Hypoxia-induced sensitisation of TRPA1 in painful dysesthesia evoked by transient hindlimb ischemia/reperfusion in mice

So, Kanako; Tei, Yuna; Zhao, Meng; Miyake, Takahito; Hiyama, Haruka; Shirakawa, Hisashi; Imai, Shoichi; Mori, Yasuo; Nakagawa, Takayuki; Matsubara, Kazuo; Kaneko, Shuji

doi:10.1038/srep23261

Cited by 42 publications

(40 citation statements)

References 41 publications

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“…However, we found that mutant hTRPA1 lacking a hydroxylation-susceptible Pro 394 residue (hTRPA1-P394A) shows cold sensitivity. Similar results were obtained in wild-type hTRPA1-expressing cells pretreated with the PHD inhibitor DMOG for 2 h. Because cold stimulation evokes mitochondria-derived ROS generation, 74) the Fig. 1.…”

Section: Molecular Mechanism Of Oxaliplatin-induced Trpa1 Sensitizationsupporting

confidence: 79%

Roles of Transient Receptor Potential Ankyrin 1 in Oxaliplatin-Induced Peripheral Neuropathy

Nakagawa

Kaneko

2017

Biological & Pharmaceutical Bulletin

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Chemotherapy-induced peripheral neuropathy (CIPN), characterized by symptoms of paresthesia, dysesthesia, numbness, and pain, is a common adverse effect of several chemotherapeutic agents, including platinum-based agents, taxanes, and vinca alkaloids. However, no effective prevention or treatment strategies exist for CIPN because the mechanisms underpinning this neuropathy are poorly understood. Recent accumulating evidence suggests that some transient receptor potential (TRP) channels functioning as nociceptors in primary sensory neurons are responsible for CIPN. In this review, we focus on the specific roles of redox-sensitive TRP ankyrin 1 (TRPA1), which was first reported to be a cold nociceptor, in acute cold hypersensitivity induced by oxaliplatin, a platinum-based agent, because it induces a peculiar cold-triggered CIPN during or within hours after its infusion. Oxaliplatin-induced rapid-onset cold hypersensitivity is ameliorated by TRPA1 blockade or deficiency in mice. Consistent with this, oxaliplatin enhances the responsiveness of TRPA1 stimulation, but not of TRP melastatin 8 (TRPM8) and TRP vanilloid 1 (TRPV1), in mice and cultured mouse dorsal root ganglion neurons. These responses are mimicked by an oxaliplatin metabolite, oxalate. In human TRPA1 (hTRPA1)-expressing cells, oxaliplatin or oxalate causes TRPA1 sensitization to reactive oxygen species (ROS) by inhibiting prolyl hydroxylases (PHDs). Inhibition of PHD-mediated hydroxylation of a proline residue within the N-terminal ankyrin repeat of hTRPA1 endows TRPA1 with cold sensitivity by its sensing of cold-evoked ROS. This review discusses these findings and summarizes the evidence demonstrating that oxaliplatin-induced acute cold hypersensitivity is caused by TRPA1 sensitization to ROS via PHD inhibition, which enables TRPA1 to convert ROS signaling into cold sensitivity.

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Section: Molecular Mechanism Of Oxaliplatin-induced Trpa1 Sensitizationsupporting

confidence: 79%

Roles of Transient Receptor Potential Ankyrin 1 in Oxaliplatin-Induced Peripheral Neuropathy

Nakagawa

Kaneko

2017

Biological & Pharmaceutical Bulletin

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“…Furthermore, it has been shown that peripheral sensory neurons become sensitised upon reduced perfusion (So et al . ), leading us to speculate that the changes in the spinal cord vascular network, as a result of hyperglycaemia that we report, could alter the microenvironment of the spinal cord sensory neurons and thus alter their level of activation. This would be anticipated to contribute to changes in pain perception and underlie neuropathic pain development.…”

Section: Discussionmentioning

confidence: 68%

Diabetes‐induced microvascular complications at the level of the spinal cord: a contributing factor in diabetic neuropathic pain

