, 2000) Using rodent model of neuropathy, it has been demonstrat

, 2000). Using rodent model of neuropathy, it has been demonstrated that systemic inhibition of AK295 reduces the behavioral and electrophysiological function associated with neuropathy without interfering with the primary Doramapimod antineoplastic effects of taxol on microtubules and cell death ( Wang et al., 2004). Oxaliplatin leads to an increase in the TUNEL-positive cells in rat DRG neurons

that is completely reversed by z-VAD-fmk, a caspase inhibitor ( Ta et al., 2006) indicating the involvement of caspase mediated apoptosis in oxaliplatin neurotoxicity. The studies have shown the involvement of the MAPKs family in platinum derivative (ciaplatin and oxaliplatin)-induced peripheral neuropathy (Scuteri et al., 2009). The prolonged exposure to oxaliplatin induces early activation of p38 and ERK1/2 in DRG neurons, which in-turn mediate neuronal apoptosis. On the other hand, oxaliplatin down regulates JNK/Sapk which in-turn is responsible for neurotoxic effects (Rutkove, 2001). Recently, Metabolism inhibitor it has been demonstrated that nerve growth factor protects DRG neurons from oxaliplatin-induced toxicity by restoring the MAPK activation. Furthermore, administration of retinoic acid, a pro-differentiative agent able to activate both JNK/Sapk and ERK1/2, is shown to prevent the toxicity

suggesting the dual role of ERK1/2 depending on the cellular stimulation (Scuteri et al., 2010). Excitotoxic glutamate release leading to excessive glutamatergic neurotransmission and activation of N-methyl-d-aspartate Cediranib (AZD2171) (NMDA) receptors, is associated

with neuronal damage and death in several nervous system disorders. An earlier study had shown that even with a maximally tolerated dose of the potent NMDA receptor antagonist, MK-801, no significant reversal of the mechanical allodynia/hyperalgesia takes place in paclitaxel-induced neuropathic pain (Flatters and Bennett, 2004). However in later studies, the role of glutamate and its NMDA in development of anti-cancer agents-induced neuropathic pain has been described. A recent study has shown that administration of ketamine, NMDA receptor antagonist, attenuates paclitaxel-induced mechanical and thermal hyperalgesia (Pascual et al., 2010). The pharmacological inhibition of enzyme glutamate carboxypeptidase (hydrolyses N-acetyl-aspartyl-glutamate to produce glutamate) leading to decreased glutamate is associated with neuroprotective effects in animal models of cisplatin, paclitaxel and bortezomib-induced peripheral neuropathy (Carozzi et al., 2010). In oxaliplatin-induced neuropathy, an increased expression of NMDA receptors subtype, NR2B (subtypes of NMDA receptors) protein and mRNA in the rat spinal cord is reported during late phase, but not in early phase. Administration of selective NR2B antagonists Ro25-6981 and ifenprodil significantly attenuates the oxaliplatin-induced pain behavior.

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