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Paclitaxel (PTX) is an antineoplastic drug extracted from the Taxus species, and peripheral neuropathy is a common side effect. Paclitaxel-induced peripheral neuropathy (PIPN) seriously affects patient quality of life. Currently, the mechanism of PIPN is still unknown, and few treatments are recognized clinically. Duloxetine is recommended as the only potential treatment of chemotherapy-induced peripheral neuropathy (CIPN) by the American Society of Clinical Oncology. However, this guidance lacks a theoretical basis and experimental evidence. Our study suggested that duloxetine could improve PIPN and provide neuroprotection. We explored the potential mechanisms of duloxetine on PIPN. As a result, duloxetine acts by inhibiting poly ADP-ribose polymerase cleavage (PARP) and tumor suppressor gene p53 activation and regulating apoptosis regulator the Bcl2 family to reverse PTX-induced oxidative stress and apoptosis. Taken together, the present study shows that using duloxetine to attenuate PTX-induced peripheral nerve injury and peripheral pain may provide new clinical therapeutic targets for CIPN. SIGNIFICANCE STATEMENT: This study reported that duloxetine significantly alleviates neuropathic pain induced by paclitaxel and is related to poly ADP-ribose polymerase (PARP), tumor suppressor gene p53, and apoptosis regulator the Bcl2 family. Our findings thus not only provide important guidance to support duloxetine to become the first standard chemotherapy-induced peripheral neuropathy (CIPN) drug but also will find potential new targets and positive control for new CIPN drug development., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)

Activation of transient receptor potential melastatin 2 (TRPM2), an oxidative stress-sensitive Ca 2+ -permeable channel, contributes to the aggravation of cerebral ischemia-reperfusion (CIR) injury. Recent studies indicated that treatment with the antidepressant duloxetine for 24 hours (long term) attenuates TRPM2 activation in response to oxidative stress in neuronal cells. To examine the direct effects of antidepressants on TRPM2 activation, we examined their short-term (0-30 minutes) treatment effects on H 2 O 2 -induced TRPM2 activation in TRPM2-expressing human embryonic kidney 293 cells using the Ca 2+ indicator fura-2. Duloxetine exerted the strongest inhibitory effects on TRPM2 activation among the seven antidepressants tested. These inhibitory effects appeared to be due to the inhibition of H 2 O 2 -induced TRPM2 activation via an open-channel blocking-like mechanism, because duloxetine reduced the sustained phase but not the initial phase of increases in intracellular Ca 2+ concentrations. In a whole-cell patch-clamp study, duloxetine reduced the TRPM2-mediated inward current during the channel opening state. We also examined the effects of duloxetine in a mouse model of CIR injury. The administration of duloxetine to wild-type mice attenuated CIR injury, similar to that in Trpm2 knockout (KO) mice. The administration of duloxetine did not reduce CIR injury further in Trpm2 KO mice, suggesting that it exerts neuroprotective effects against CIR injury by inhibiting TRPM2 activation. Regarding drug repositioning, duloxetine may be a useful drug in reperfusion therapy for ischemic stroke because it has already been used clinically in therapeutics for several disorders, including depression., (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)

The inhibition of nicotinic acetylcholine receptors (nAChRs) has been proposed as a potential strategy to develop new antidepressant drugs. This is based on the observation that antidepressants that selectively block noradrenaline (NA) or serotonin (5-HT) reuptake also inhibit nAChRs. Dual antidepressants blocking both NA and 5-HT reuptake were proposed to shorten the delay in exerting their clinical effects; whether duloxetine, a prototype of dual antidepressants, also blocks nAChRs is unknown. Here we explored this question in bovine chromaffin cells (BCCs) that express native α 3 , α 5 , and α 7 nAChRs and in cell lines expressing human α 7 , α 3 β 4 , or α 4 β 2 nAChRs. We have found that duloxetine fully blocked the acetylcholine (ACh)-elicited nicotinic currents in BCCs with an IC 50 of 0.86 µ M. Such blockade seemed to be noncompetitive, voltage dependent, and partially use dependent. The ACh-elicited membrane depolarization, the elevation of cytosolic calcium ([Ca 2+ ] c ), and catecholamine release in BCCs were also blocked by duloxetine. This blockade developed slowly, and the recovery of secretion was also slow and gradual. Duloxetine did not affect Na + or Ca 2+ channel currents neither the high-K + -elicited [Ca 2+ ] c transients and secretion. Of interest was that in cell lines expressing human α 7 , α 3 β 4 , and α 4 β 2 nAChRs, duloxetine blocked nicotinic currents with IC 50 values of 0.1, 0.56, and 0.85 µ M, respectively. Thus, in blocking α 7 receptors, which are abundantly expressed in the brain, duloxetine exhibited approximately 10-fold to 100- fold higher potency with respect to reported IC 50 values for various antidepressant drugs. This may contribute to the antidepressant effect of duloxetine., (Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.)