Objective To explore the mechanism of ligustrazine (LC) in improving chemotherapy-induced neuropathic pain (CINP) by regulating the Ras homolog gene family member A (RhoA)/p38 mitogen-activated protein kinase (p38MAPK) signaling pathway.
Methods Sixty SD rats were randomly divided into five groups: control group (Con group), model group (Model group), low-dose LC group (L-LC group), high-dose LC group (H-LC group), and high-dose LC+lysophosphatidic acid group (H-LC+LPA group), with 12 rats in each group. Pain behavioral tests were performed on the rats. Neuronal lesions were observed using hematoxylin-eosin staining. The levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-10 (IL-10) were detected using enzyme-linked immunosorbent assay (ELISA). The expression levels of apoptosis, autophagy, and RhoA/p38MAPK signaling pathway-related proteins were detected using western blot. The apoptosis level in the spinal dorsal horn tissue was detected using TUNEL.
Results On 3, 5, and 7 d after surgery, the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWT) in the Model group were lower than those in the Con group. The MWT and TWT in the L-LC group and H-LC group were higher than those in the Model group, and the MWT and TWT in the H-LC group were higher than those in the L-LC group (P < 0.05). The MWT and TWT in the H-LC+LPA group were lower than those in the H-LC group (P < 0.05). Compared with the Con group, the expression levels of IL-10, SOD, B-cell lymphoma-2 (Bcl-2), autophagy-related protein (Beclin-1), BNIP protein, and LC3-Ⅱ/LC3-Ⅰ were decreased in the Model group, while the levels of TNF-α, IL-1β, ROS, MDA, caspase-1, Bax, RhoA, phosphorylated p38 mitogen-activated protein kinase (P-p38MAPK)/p38MAPK protein expression, and apoptosis rate were increased (P < 0.05). Compared with the Model group, the expression levels of IL-10, SOD, Bcl-2, Beclin-1, BNIP protein, and LC3-Ⅱ/LC3-Ⅰ were increased in the L-LC group and H-LC group, while the levels of TNF-α, IL-1β, ROS, MDA, caspase-1, Bax, RhoA, P-p38MAPK/p38MAPK protein expression, and apoptosis rate were decreased in a dose-dependent manner (P < 0.05). Compared with the H-LC group, the MWT, TWT, expression levels of IL-10, SOD, Bcl-2, Beclin-1, BNIP protein, and LC3-Ⅱ/LC3-Ⅰ were significantly decreased in the H-LC+LPA group, while the levels of TNF-α, IL-1β, ROS, MDA, caspase-1, Bax, RhoA, P-p38MAPK/p38MAPK protein expression, and apoptosis rate were increased (P < 0.05).
Conclusion LC may alleviate the neuropathic disease symptoms in CINP rats by inhibiting the RhoA/p38MAPK signaling pathway, thereby inhibiting oxidative stress, neuroinflammation, and apoptosis, and promoting autophagy.
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