Cisplatin-induced neuropathic pain is mediated by upregulation of N-type voltage-gated calcium channels in dorsal root ganglion neurons

Leo, Markus; Schmitt, Linda-Isabell; Erkel, Martin; Melnikova, Margarita; Thomale, Jürgen; Hagenacker, Tim

doi:10.1016/j.expneurol.2016.11.003

Cited by 47 publications

(49 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Interestingly, antineoplastics also alter α 2 δ subunit expression. Oxaliplatin, cisplatin, and paclitaxel increase α 2 δ expression in DRG neurons, 49–51,55 while paclitaxel increases α 2 δ expression in the dorsal horn. 50,52 Gabapentin, a clinically relevant anti-epileptic drug that binds to the Ca V α 2 δ subunit, 126 has been shown to have anti-hyperalgesic properties in CIPN.…”

Section: Calcium Channelsmentioning

confidence: 93%

“…Short-term increase in N-type currents occurs via protein kinase C (PKC), but long-term changes are mediated via CaMKII. 55 Regulation of intracellular Ca 2+ has important consequences on cell survival as nimodipine, an L-type (i.e., Ca V 1.1–1.4) Ca 2+ channel inhibitor, or ω-conotoxin, an N-type (i.e., Ca V 2.2) Ca 2+ channel inhibitor, reduce cisplatin-induced DRG neuronal death in vitro. 55,123 …”

Section: Calcium Channelsmentioning

confidence: 99%

See 1 more Smart Citation

Ion channels and neuronal hyperexcitability in chemotherapy-induced peripheral neuropathy

Aromolaran

Goldstein

2017

Mol Pain

View full text Add to dashboard Cite

Cancer is the second leading cause of death worldwide and is a major global health burden. Significant improvements in survival have been achieved, due in part to advances in adjuvant antineoplastic chemotherapy. The most commonly used antineoplastics belong to the taxane, platinum, and vinca alkaloid families. While beneficial, these agents are frequently accompanied by severe side effects, including chemotherapy-induced peripheral neuropathy (CPIN). While CPIN affects both motor and sensory systems, the majority of symptoms are sensory, with pain, tingling, and numbness being the predominant complaints. CPIN not only decreases the quality of life of cancer survivors but also can lead to discontinuation of treatment, thereby adversely affecting survival. Consequently, minimizing the incidence or severity of CPIN is highly desirable, but strategies to prevent and/or treat CIPN have proven elusive. One difficulty in achieving this goal arises from the fact that the molecular and cellular mechanisms that produce CPIN are not fully known; however, one common mechanism appears to be changes in ion channel expression in primary afferent sensory neurons. The processes that underlie chemotherapy-induced changes in ion channel expression and function are poorly understood. Not all antineoplastic agents directly affect ion channel function, suggesting additional pathways may contribute to the development of CPIN Indeed, there are indications that these drugs may mediate their effects through cellular signaling pathways including second messengers and inflammatory cytokines. Here, we focus on ion channelopathies as causal mechanisms for CPIN and review the data from both pre-clinical animal models and from human studies with the aim of facilitating the development of appropriate strategies to prevent and/or treat CPIN.

show abstract

Section: Calcium Channelsmentioning

confidence: 93%

Section: Calcium Channelsmentioning

confidence: 99%

Ion channels and neuronal hyperexcitability in chemotherapy-induced peripheral neuropathy

Aromolaran

Goldstein

2017

Mol Pain

View full text Add to dashboard Cite

show abstract

“…Overview of possible effects of oxaliplatin and cisplatin on the immune system (Raghavendra et al, 2003; Callizot et al, 2008; Boyette-Davis and Dougherty, 2011; Wang et al, 2012; Di Cesare Mannelli et al, 2014; Janes et al, 2015), microglia (Di Cesare Mannelli et al, 2014) and peripheral neurons (Zwelling et al, 1979; Thompson et al, 1984; Faivre et al, 2003; Tomaszewski and Busselberg, 2007; Todd and Lippard, 2009; Tesniere et al, 2010; Alcindor and Beauger, 2011; Boyette-Davis and Dougherty, 2011; Deuis et al, 2013; Areti et al, 2014; Boehmerle et al, 2014; Dasari and Tchounwou, 2014; Canta et al, 2015; Leo et al, 2017) leading to neuronal inflammation (Janes et al, 2015) and altered neuronal excitability (Adelsberger et al, 2000; Krishnan et al, 2005; Kagiava et al, 2008; Gauchan et al, 2009; Ta et al, 2010; Descoeur et al, 2011; Nassini et al, 2011; Schulze et al, 2011; Sittl et al, 2012; Deuis et al, 2013, 2014; Yamamoto et al, 2015; Mizoguchi et al, 2016). TNFα, Tumor necrosis factor alpha; DNA, deoxyribonucleic acid; ROS, Reactive oxygen species; Na V , Voltage-gated sodium channel; K V , Voltage-gated potassium channel; TRP, Transient receptor potential channel; Ca V , Voltage-gated calcium channel.…”

