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Update on the Molecular Mechanisms
Molecular causes of DIPN have been addressed in several studies. Specific neuronal and non-neuronal dysfunctions leading to disruption of common pathways have been postulated and are summarized in Table 1 and Fig. 1; these include DRG cytotoxic inflammatory changes, mitotoxicity and enhanced oxidative stress, microtubular function dysruption, voltage-gated ion channel (VGIC) dysfunction, functional impairment of ion channels of the transient receptor potential (TRP) family, induction of neuronal apoptosis in DRG, demyelination, and reduction of VEGF neuroprotective action.
Inflammation
Endoneurial macrophage infiltration and subsequent secretion of pro-inflammatory cytokines [tumor necrosis factor alpha (TNFα), interleukin 1 beta (IL-1β), IL-6, and IL-8, and chemokines C-C motif ligand 2 (CCL2), CXC family], growth factors, and inflammatory mediators such as bradykinin, prostaglandins, serotonin, and nitric oxide have been correlated with acute and chronic neuropathic pain in human CIPN or in patients receiving highly active antiretroviral therapy (HAART) agents. In animal models, overexpression of matrix metalloproteinases mediating myelin turnover and phenotypic remodeling of glial and neuronal cells, as well as secondary activation of inflammatory cascades, have been recently reviewed.
In some DIPNs, medication-induced immune perturbation presumably triggers a dysimmune attack directed at unidentified peripheral nerve myelin epitopes; true peripheral nerve toxicity (i.e. dependent on accumulative dose or serum level) plays no identified role. TNF[alpha] blocking molecules and other immunomodulatory, immunosuppressive, or antineoplastic agents, widely used to treat several forms of inflammatory diseases, have been associated with dysimmune conditions, including various forms of demyelinating neuropathies.
Mitochondrial Toxicity and Oxidative Stress
The recently discovered mechanisms of mitotoxicity include a link between abnormal opening of the mitochondrial permeability transition pore (mPTP), a mitochondrial calcium leak, and a secondary organelle swelling leading to neuronal hyperexcitability; disruption of the mitochondrial electron transport chain (mETC) in inflammatory-induced neuropathic pain, with the demonstration that inhibition of the mETC complexes can counteract dideoxycytidine and TNF[alpha]-induced neuropathic pain; and enhanced oxidative stress, with impairment in the mediated respiration complexes following the administration of paclitaxel, docetaxel vincristine, oxaliplatin, and bortezomib, causing secondary production of pro-inflammatory cytokines. Oxidative stress may be particularly important, based on the significant correlation between the glutathione-S-transferase P1 (GSTP1) genotype and the development of more severe or earlier-onset CIPN following docetaxel administration.
Ion Channels
Dysfunction of the peripheral nerve VGICs has been advocated as a potential cause of DIPN.
Sodium
Oxaliplatin-induced neuropathy has been suggested from human ex-vivo and animal models to be hyperexcitability secondary to an altered state of the voltage-gated sodium channel, in particular the channel Nav1.6. These results have led to the experimental use of sodium channel blockers in animal disease models.
Potassium
Other authors, using a cellular model of oxaliplatin-induced neuropathy, have noted that dysfunction of the voltage-gated potassium channel may also be associated with nerve hyperexcitability.
Calcium
Alterations in voltage-gated calcium channel currents in the rat DRG interfering with calcium homeostasis have been associated with CIPN, especially with platinum compounds and taxanes.
Transient Receptor Potential Ion Channels
TRP channels are a group of ion channels widely expressed in neuronal (e.g. sensory DRG and trigeminal ganglia neurons) and in non-neuronal cells, located mainly on the plasma membrane. They are rather nonselectively permeable to sodium, calcium, and magnesium, and mainly involved in the transduction of a variety of painful or thermal stimuli. Several members of this family of receptors have been linked to DIPN, mainly secondary to oxaliplatin and paclitaxel, through a mechanism of oxidative stress generation; these include TRP vanilloid 1 (TRPV1, capsaicin receptor), 2, 3, 4, and 8 (menthol receptor), and ankyrin 1 (TRPA1).
Microtubules
Perturbation of axonal transport secondary to inhibition of microtubule dynamics or excessive tubulin polymerization has been well described in toxic and CIPN, and has been recently extensively reviewed.
Apoptosis
A painful sensory neuropathy has been associated with VEGF-neutralizing antibodies (bevacizumab) or VEGF receptor inhibitors (sorafenib, sunitinib; see 'What have we learned from animal models?' section above), which are usually administered in combined chemotherapy regimens. This involves disruption of the neuroprotective effect of VEGF, leading to neuronal stress and apoptosis through a mechanism involving VEGF receptor-2-mediated expression of the antiapoptotic protein Bcl2.
In another setting, mefloquine, an efficient therapeutic option for drug-resistant Plasmodium falciparum malaria, is associated with a clinically well described, but pathophysiologically poorly understood, neurotoxicity. A recent study linked mefloquine to a down-regulation of a nonreceptor tyrosine kinase, Pyk2, involved in ion channel regulation through activation of the MAP kinase signaling pathway, ultimately leading to oxidative injury and apoptosis.
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