Altered phosphorylation of mitogen-activated protein kinases in dorsal root ganglia and sciatic nerve of rats with cisplatin-induced neuropathy

Background: Peripheral neuropathy is a major side effect of cisplatin. Cisplatin preferentially accumulates in the dorsal root ganglia (DRG) and causes neuronal apoptosis. In vitro studies have implicated mitogen-activated protein kinases (MAPKs) in cisplatin-induced apoptosis. However, this has not been confirmed in vivo. Objective: We studied the phosphorylation of MAPKs, ERK, JNK, and p38, in the DRG and sciatic nerve of rats treated with cisplatin, and correlated it with the neuropathic abnormalities. Methods: Cisplatin 2 mg/kg was intraperitoneally injected in rats twice a week for five consecutive weeks. Neuropathy was assessed by measuring hind-paw thermal and mechanical thresholds, sciatic motor nerve conduction velocity (MNCV) and morphometric evaluation of DRG and sciatic nerve at various time points after the start of cisplatin treatment. Western blot analysis was done to determine the ratio of phosphorylated to total forms of MAPKs in the DRG and sciatic nerve. Results: Cisplatin induced transient thermal hypoalgesia, late reduction in MNCV and histopathological abnormalities of DRG and sciatic nerve indicating the neuropathy. ERK was activated in the nerve and DRG in the eighth and twelfth weeks, respectively. Transient activation of JNK in the nerve and DRG was observed only in the first week. At the same time point to INK, p38 was temporarily inhibited in the DRG. Late activation of ERK was correlated with the presence of pathological changes, suggesting the possible role of ERK in these abnormalities. No correlation between MAPKs and functional abnormalities was observed. Conclusion: MAPK ERK might play a role in cisplatin-induced structural alterations in the DRG and sciatic nerve and can be the therapeutic target. However, to prove this hypothesis, future studies using the ERK inhibitor must be done.