Pharmacological inhibition of MKP-1 exacerbates central post-stroke pain and neuroinflammation in mice
TL;DR
Findings suggest that MKP-1 may function as an endogenous negative regulator of microglia-mediated neuroinflammation following thalamic hemorrhage, and Pharmacological modulation of MKP-1 signaling warrants further investigation as a potential approach for CPSP.
Abstract
Central post-stroke pain (CPSP) remains difficult to treat due to limited understanding of its underlying mechanisms. Emerging evidence implicates microglia-driven neuroinflammation in CPSP development. Mitogen-activated protein kinase phosphatase-1 (MKP-1) negatively regulates MAPK signaling and modulates inflammation in neurological disorders, yet its role in CPSP is unclear. Using a mouse model of thalamic hemorrhage, we examined MKP-1 expression and function in CPSP. Behavioral testing assessed pain hypersensitivity and affective disturbances. Immunofluorescence and western blot evaluated MKP-1 expression, microglial activation, and inflammatory signaling in the thalamus. Pharmacological MKP-1 inhibition was employed to assess functional contributions. Thalamic hemorrhage induced persistent mechanical hypersensitivity and anxiety-like behaviors, accompanied by pronounced microglial activation in the peri-lesional thalamus. MKP-1 expression increased significantly after stroke and localized primarily to microglia. MKP-1 inhibition exacerbated pain behaviors and enhanced microglial activation, with corresponding increases in pro-inflammatory mediators and p38 MAPK phosphorylation. These findings suggest that MKP-1 may function as an endogenous negative regulator of microglia-mediated neuroinflammation following thalamic hemorrhage. Pharmacological modulation of MKP-1 signaling warrants further investigation as a potential approach for CPSP.