Identifying the Role of Novel Protein Kinase C Isoforms in Mediating Paclitaxel-Induced Peripheral Neuropathy

Abstract

Review of He and WangPaclitaxel (Taxol) is a commonly prescribed chemotherapeutic drug that stabilizes microtubules and consequently prevents progression of mitosis in rapidly dividing tumor cells. Like many other chemotherapeutics, paclitaxel is not selective, and it can therefore produce many undesired side effects. One debilitating effect experienced by individuals receiving the drug is paclitaxelinduced peripheral neuropathy (PIPN). The neuropathy is characterized by spontaneous pain, as well as evoked hyperalgesia and allodynia. Due to a limited physiological understanding of PIPN, there are few treatments available for patients experiencing PIPN (Scripture et al., 2006).Multiple second messenger signaling molecules have been implicated in the pathophysiology of PIPN, including cAMP, protein kinase A, and protein kinase C (PKC) (Hucho and Levine, 2007). Although each is necessary for pain transmission, PKC plays a predominant role in the nociceptive pathway involved in chronic pain and PIPN. Specifically, inhibition of the PKC isoform in chronic pain models has been shown to block hyperalgesia, whereas inhibition of other second messengers, like cAMP, only partially block hyperalgesia. Many chronic pain studies have focused on the role of PKC in evoked pain, while neglecting its role in spontaneous pain. Furthermore, in attempts to understand chronic pain, most research has focused primarily on PKC; other isoforms of PKC (e.g., PKC␤II and PKC␦) have yet to be tested. In a recently article published in The Journal of Neuroscience, He and Wang (2015) set out to further investigate the unique roles of various PKC isoforms in both spontaneous and evoked adverse pain associated with rodent models of PIPN.Because the dorsal root ganglion (DRG) is an important site for excitatory nociceptive transmission, He and Wang (2015) focused their investigation in this region. Upon in vitro application of paclitaxel, PKC␤II and PKC␦, in addition to PKC, translocated to the plasma membrane that indicated an activated state. To determine the importance of PKC isoform activation in PIPN, He and Wang (2015) pharmacologically manipulated PKC by using specific PKC isoform inhibitors to block paclitaxel's effects on isolated DRG neurons. In normal pain transmission, calcitonin gene-related peptide (CGRP), an excitatory neuropeptide, is released from primary sensory afferents. CGRP was upregulated with paclitaxel exposure, and inhibiting any of the three PKC isoforms restored CGRP to basal concentrations, indicating that these PKC isoforms were involved in CGRP regulation. These results confirmed the previously established role for PKC in pain transmission, and identified a novel role for PKC␤II and PKC␦ as two additional PKC isoforms activated by paclitaxel treatment that are necessary for CGRP release in the nociceptive pathway and thus possibly in pain transmission.The activation of multiple PKC isoforms after paclitaxel exposure raises the possibility that differential isoform activation is associated with functional difference...

Quercetin ameliorates paclitaxel-induced neuropathic pain by stabilizing mast cells, and subsequently blocking PKCε-dependent activation of TRPV1

“…Undesirable side effects, such as hyperalgesia and allodynia, often occur during chemotherapy due to the nonselective properties of this medicine. The dose-dependent neuropathic pain that paclitaxel elicits is characterized by numbness, tingling, burning sensations, and other symptoms that significantly limit the clinical use of paclitaxel [18] . To date, few effective drugs have been developed to solve this problem.…”

“…Among these isoforms, PKCε is the most dominant in paclitaxel-induced neuropathy [18] . The activation of PKCε by other inflammatory mediators, such as bradykinin, has been proven to enhance the sensitivity of nociceptive neurons to heat stimulation [44] .…”

Corydalis saxicola Bunting total alkaloids attenuate paclitaxel-induced peripheral neuropathy through PKCε/p38 MAPK/TRPV1 signaling pathway

“…There are three isoforms of PKC that are co-labeled with TRPV1 on nociceptors [ 6 , 45 ]. Among these isoforms, PKCε is the most important in paclitaxel-induced neuropathy [ 47 ]. PKCε, one of the subtypes of PKC, induces intracellular signaling pathways in primary nociceptor receptors and mediates cytokine-induced nociceptor receptors activation.…”

Corydalis Saxicola Bunting Total Alkaloids Inhibits Paclitaxel-Induced Peripheral Neuropathy By Regulating PKCε-TRPV1 and p38 MAPK-TRPV1 Signaling Pathways

“…There are three isoforms of PKC that are co-labeled with TRPV1 on nociceptors [6,13]. Among these isoforms, PKCε is the most dominant in paclitaxel-induced neuropathy [14]. Mitogenactivated protein kinases (MAPK) convert extracellular stimuli into a variety of intracellular reactions by changing the modi cation of target proteins after transcription and translation.…”