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@ARTICLE{Boehmerle:140030,
author = {Boehmerle, Wolfgang and Huehnchen, Petra and Lee, Sabrina
Lin Lin and Harms, Christoph and Endres, Matthias},
title = {{TRPV}4 inhibition prevents paclitaxel-induced
neurotoxicity in preclinical models.},
journal = {Experimental neurology},
volume = {306},
issn = {0014-4886},
address = {Orlando, Fla.},
publisher = {Academic Press},
reportid = {DZNE-2020-06352},
pages = {64-75},
year = {2018},
abstract = {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.},
keywords = {Animals / Antineoplastic Agents, Phytogenic: toxicity /
Calcium Channels: drug effects / Calcium Channels:
metabolism / Calcium Signaling: drug effects / Cell Death:
drug effects / Cell Membrane: drug effects / Cell Membrane:
metabolism / Endoplasmic Reticulum: drug effects /
Endoplasmic Reticulum: metabolism / Ganglia, Spinal:
pathology / Immunohistochemistry / Inositol
1,4,5-Trisphosphate Receptors: genetics / Mice, Inbred C57BL
/ Neurotoxicity Syndromes: pathology / Neurotoxicity
Syndromes: prevention $\&$ control / Paclitaxel: toxicity /
Rats / Rats, Wistar / TRPV Cation Channels: antagonists $\&$
inhibitors / Transfection / Antineoplastic Agents,
Phytogenic (NLM Chemicals) / Calcium Channels (NLM
Chemicals) / Inositol 1,4,5-Trisphosphate Receptors (NLM
Chemicals) / TRPV Cation Channels (NLM Chemicals) / Trpv4
protein, mouse (NLM Chemicals) / Trpv4 protein, rat (NLM
Chemicals) / Paclitaxel (NLM Chemicals)},
cin = {AG Endres},
ddc = {610},
cid = {I:(DE-2719)1811005},
pnm = {344 - Clinical and Health Care Research (POF3-344)},
pid = {G:(DE-HGF)POF3-344},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:29715474},
doi = {10.1016/j.expneurol.2018.04.014},
url = {https://pub.dzne.de/record/140030},
}