Abstract
Our previous studies have shown that early systemic granulocyte colony-stimulating factor (G-CSF) treatment can attenuate neuropathic pain in rats with chronic constriction injury (CCI) by modulating expression of different proinflammatory cytokines, microRNAs, and proteins. Besides the modulation of inflammatory mediators’ expression, previous studies have also reported that G-CSF can modulate autophagic and apoptotic activity. Furthermore, both autophagy and apoptosis play important roles in chronic pain modulation. In this study, we evaluated the temporal interactions of autophagy, and apoptosis in the dorsal root ganglion (DRG) and injured sciatic nerve after G-CSF treatment in CCI rats. We studied the behaviors of CCI rats with or without G-CSF treatment and the various levels of autophagic, proinflammatory, and apoptotic proteins in injured sciatic nerves and DRG neurons at different time points using Western blot analysis and immunohistochemical methods. The results showed that G-CSF treatment upregulated autophagic protein expression in the early phase and suppressed apoptotic protein expression in the late phase after nerve injury. Thus, medication such as G-CSF can modulate autophagy, apoptosis, and different proinflammatory proteins in the injured sciatic nerve and DRG neurons, which have the potential to treat neuropathic pain. However, autophagy-mediated regulation of neuropathic pain is a time-dependent process. An increase in autophagic activity in the early phase before proinflammatory cytokines reach the threshold level to induce neuropathic pain can effectively alleviate further neuropathic pain development.
Highlights
We studied the interactions between autophagy, proinflammatory cytokines, and apoptosis in dorsal root ganglion (DRG) neurons and injured sciatic nerves in constriction injury (CCI) rats with or without granulocyte colony-stimulating factor (G-CSF) treatment at different time points after nerve injury using behavioral tests, Western blot analysis, and immunohistochemical methods
Mechanical allodynia in G-CSF-treated CCI rats was significantly attenuated compared to vehicle-treated CCI rats from the 1st to the 7th day after nerve injury (p < 0.01)
N = 8 in each group. (C) Western blot analysis revealed significantly lower phospho-c-Jun protein levels in the injured sciatic nerve in G-CSF-treated CCI rats than in vehicle-treated CCI rats (* p < 0.05: G-CSF-treated CCI rats compared to vehicle-treated CCI rats) on the 1st day after nerve injury
Summary
Previous studies, including ours, have shown that granulocyte colony-stimulating factor (G-CSF) treatment can attenuate neuropathic pain in rats with chronic constriction. Previous studies have reported that G-CSF treatment recruits opioid-containing polymorphonuclear granulocytes (PMNs), upregulates Mu opioid receptors (MORs) on injured nerves, suppresses proinflammatory cytokines (Interleukin-6 [IL-6], Tumor Necrosis Factor-α [TNF-α] and monocyte chemoattractant protein-1 [MCP-1]) in dorsal root ganglia (DRG) neurons and downregulates phosphorylated p38 and microglial activity in the spinal dorsal horn, attenuating neuropathic pain in CCI rats [1,2,3,4,5]. Guo et al reported that systemic G-CSF treatment in rats with spinal cord injury could improve motor function and reduce damage to neural tissue in the spinal cord by promoting autophagy and inhibiting apoptosis [9]
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