Increases in the urinary levels of the 5-HT metabolite, 5-HIAA, correlate with periods of nausea and emesis in humans

Increases in the urinary levels of the 5-HT metabolite, 5-HIAA, correlate with periods of nausea and emesis in humans. development of drugs that can protect the nervous system, reduce symptoms experienced by millions of patients, and improve the outcome of the treatment and patients quality of life. and showed functional and morphological Losartan damage after platinum exposure; mitochondria appeared swollen and vacuolated with impaired mtDNA replication and ATP production (Canta et al., 2015). Additionally, mitochondria are localized Losartan in the axons of the neurons of the PNS, thus causing alterations in the axonal transport; this phenomenon is thought to be involved in the onset of neuropathic pain (Chiorazzi et al., 2015). Mitochondria and endoplasmic reticulum are internal storages for Ca2+; when damaged, intracellular levels of Ca2+ are increased, with the consequent alteration in neuronal excitability and activation of calpain causing axonal degeneration (Wang et al., 2012). Besides the chronic neuropathy, oxaliplatin presents a unique characteristic: its administration associates with an acute and transient neuropathy, which consists of muscle tightness, cramps, paresthesias, and dysesthesias in the limbs and perioral region that are worsened by cold (Lehky et al., 2004; Wolf et al., 2008; Lucchetta et al., 2012). The mechanisms of this phenomenon seem to be due to acidification of intracellular Losartan pH of DRG neurons, which does not occur in cells treated with cisplatin at equimolar concentrations. The authors hypothesize that the acidification hypersensitizes the transient receptor potential (TRP)A1 channel but could also be explained by the participation of TRPM8 and TRPV1 channels, which have been PIK3R5 implicated in this side effect (Riva et al., 2018). Growing evidence suggests an important neuro-inflammatory contribution in the development of peripheral neuropathy and structural damage caused by the direct mechanism of antitumoral agents. Although the participation of the immune system has been more profoundly studied in paclitaxel-induced neuropathy (see below), a previous study demonstrated that a single administration of oxaliplatin increased the levels of the chemokine, CCL2, and its receptor, CCR2, at the same time as mechanical hypersensitivity developed; pretreatment with the CCL2 antibody predictably prevented the development of allodynia (Illias et al., 2018). The chemokine, CX3CL1, has also been shown to be upregulated in DRG neurons and contributes to thermal hyperalgesia and an increase in the number of action potentials Losartan in small diameter neurons of the DRG in a model of oxaliplatin-induced chronic neuropathy. The increase in CX3CL1 was mediated through nuclear factor B (NF-B) pathways (Wang et al., 2017). Additionally, the chemokine, CXCL12, has been shown to be upregulated following chronic oxaliplatin administration and contributes to mechanical and thermal hypersensitivity via the TNF-/IL-1Cdependent STAT3 pathway. High mobility group box-1 (HMGB1) is a DNA binding nuclear protein that activates toll-like receptor (TLR) 4 signalling and induces inflammatory processes. Curiously, an anti-HMGB1 antibody reversed mechanical but not cold hypersensitivity induced by oxaliplatin treatment. Antagonism of HMGB1 receptors, TLR4, receptor for advanced glycation end products (RAGE) and CXCR4, prevented the appearance of mechanical allodynia, whilst only RAGE was overexpressed in the DRG; no modifications of TLR4, CXCR4 and RAGE were observed in the sciatic nerve (Tsubota et al., 2019). Additionally, and in contrast to paclitaxel treatment, oxaliplatin did not increase macrophage infiltration or accumulation in the sciatic nerve, and treatment with a macrophage depletor did not prevent or reverse allodynia in mice, but pretreatment with thrombomodulin (an endothelial transmembrane protein that sequestrates and degrades HMGB1) did prevent oxaliplatin-induced sensory neuropathy (Tsubota et al., 2019). Thus, the authors proposed that HMGB1 derived from non-macrophage cells mediates oxaliplatin-induced neuropathy (Tsubota et al., 2019). On the contrary, an increase in macrophage infiltration into DRGs did occur after repeated oxaliplatin administration, where both neurons and macrophages secreted matrix metallopeptidase (MMP) 9-2 (proteolytic enzymes involved in neuroinflammation and chronic pain), by activating TLR4 through HMGB1 protein; this mechanism contributes to the onset of mechanical hypersensitivity through the HMGB1-TLR4-PI3K/Akt-MMP9 axis (Gu et al., 2020). These data demonstrate that although the symptoms that these drugs induce are similar, the initiating factors are different, thus future drugs with different and more selective action mechanisms can be developed. Additionally, an acute administration of oxaliplatin upregulates the phosphoinositide 3-kinases – mammalian target of rapamycin receptor (PI3K-mTOR) pathways and the resultant expression of cytokines, interleukin (IL)-6, IL-1 and tumor necrosis factor (TNF)-, whilst inhibiting PI3K signalling reduces mechanical and cold hypersensitivity and the levels of proinflammatory cytokines (Duan et al., 2018). Sex dimorphism has been shown.