Proto-oncogene tyrosine-protein kinase SRC (Src) inhibition in microglia relieves neuroinflammation in neuropathic pain mouse models

Abstract

Chronic neuroinflammation is an important factor in the development of neuropathic pain (NP). Excess microglia activation releases a mass of pro-inflammatory cytokines during neuroinflammation process, leading to a constant painful irritation of the sensory nerve. Src belongs to a non-receptor tyrosine kinase associated with sarcoma, whereas the role of Src in neuropathic pain is controversial. We designed to testify the inflammation-regulatory role of Src in the lipopolysaccharide (LPS)-induced BV2 microglia line and the mouse model of neuropathic pain by partial sciatic nerve ligation (PNL). In BV2 microglia, Src expression was inhibited using a Src family kinase inhibitor PP2 after LPS induced inflammatory response. In vivo , the neuropathic pain in mice was induced by PNL surgery and then treated with PP2. The neuroinflammation level in vitro was detected by enzyme-linked immunosorbent assay (ELISA), immunofluorescence (IF), trans-well and Western blotting (WB) assays, in vivo was examined in PNL mice using immunohistochemistry (IHC) and IF. Finally, mechanical allodynia and thermal hyperalgesia assays were used to access the functional evaluation. Inhibition of Src was decreased microglial inflammation and migration after LPS stimuli. Mechanistically, the expression of nuclear factor kappa B (NF-κB) pathway decreased after Src inhibition. The data in vivo showed that the decrease expression of Src reduced neuroinflammation and the amount of microglia in spinal dorsal horn (SDH), the mechanical allodynia of mice thereby attenuated after Src inhibition. These results indicated that the inhibition of Src took a protective effect in neuropathic pain mouse models via reducing microglia-induced neuroinflammation.

Mechanism of Action of Tripterygium wilfordii on Systemic Lupus Erythematosus Based on Network Pharmacology and Molecular Docking

“…SRC is a tyrosine kinase involved in a variety of cellular processes [24] and it has been reported to mediate inflammatory responses. Animal experiments have shown that inhibition of SRC expression can reduce microglia-induced neuroinflammation and has a protective effect on a mouse model of neuropathic pain [25] . At the same time, studies have shown that abnormal immune metabolism of Clusters of differentiation 4 + (CD4 + ) T cells and their subsets can affect the occurrence and development of SLE [26] , and the expression of SRC is also related to cell metabolism regulation [27] .…”

Ligusticum chuanxiong Hort. Ameliorates Neuropathic Pain by Regulating Microglial M1 Polarization: A Study Based on Network Pharmacology

“…SRC inhibition has been reported to play a protective role in a mouse model with NP by reducing microglia-induced neuroinflammation. 32 BCL2 is an anti-apoptotic protein that plays a key role in apoptosis regulation. 33 Ajugarin-I inhibits vincristine-induced NP by modulating Nrf2/NF-κB and BCL2 signaling.…”

Research trends and hotspots of neuropathic pain in neurodegenerative diseases: a bibliometric analysis

“…Cellular damage leads to cytokine necrosis, which causes apoptosis and further aggravates neuroinflammation. This forms a recurrent cycle ( Figure 7 ) that eventually induces central and peripheral sensitization, leading to NP ( 19 , 20 ). According to the keyword analysis, MS, PD, and AD were the three categories of neurodegenerative diseases with the highest attention in this field.…”