Glycolytic metabolite methylglyoxal inhibits cold and menthol activation of the transient receptor potential melastatin type 8 channel

Ciobanu, Alexandru Cristian; Şelescu, Tudor; Gasler, I.; Soltuzu, L.; Babeș, Alexandru

doi:10.1002/jnr.23700

Cited by 6 publications

(3 citation statements)

References 61 publications

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“…Cold allodynia refers to pain induced by a normally innocuous cold temperature, and is one of the main clinical symptoms experienced by patients undergoing chemotherapy. It can also occur in patients with other conditions such as diabetic neuropathy 13 , fibromyalgia, and traumatic neuropathy 11 . Cold hyperalgesia, in which a noxious stimulus results in a prolonged or intense pain response, commonly occurs with chronic inflammation 14 , such as in rheumatoid arthritis 15 .…”

Section: Introductionmentioning

confidence: 99%

Novel selective, potent naphthyl TRPM8 antagonists identified through a combined ligand- and structure-based virtual screening approach

Beccari

Gemei

Monte

et al. 2017

Sci Rep

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Transient receptor potential melastatin 8 (TRPM8), a nonselective cation channel, is the predominant mammalian cold temperature thermosensor and it is activated by cold temperatures and cooling compounds, such as menthol and icilin. Because of its role in cold allodynia, cold hyperalgesia and painful syndromes TRPM8 antagonists are currently being pursued as potential therapeutic agents for the treatment of pain hypersensitivity. Recently TRPM8 has been found in subsets of bladder sensory nerve fibres, providing an opportunity to understand and treat chronic hypersensitivity. However, most of the known TRPM8 inhibitors lack selectivity, and only three selective compounds have reached clinical trials to date. Here, we applied two virtual screening strategies to find new, clinics suitable, TRPM8 inhibitors. This strategy enabled us to identify naphthyl derivatives as a novel class of potent and selective TRPM8 inhibitors. Further characterization of the pharmacologic properties of the most potent compound identified, compound 1, confirmed that it is a selective, competitive antagonist inhibitor of TRPM8. Compound 1 also proved itself active in a overreactive bladder model in vivo. Thus, the novel naphthyl derivative compound identified here could be optimized for clinical treatment of pain hypersensitivity in bladder disorders but also in different other pathologies.

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Section: Introductionmentioning

confidence: 99%

Novel selective, potent naphthyl TRPM8 antagonists identified through a combined ligand- and structure-based virtual screening approach

Beccari

Gemei

Monte

et al. 2017

Sci Rep

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“…Accumulating evidence suggests that TRPA1 is responsible for cold hypersensitivity in various rodent pain models. 27,49–52 Although we cannot fully exclude the possibility of the involvement of TRP melastatin 8, a cold-sensitive TRP channel, 53,54 the present results showed that cold hypersensitivity is accompanied by TRPA1 sensitization in the early phase of STZ-induced DPN. Consistent with a previous finding, 53 the TRPA1 mRNA expression level in the DRG was not changed in STZ-induced diabetic mice in the present study, suggesting that the enhanced responsiveness of TRPA1 is caused by functional sensitization rather than by upregulation.…”

Section: Discussionmentioning

confidence: 50%

TRPA1 sensitization during diabetic vascular impairment contributes to cold hypersensitivity in a mouse model of painful diabetic peripheral neuropathy

