Selective HCN1 block as a strategy to control oxaliplatin-induced neuropathy

Abstract

a b s t r a c tChemotherapy-Induced Peripheral Neuropathy (CIPN) is the most frequent adverse effect of pharmacological cancer treatments. The occurrence of neuropathy prevents the administration of fully-effective drug regimen, affects negatively the quality of life of patients, and may lead to therapy discontinuation. CIPN is currently treated with anticonvulsants, antidepressants, opioids and non-opioid analgesics, all of which are flawed by insufficient anti-hyperalgesic efficacy or addictive potential. Understandably, developing new drugs targeting CIPN-specific pathogenic mechanisms would dramatically improve efficacy and tolerability of anti-neuropathic therapies. Neuropathies are associated to aberrant excitability of DRG neurons due to the alteration in the expression or function of a variety of ion channels. In this regard, Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels are overexpressed in inflammatory and neuropathic pain states, and HCN blockers have been shown to reduce neuronal excitability and to ameliorate painful states in animal models. However, HCN channels are critical in cardiac action potential, and HCN blockers used so far in pre-clinical models do not discriminate between cardiac and non-cardiac HCN isoforms. In this work, we show an HCN current gain of function in DRG neurons from oxaliplatin-treated rats. Biochemically, we observed a downregulation of HCN2 expression and an upregulation of the HCN regulatory beta-subunit MirP1. Finally, we report the efficacy of the selective HCN1 inhibitor MEL57A in reducing hyperalgesia and allodynia in oxaliplatin-treated rats without cardiac effects. In conclusion, this study strengthens the evidence for a disease-specific role of HCN1 in CIPN, and proposes HCN1-selective inhibitors as new-generation pain medications with the desired efficacy and safety profile.

Characterization in Dual Activation by Oxaliplatin, a Platinum-Based Chemotherapeutic Agent of Hyperpolarization-Activated Cation and Electroporation-Induced Currents

“…As HCN2, HCN3, or mixed HCN2 + HCN3 channels are functionally expressed in GH 3 cells [24], OXAL-induced stimulation of I h in native cells does not tend to be isoform specific, although our experimental results showed that OXAL could modify the amplitude and gating of I h in GH 3 and R1220 cells. Because of the importance of I h (i.e., HCNx-encoded currents) in contributing to excitability and automaticity of electrically excitable cells [18,22,28,38,40,50], findings from the present results could provide novel insights into electrophysiological and pharmacological properties of OXAL or other structurally related compounds [19,20].…”

“…For example, OXAL has been demonstrated to suppress different types of voltage-gated K + or Na + currents in various preparations, such as myelinated axons, sciatic-nerve preparations, and motoneuron-like cells [11,[13][14][15][16]. Of interest, this agent was also recently reported to activate I h in isolated dorsal root ganglion neurons, and this action is thought to be implicated in its modifications of pain sensation [17][18][19][20].…”

Inhibitory Effective Perturbations of Cilobradine (DK-AH269), A Blocker of HCN Channels, on the Amplitude and Gating of Both Hyperpolarization-Activated Cation and Delayed-Rectifier Potassium Currents

“…It is also necessary to point out that the potential of HCN blockers in cardiac pathologies and in the management of pain is well established and that the compounds able to increase I h (e.g., oxaliplatin) may have the therapeutic potential [42,43]. Caution thus entails being raised in attributing the action of CIL on either cardiac function or neuronal networks widely to the block of I h [2,18,19,30,[34][35][36]44,45].…”

Characterization of Inhibitory Effectiveness in Hyperpolarization-Activated Cation Currents by a Group of ent-Kaurane-Type Diterpenoids from Croton tonkinensis

“…In the next set of experiments, we examined and compared the effects of croton-03, YS-035, zatebradine, croton-03 plus SQ-22536, and croton-03 plus oxaliplatin on I h amplitude in GH 3 cells. YS-035 or zatebradine was recognized as an inhibitor of I h [19,29], oxaliplatin was recently demonstrated to stimulate I h [30,31], and SQ-22536 is an inhibitor adenylate cyclase. As illustrated in Figure 4, similar to the effect of croton-03 on I h described above, the addition of either YS-053 (3 µM) or zatebradine (3 µM) was effective at depressing I h amplitude.…”