Paclitaxel (PTX), the parent of taxanes, is included among first line treatments of a plethora of common cancers such as breast and ovarian cancers [1,2]. Although, PTX produces a significant reduction in tumor progression and improves survival rates [3,4], it is associated with peripheral neuropathy [5]. Paclitaxel-induced peripheral neuropathy (PIPN) presents predominantly as a sensory neuropathy which develops in a symmetric, distal, stocking and glove distribution. Symptoms include tactile allodynia and numbness which is sometimes accompanied with spontaneous pain, and patients often define their symptoms as “walking on needles”. Thus, for patients undergoing chemotherapy, dose reduction is the main approach to dilute neurotoxicity, while for patients with established PIPN after chemotherapy, the major practice is management of symptoms [6] which commonly persist for up to 2 years after treatment cessation. Thus, beside the imposed limitation over the use of PTX for cancer patients, PIPN significantly downgrades the quality of life of cancer survivors and rises the overall healthcare burden [7]. Albeit, extensive researches have been done in the arena, the mechanisms of PIPN remain poorly understood. Thus, up till now no standard prevention therapy is approved and only duloxetine is used for established neuropathy even though, its efficacy is limited [8].

Various mechanisms have been suggested to elucidate PIPN. Mitochondrial dysfunction which is implicated in oxidative stress [9], dysregulation of calcium and impaired regulation of ion channels are all included in the pathogenesis of PIPN [[10], [11], [12], [13]]. Neuroinflammation is found implicated in precipitating PIPN. PTX induces a chaotic disruption in levels of both proinflammatory and anti-inflammatory interleukins which promotes PIPN [[14], [15], [16], [17]]. Toll like receptor 4 (TLR4) mediates many pathological aspects of the neuroinflammation associated with PIPN [18]. TLR4, which is expressed in both nociceptors and macrophages [19,20], results in activation of p38 and nuclear factor kappa-B NF-κB. Ultimately, TLR4 activation induces secretion of proinflammatory cytokines such as tumor necrosis factor-α (TNFα) and pro-inflammatory interleukins e.g IL-1β and IL- 8 [[21], [22], [23]]. Furthermore Resman, Oblak [24] demonstrated that PTX is considered an agonist of TLR4 [25].Our concern about TLR4 as a possible target for control of PIPN swelled due to the fact that activation of TLR4 in tumor cells is associated with increased chemoresistance to PTX [[26], [27], [28]]. Thus, it is plausible to think that inhibition of PTX-induced activation of TLR4 in neuronal tissues would prevent its neuronal toxicity and interferes with development of resistance to PTX in tumor cells.

In this study we attempted to investigate the possible role of trimetazidine (TMZ), a clinically used drug for heart failure and angina, in preventing PIPN. Some reports suggest TMZ as cotreatment for cancer chemotherapy for variable reasons. TMZ, via its metabolic effects, is reported to restore muscle strength in cachectic tumor-bearing mice [29]. Furthermore, Yang, Li [30] showed that TMZ prevents Sunitinib-induced cardiotoxicity. Our hypothesis is supported by recent data suggesting that TMZ exerted an anticancer effect via downregulation of TLR4 in pancreatic tumor cells [31]. Thus, TMZ as a an approved drug with good safety profile [32] and evidence of possible virulence against tumor cells [33] is a good candidate for a repurposing trial towards its use as a neuroprotective agent. To achieve this aim, we investigated the effect of TMZ on PTX induced neuropathy as well as its anticancer effect. In addition, we studied the possible role of TLR4/p38/NF-κB pathway in this context.