Section: Cancer Chemotherapy: Drug Mechanism Of Action and Metabolitesmentioning

confidence: 99%

“…In sensory neurons, cisplatin increased the expression of the N-type voltage-gated Ca 2+ channels (Ca V 2.2), although it differentially affects the function of specific Ca V channel subtypes (Tomaszewski and Busselberg, 2007; Leo et al, 2017). However, the contribution of these effects to the clinical presentation of cisplatin-induced neuropathy remains unclear.…”

Section: Pathological Mechanisms Contributing To Cipnmentioning

confidence: 99%

Pathophysiology of Chemotherapy-Induced Peripheral Neuropathy

Starobova

Vetter

2017

Front. Mol. Neurosci.

472

400

View full text Add to dashboard Cite

Chemotherapy-induced neuropathy is a common, dose-dependent adverse effect of several antineoplastics. It can lead to detrimental dose reductions and discontinuation of treatment, and severely affects the quality of life of cancer survivors. Clinically, chemotherapy-induced peripheral neuropathy presents as deficits in sensory, motor, and autonomic function which develop in a glove and stocking distribution due to preferential effects on longer axons. The pathophysiological processes are multi-factorial and involve oxidative stress, apoptotic mechanisms, altered calcium homeostasis, axon degeneration and membrane remodeling as well as immune processes and neuroinflammation. This review focusses on the commonly used antineoplastic substances oxaliplatin, cisplatin, vincristine, docetaxel, and paclitaxel which interfere with the cancer cell cycle—leading to cell death and tumor degradation—and cause severe acute and chronic peripheral neuropathies. We discuss drug mechanism of action and pharmacokinetic disposition relevant to the development of peripheral neuropathy, the epidemiology and clinical presentation of chemotherapy-induced neuropathy, emerging insight into genetic susceptibilities as well as current understanding of the pathophysiology and treatment approaches.

show abstract

“…Initial studies using whole cell patch-clamp electrophysiological technique reported that cisplatin decreases the calcium channel currents, particularly in small-diameter neurons of rat DRG[ 38 ]. However, a new study revealed an increase in calcium influx through N-type calcium channels in rat DRG neurons after exposure to cisplatin[ 39 ]. This was mainly caused by the upregulation of the N-type calcium channels.…”

Section: Introductionmentioning

confidence: 99%

Platinum-induced neurotoxicity: A review of possible mechanisms

Kanat

Ertas

Caner

2017

WJCO

126

View full text Add to dashboard Cite

Patients treated with platinum-based chemotherapy frequently experience neurotoxic symptoms, which may lead to premature discontinuation of therapy. Despite discontinuation of platinum drugs, these symptoms can persist over a long period of time. Cisplatin and oxaliplatin, among all platinum drugs, have significant neurotoxic potential. A distal dose-dependent symmetrical sensory neuropathy is the most common presentation of platinum neurotoxicity. DNA damage-induced apoptosis of dorsal root ganglion (DRG) neurons seems to be the principal cause of neurological symptoms. However, DRG injury alone cannot explain some unique symptoms such as cold-aggravated burning pain affecting distal extremities that is observed with oxaliplatin administration. In this article, we briefly reviewed potential mechanisms for the development of platinum drugs-associated neurological manifestations.

show abstract

Cisplatin-induced neuropathic pain is mediated by upregulation of N-type voltage-gated calcium channels in dorsal root ganglion neurons

Cited by 47 publications

References 55 publications

Ion channels and neuronal hyperexcitability in chemotherapy-induced peripheral neuropathy

Ion channels and neuronal hyperexcitability in chemotherapy-induced peripheral neuropathy

Pathophysiology of Chemotherapy-Induced Peripheral Neuropathy

Platinum-induced neurotoxicity: A review of possible mechanisms

Contact Info

Product

Resources

About