Hiyama

Yano

et al. 2018

Mol Pain

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BackgroundDiabetic peripheral neuropathy is a common long-term complication of diabetes. Accumulating evidence suggests that vascular impairment plays important roles in the pathogenesis of diabetic peripheral neuropathy, while the mechanism remains unclear. We recently reported that transient receptor potential ankyrin 1 (TRPA1) is sensitized by hypoxia, which can contribute to cold hypersensitivity. In this study, we investigated the involvement of TRPA1 and vascular impairment in painful diabetic peripheral neuropathy using streptozotocin-induced diabetic model mice.ResultsStreptozotocin-induced diabetic model mice showed mechanical and cold hypersensitivity with a peak at two weeks after the streptozotocin administration, which were likely to be paralleled with the decrease in the skin blood flow of the hindpaw. Streptozotocin-induced cold hypersensitivity was significantly inhibited by an antagonist HC-030031 (100 mg/kg) or deficiency for TRPA1, whereas mechanical hypersensitivity was unaltered. Consistent with these results, the nocifensive behaviors evoked by an intraplantar injection of the TRPA1 agonist allyl isothiocyanate (AITC) were enhanced two weeks after the streptozotocin administration. Both streptozotocin-induced cold hypersensitivity and the enhanced AITC-evoked nocifensive behaviors were significantly inhibited by a vasodilator, tadalafil (10 mg/kg), with recovery of the decreased skin blood flow. Similarly, in a mouse model of hindlimb ischemia induced by the ligation of the external iliac artery, AITC-evoked nocifensive behaviors were significantly enhanced three and seven days after the ischemic operation, whereas mechanical hypersensitivity was unaltered in TRPA1-knockout mice. However, no difference was observed between wild-type and TRPA1-knockout mice in the hyposensitivity for current or mechanical stimulation or the deceased density of intraepidermal nerve fibers eight weeks after the streptozotocin administration.ConclusionThese results suggest that TRPA1 sensitization during diabetic vascular impairment causes cold, but not mechanical, hypersensitivity in the early painful phase of diabetic peripheral neuropathy. However, TRPA1 may play little or no role in the progression of diabetic peripheral neuropathy.

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“…Previous studies have shown that MG, as a reactive byproduct of several metabolic pathways in cells, has been linked to painful neuropathies ( Bierhaus et al, 2012 ; Ciobanu et al, 2016 ; Barragan-Iglesias et al, 2019 ). Our previous study also showed that MG accumulation contributed to radicular leg pain in patients with LDH and the NP implantation-induced LDH rat model ( Liu et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

TNF-ɑ Induces Methylglyoxal Accumulation in Lumbar Herniated Disc of Patients With Radicular Pain

Zhang

Wang

Gao

et al. 2021

Front. Behav. Neurosci.

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Lumbar disc herniation (LDH) with radicular pain is a common and complicated musculoskeletal disorder. Our previous study showed that LDH-induced methylglyoxal (MG) accumulation contributed to radicular pain. The underlying mechanisms through which MG accumulates are poorly understood. In the present study, we found that both MG and tumor necrosis factor-alpha (TNF-ɑ) levels in the herniated disc of patients with radicular pain were significantly increased, and the activity of Glyoxalase 1 (GLO1), the rate-limiting enzyme that metabolizes MG, was decreased. In rats, the LDH model was mimicked by implantation of autologous nucleus pulposus (NP) to the left lumbar five spinal nerve root. The mechanical allodynia was observed in LDH rats. Besides, MG and TNF-ɑ levels were increased, and GLO1 activity was significantly decreased in the implanted NP. In cultured rat NP cells, stimulation with the inflammatory mediator TNF-ɑ reduced GLO1 activity and expression. These results suggested that TNF-ɑ-induced GLO1 activity decrease contributed to MG accumulation in the herniated disc of patients with radicular pain.

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Glycolytic metabolite methylglyoxal inhibits cold and menthol activation of the transient receptor potential melastatin type 8 channel

Cited by 6 publications

References 61 publications

Novel selective, potent naphthyl TRPM8 antagonists identified through a combined ligand- and structure-based virtual screening approach

Novel selective, potent naphthyl TRPM8 antagonists identified through a combined ligand- and structure-based virtual screening approach

TRPA1 sensitization during diabetic vascular impairment contributes to cold hypersensitivity in a mouse model of painful diabetic peripheral neuropathy

TNF-ɑ Induces Methylglyoxal Accumulation in Lumbar Herniated Disc of Patients With Radicular Pain

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