang Y, Yang X, Gao Y, Sun D, Sun H - "Fasudil attenuates fluoride-induced neuronal synaptic damage by inhibiting microglial inflammation" Environ Toxicol Pharmacol 126:105126 (2026)
https://doi.org/10.1016/j.etap.2026.105126

Abstract

Exposure to high levels of fluoride in drinking water has been linked to cognitive impairment, but the molecular mechanisms underlying this neurotoxicity are not fully understood. In this study, a subchronic rat model was used to investigate whether fluoride-induced synaptic damage involves RhoA/ROCK pathway-mediated microglial activation and inflammation. The role of fasudil, a specific RhoA/ROCK inhibitor, was also evaluated. The results demonstrated that fluoride activated the RhoA/ROCK cascade, stimulated microglial activation and subsequent release of pro-inflammatory cytokines, and resulted in hippocampal synaptic injury. Conversely, fasudil attenuated these effects by downregulating Iba1, TNF-α, and ROCK2 expression. Taken together, these findings establish that RhoA/ROCK signaling critically mediates fluoride-induced neuroinflammation and synaptic damage, thereby offering a mechanistic basis for assessing the neurotoxic risk of environmental fluoride exposure.

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PFPC Commentary:

The authors identify fluoride-induced activation of the RhoA/ROCK pathway but do not investigate the G-protein signalling immediately upstream of RhoA. Gq/11 provides a well-established route to RhoA activation through p63RhoGEF and related RhoGEFs, in addition to its canonical PLCβ pathway. Their findings therefore extend the growing evidence for fluoride effects on Gq/11-linked signalling, while leaving the initiating G-protein mechanism unresolved.

fluoride -> ? -> Gq/11 -> p63RhoGEF/Trio/Kalirin -> RhoA -> ROCK -> microglial inflammation -> synaptic injury

Lutz S, Freichel-Blomquist A, Yang Y, Rümenapp U, Jakobs KH, Schmidt M, Wieland T - "The Guanine Nucleotide Exchange Factor p63RhoGEF, a Specific Link between Gq/11-coupled Receptor Signaling and RhoA" J Biol Chem 280(12):11134-11139 (2005)
https://doi.org/10.1074/jbc.M411322200
"Gq/11-coupled receptors specifically induce Rho signaling through a direct interaction of activated Gαq/11 subunits with p63RhoGEF."