TY  - JOUR
AU  - Boehmerle, Wolfgang
AU  - Huehnchen, Petra
AU  - Lee, Sabrina Lin Lin
AU  - Harms, Christoph
AU  - Endres, Matthias
TI  - TRPV4 inhibition prevents paclitaxel-induced neurotoxicity in preclinical models.
JO  - Experimental neurology
VL  - 306
SN  - 0014-4886
CY  - Orlando, Fla.
PB  - Academic Press
M1  - DZNE-2020-06352
SP  - 64-75
PY  - 2018
AB  - Paclitaxel is a cytotoxic drug which frequently causes sensory peripheral neuropathy in patients. Increasing evidence suggests that altered intracellular calcium (Ca2+) signals play an important role in the pathogenesis of this condition. In the present study, we examined the interplay between Ca2+ release channels in the endoplasmic reticulum (ER) and Ca2+ permeable channels in the plasma membrane in the context of paclitaxel mediated neurotoxicity. We observed that in small to medium size dorsal root ganglia neurons (DRGN) the inositol-trisphosphate receptor (InsP3R) type 1 was often concentrated in the periphery of cells, which is in contrast to homogenous ER distribution. G protein-coupled designer receptors were used to further elucidate phosphoinositide mediated Ca2+ signaling: This approach showed strong InsP3 mediated Ca2+ signals close to the plasma membrane, which can be amplified by Ca2+ entry through TRPV4 channels. In addition, our results support a physical interaction and partial colocalization of InsP3R1 and TRPV4 channels. In the context of paclitaxel-induced neurotoxicity, blocking Ca2+ influx through TRPV4 channels reduced cell death in cultured DRGN. Pretreatment of mice with the pharmacological TRPV4 inhibitor HC067047 prior to paclitaxel injections prevented electrophysiological and behavioral changes associated with paclitaxel-induced neuropathy. In summary, these results underline the relevance of TRPV4 signaling for the pathogenesis of paclitaxel-induced neuropathy and suggest novel preventive strategies.
KW  - Animals
KW  - Antineoplastic Agents, Phytogenic: toxicity
KW  - Calcium Channels: drug effects
KW  - Calcium Channels: metabolism
KW  - Calcium Signaling: drug effects
KW  - Cell Death: drug effects
KW  - Cell Membrane: drug effects
KW  - Cell Membrane: metabolism
KW  - Endoplasmic Reticulum: drug effects
KW  - Endoplasmic Reticulum: metabolism
KW  - Ganglia, Spinal: pathology
KW  - Immunohistochemistry
KW  - Inositol 1,4,5-Trisphosphate Receptors: genetics
KW  - Mice, Inbred C57BL
KW  - Neurotoxicity Syndromes: pathology
KW  - Neurotoxicity Syndromes: prevention & control
KW  - Paclitaxel: toxicity
KW  - Rats
KW  - Rats, Wistar
KW  - TRPV Cation Channels: antagonists & inhibitors
KW  - Transfection
KW  - Antineoplastic Agents, Phytogenic (NLM Chemicals)
KW  - Calcium Channels (NLM Chemicals)
KW  - Inositol 1,4,5-Trisphosphate Receptors (NLM Chemicals)
KW  - TRPV Cation Channels (NLM Chemicals)
KW  - Trpv4 protein, mouse (NLM Chemicals)
KW  - Trpv4 protein, rat (NLM Chemicals)
KW  - Paclitaxel (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:29715474
DO  - DOI:10.1016/j.expneurol.2018.04.014
UR  - https://pub.dzne.de/record/140030
ER  -