Ved

Lobo

Bestall

et al. 2018

The Journal of Physiology

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Key points Diabetes is thought to induce neuropathic pain through activation of dorsal horn sensory neurons in the spinal cord.Here we explore the impact of hyperglycaemia on the blood supply supporting the spinal cord and chronic pain development.In streptozotocin‐induced diabetic rats, neuropathic pain is accompanied by a decline in microvascular integrity in the dorsal horn. Hyperglycaemia‐induced degeneration of the endothelium in the dorsal horn was associated with a loss in vascular endothelial growth factor (VEGF)‐A165b expression. VEGF‐A165b treatment prevented diabetic neuropathic pain and degeneration of the endothelium in the spinal cord.Using an endothelial‐specific VEGFR2 knockout transgenic mouse model, the loss of endothelial VEGFR2 signalling led to a decline in vascular integrity in the dorsal horn and the development of hyperalgesia in VEGFR2 knockout mice.This highlights that vascular degeneration in the spinal cord could be a previously unidentified factor in the development of diabetic neuropathic pain. AbstractAbnormalities of neurovascular interactions within the CNS of diabetic patients is associated with the onset of many neurological disease states. However, to date, the link between the neurovascular network within the spinal cord and regulation of nociception has not been investigated despite neuropathic pain being common in diabetes. We hypothesised that hyperglycaemia‐induced endothelial degeneration in the spinal cord, due to suppression of vascular endothelial growth factor (VEGF)‐A/VEGFR2 signalling, induces diabetic neuropathic pain. Nociceptive pain behaviour was investigated in a chemically induced model of type 1 diabetes (streptozotocin induced, insulin supplemented; either vehicle or VEGF‐A165b treated) and an inducible endothelial knockdown of VEGFR2 (tamoxifen induced). Diabetic animals developed mechanical allodynia and heat hyperalgesia. This was associated with a reduction in the number of blood vessels and reduction in Evans blue extravasation in the lumbar spinal cord of diabetic animals versus age‐matched controls. Endothelial markers occludin, CD31 and VE‐cadherin were downregulated in the spinal cord of the diabetic group versus controls, and there was a concurrent reduction of VEGF‐A165b expression. In diabetic animals, VEGF‐A165b treatment (biweekly i.p., 20 ng g−1) restored normal Evans blue extravasation and prevented vascular degeneration, diabetes‐induced central neuron activation and neuropathic pain. Inducible knockdown of VEGFR2 (tamoxifen treated Tie2CreERT2‐vegfr2flfl mice) led to a reduction in blood vessel network volume in the lumbar spinal cord and development of heat hyperalgesia. These findings indicate that hyperglycaemia leads to a reduction in the VEGF‐A/VEGFR2 signalling cascade, resulting in endothelial dysfunction in the spinal cord, which could be an undiscovered contributing factor to diabetic neuropathic pain.

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“…35 Two studies investigated the hypothesis that TRPA1 channels, which are present in sensory and vagal afferent neurons in the lungs and the heart, are cellular sensors of local oxygen concentration. 96,97 Measuring Ca 2+ influx in an HEK expression system, Takahashi et al 96 showed that during "normoxic" conditions, defined by the authors as a partial pressure of O 2 (pO 2 ) of ~150 mm Hg, TRPA1 activity was undetectable. In contrast, when pO 2 was ~100 mm Hg, TRPA1 activity was present, and at a pO 2 of 80 mm Hg (defined by the authors as hypoxia), TRPA1-mediated Ca 2+ influx was nearly maximal.…”

Section: Physiological Redox Signaling Regulates Trpa1 Activitymentioning

confidence: 99%

Redox regulation of transient receptor potential channels in the endothelium

Pires

Earley

2017

Microcirculation

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Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are important mediators of signaling pathways in the endothelium. Specific members of the transient receptor potential (TRP) superfamily of cation channels act as important Ca2+ influx pathways in endothelial cells, and are involved in endothelium-dependent vasodilation, regulation of barrier permeability, and angiogenesis. ROS and RNS can modulate the activity of certain TRP channels mainly by modifying specific cysteine residues or by stimulating the production of second messengers. In this review we highlight the recent literature describing in redox regulation of TRP channel activity in endothelial cells as well as the physiological importance of these pathways and implication for cardiovascular diseases.

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Hypoxia-induced sensitisation of TRPA1 in painful dysesthesia evoked by transient hindlimb ischemia/reperfusion in mice

Cited by 42 publications

References 41 publications

Roles of Transient Receptor Potential Ankyrin 1 in Oxaliplatin-Induced Peripheral Neuropathy

Roles of Transient Receptor Potential Ankyrin 1 in Oxaliplatin-Induced Peripheral Neuropathy

Diabetes‐induced microvascular complications at the level of the spinal cord: a contributing factor in diabetic neuropathic pain

Redox regulation of transient receptor potential channels in the endothelium

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