The mechanism of neuropathic pain caused by chemotherapeutic agents

In previous paper, Xiao et al. reported their study results about the roles of mitochondria in neuropathic pain. As expected, rates treated with paclitaxel or oxaliplatin have shown the significant mechano-allodynia and mechano-hyperalgesia. As is known, rotenone is an inhibitor of respiratory complex I, oligomycin is an inhibitor of ATP synthase, and auranofinan is identified as the inhibitor of the thioredoxin-thioredoxin reductase mitochondrial antioxidant defense system. The studies of Xiao demonstrate that all the three agents remarkablely increase the severity of paclitaxel-evoked and oxaliplatin-evoked mechano-allodynia and mechano-hyperalgesia without obvious effect on the mechano-sensitivity in control rats. In addition, chemotherapy-evoked peripheral neuropathic pain is also considered to be related to an abnormal spontaneous discharge in primary afferent A fibers and C fibers, and oligomycin further is confirmed to increase the frequency of discharge in both A fibers and C fibers in rats treated by paclitaxel or oxaliplatin.

In summary, treatment of chemotherapy drugs, such as paclitaxel and oxaliplatin, can contribute to the development of neuropathic pain by impacting mitochondrial function, and the effects can be enhanced by the toxins including rotenone, oligomycin, and auranofinan, which can inhibit the mitochondrial function. Therefore, drugs that have positive effects on mitochondrial function may be the potential agents in the treatment and prevention of neuropathic pain.

In a recent paper, Nicolas et al. Report their newest findings about the subject. The data show that JAK inhibitor AG490 has a highly specific effect on the induction of NMDAR-LTD, and three other JAK inhibitors, including CP690550, JAK inhibitor I, and WP1066, are also fully found to block the induction of NMDAR-LTD, suggesting that JAK is required for the induction of NMDAR-LTD. Further studies demonstrate that theJak2 is critically involved in this process, since JAK2 has more expression levels at synapses, and is activated during LTD in an NMDAR, Ca2+ and PP1/PP2B dependent manner. In addition, STAT3 is also the isoform involved in NMDAR-LTD, since the synaptic activation of NMDARs can lead to the activation and translocaion to the nucleus of STAT3 in dendrites, and activation of STAT3 is demonstrated to be required for the induction and early expression of NMDAR-LTD.

In summary, many factors in the JAK/STAT pathway, including JAK2, STAT3 are reported to play an essential role in the induction of NMDA-receptor dependent long-term depression (NMDAR-LTD) in the hippocampus. Therefore, the JAK/STAT pathway is involved in synaptic plasticity in the brain, and the corresponding kinase inhibitors may be the potential therapy against the diseases. Studies of other pathways may help improving the knowledge about Epigenetics

Numerologist Warda is hooked on OG-L002 fishing, collecting. And lastly her encouragement comes from socializing along with her companions.