Tetrahydropalmatinee alleviates diabetic neuropathic pain by inhibiting the inflammation via p38-MAPK signaling pathway in microglia

Abstract

Object: Exploring the effect of Tetrahydropalmatine (THP) on diabetic neuropathic pain (DNP) and its possible mechanism. Methods: The type 2 diabetic (T2DM) rat models were prepared by high-fat and high-sugar feeding combined with a single small-dose intraperitoneal injection of streptozotocin (STZ). When the mechanical withdrawal threshold (MWT) and the thermal withdrawal latency (TWL) of T2DM model rats decreased to less than 85% which were judged as DNP-bearing rats. After treatment with or without THP, the protein expression of hypertonic glycerol reactive kinase (p38), phosphorylated hypertonic glycerol-responsive kinase (p-p38) and OX42 (a specific marker of microglia) were detected by Western Blot and and the mRNA content of p38 and OX42 were detected by qRT-PCR. The expression of pro-inflammatory factors IL-1β, IL-6, TNF-α, as well as chemotactic factors and their receptors including CXCL1, CXCR2, CCL2 and CCR2 in spinal tissues were detected by ELISA. Serum FINS and GSP content were also detected by ELISA. Double-label immunofluorescence were used to observe the expression of OX42 and p-p38 in the spinal dorsal horn. Results: Results showed that THP inhibited microglial activation of spinal in DNP rats. And after THP intervention, the MWT and TWL of DNP rats decreased, the expression of p38, p-p38 and OX42 in the spinal cord tissues of rats was significantly reduced while the mRNA of p38 and OX42 also reduced. The expression of IL-1β, IL-6, TNF-α, CXCL1, CXCR2, CCL2 and CCR2 in the spinal cord tissues of rats was significantly reduced (P < 0.01). At the same time, THP significantly proved FINS, but did not affect FBG and GSP in DNP rats. Conclusions: THP significantly alleviates pain symptoms in DNP rats, and this effect may be achieved by inhibiting the inflammatory response caused by the activation of microglia mediated by the p38-MAPK signaling pathway.

An Overview of the Mechanisms Involved in Neuralgia

“…The mechanism behind this effect was the inhibition of microglia and astrocyte activation in the rats' spinal cord, subsequently reducing the expression of the toll-like receptor-4/nuclear factor kappa B (TLR4/NF-κB) signaling pathway and levels of pro-inflammatory cytokines such as tumor necrosis factor α (TNF-α), IL-1β, and IL-6 in the spinal cord. 112 Corydalis yanhusuo has anti-inflammatory and analgesic properties due to its 113 treated rats with DNP using an extract of THP and observed that it promoted a shift from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype in lipopolysaccharide-induced BV2 microglia. This extract also inhibited the activation of the p38 MAPK signaling pathway, reduced expression levels of inflammatory factors such as NO, IL-1β, IL-6, and TNF-α, increased expression level of anti-inflammatory factor IL-10, and alleviated inflammatory response around the lesions, ultimately improving pain symptoms in the rats.…”