Activity dependent inhibition of TRPC1/4/5 channels by duloxetine involves voltage sensor-like domain

Zímová, Lucie; Ptakova, Alexandra; Michal, Mitro,; Krůšek, Jan; Vlachová, Viktorie

doi:10.1016/j.biopha.2022.113262

Cited by 5 publications

(3 citation statements)

References 34 publications

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“…and to inhibit transient receptor potential channels of the TRPC5 subtype [42]. On the other hand, the antinociceptive activity of statins involves peripheral anti-inflammatory mechanisms as well as direct effects on nociceptive neurons and/or on some types of spinal glial cells in the central nervous system.…”

Section: Discussionmentioning

confidence: 99%

“…However, some degree of redundancy in the mechanisms triggered by rosuvastatin and duloxetine cannot be ruled out. For instance, statins can inhibit [47] or activate [48] signaling pathways downstream of some pain-sensing transient receptor potential channels, and interaction with the TRPC5 channel that detects cold pain has been recently described as part of the antinociceptive effect of duloxetine [42]. Thus, it is likely that the synergy of the rosuvastatin/duloxetine combination reported here arose from the interaction between the antinociceptive properties of rosuvastatin and duloxetine in yet undetermined molecular sites other than pain-detecting transient receptor potential channels.…”

Section: Discussionmentioning

confidence: 99%

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Rosuvastatin Synergistically Enhances the Antinociceptive Efficacy of Duloxetine in Paclitaxel-Induced Neuropathic Pain in Mice

Lobos,

Lux,

Zepeda

et al. 2023

IJMS

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Paclitaxel, a widely used cancer chemotherapeutic agent, has high incidence of neurotoxicity associated with the production of neuropathic pain, for which only duloxetine has shown significant but moderate analgesic effect. Since statins, classically used to reduce hypercholesterolemia, have shown antinociceptive effect in preclinical studies on neuropathic pain, we studied whether the antinociceptive efficacy of duloxetine could be synergistically potentiated by rosuvastatin in a model of paclitaxel-induced neuropathy in mice. The astrocytic and microglial responses in the spinal cord of paclitaxel-treated mice were also assessed by measuring GFAP and CD11b proteins, respectively. Paclitaxel treatment did not impair motor coordination and balance in rotarod testing. Rosuvastatin, duloxetine, and the rosuvastatin/duloxetine combination (combined at equieffective doses) dose-dependently decreased mechanical allodynia (ED30, von Frey testing) and thermal hyperalgesia (ED50, hot plate testing) in paclitaxel-treated mice. Isobolographic analysis showed a superadditive interaction for rosuvastatin and duloxetine, as both the ED30 and ED50 for the rosuvastatin/duloxetine combination contained only a quarter of each drug compared to the individual drugs. The rosuvastatin/duloxetine combination reversed paclitaxel-induced GFAP overexpression, indicating that such effects might depend in part on astrocyte inactivation. Results suggest that statins could be useful in synergistically enhancing the efficacy of duloxetine in some chemotherapy-induced neuropathic conditions.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Rosuvastatin Synergistically Enhances the Antinociceptive Efficacy of Duloxetine in Paclitaxel-Induced Neuropathic Pain in Mice

Lobos,

Lux,

Zepeda

et al. 2023

IJMS

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“…Zimova et al [142] used molecular docking and MD tools to characterize the binding site of the drug duloxetine on the TRPC5 ion channel. Duloxetine is used to treat severe painful disorders that are difficult to manage in clinical practice [143].…”

Section: Characterization Of Drug-ion Channel Interactions By Molecul...mentioning

confidence: 99%

Recent Advances in Computer-Aided Structure-Based Drug Design on Ion Channels

Pliushcheuskaya,

Künze

2023

IJMS

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Ion channels play important roles in fundamental biological processes, such as electric signaling in cells, muscle contraction, hormone secretion, and regulation of the immune response. Targeting ion channels with drugs represents a treatment option for neurological and cardiovascular diseases, muscular degradation disorders, and pathologies related to disturbed pain sensation. While there are more than 300 different ion channels in the human organism, drugs have been developed only for some of them and currently available drugs lack selectivity. Computational approaches are an indispensable tool for drug discovery and can speed up, especially, the early development stages of lead identification and optimization. The number of molecular structures of ion channels has considerably increased over the last ten years, providing new opportunities for structure-based drug development. This review summarizes important knowledge about ion channel classification, structure, mechanisms, and pathology with the main focus on recent developments in the field of computer-aided, structure-based drug design on ion channels. We highlight studies that link structural data with modeling and chemoinformatic approaches for the identification and characterization of new molecules targeting ion channels. These approaches hold great potential to advance research on ion channel drugs in the future.

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