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.
Over the past couple of decades, endoscopic skull base surgery (ESBS) has significantly evolved and is applied to a broad range of skull base pathologies, including sinonasal malignancies. Recent ...studies have demonstrated remarkable progress of ESBS in complete resection with low morbidity and extension of its application to larger and more complex lesions. In this review, we focus on the evolution of functional preservation and multiportal approaches. Progress in preoperative assessments and surgical techniques improved the preservation of olfactory function after ESBS. The technical feasibility of olfaction preservation even after resection of olfactory groove lesions has been reported. To overcome the limitations of extending use of the endoscopic endonasal approach in surgical fields, various types of multiportal approaches, including combinations of the endoscopic endonasal and transorbital, transmaxillary, or transoral approach, have been reported, as they are useful for complete resection of extensive pathologies while limiting morbidity. These innovative techniques are still in the process of maturation. Hence, an ongoing critical evaluation is essential to ensure efficacy.
Development of next-generation analgesics requires a better understanding of the molecular and cellular mechanisms underlying pathological pain. Accumulating evidence suggests that the activation of ...glia contributes to the central sensitization of pain signaling in the spinal cord. The role of microglia in pathological pain has been well documented, while that of astrocytes still remains unclear. After peripheral nerve inflammation or injury, spinal microglia are initially activated and subsequently sustained activation of astrocytes is precipitated, which are implicated in the induction and maintenance of pathological pain. Astrocytic activation is caused by the production of diffusible factors from primary afferent neurons (neuron-to-astrocyte signals) and activated microglia (microglia-to-astrocyte signals). Although astrocyte-to-neuron signals implicated in pathological pain is poorly understood, activated astrocytes, as well as microglia, produce proinflammatory cytokines and chemokines, which lead to adaptation of the dorsal horn neurons. Furthermore, it has been suggested that glial glutamate transporters in the spinal astrocytes are down-regulated in pathological pain and that up-regulation or functional enhancement of these transporters prevents pathological pain. This review will briefly discuss novel findings on the role of spinal astrocytes in pathological pain and their potential as a therapeutic target for novel analgesics.
Microglia, the resident immune cells in the brain, survey the environment of the healthy brain. Microglial migration is essential for many physiological and pathophysiological processes. Although ...microglia express some members of the transient receptor potential (TRP) channel family, there is little knowledge regarding the physiological roles of TRP channels in microglia. Here, we explored the role of TRP vanilloid 1 (TRPV1), a channel opened by capsaicin, heat, protons, and endovanilloids, in microglia. We found that application of capsaicin induced concentration‐dependent migration in microglia derived from wild‐type mice but not in those derived from TRPV1 knockout (TRPV1‐KO) mice. Capsaicin‐induced microglial migration was significantly inhibited by co‐application of the TRPV1 blocker SB366791 and the Ca2+ chelator BAPTA‐AM. Using RT‐PCR and immunocytochemistry, we validated that TRPV1 was expressed in microglia. Electrophysiological recording, intracellular Ca2+ imaging, and immunocytochemistry indicated that TRPV1 was localized primarily in intracellular organelles. Treatment with capsaicin induced an increase in intramitochondrial Ca2+ concentrations and mitochondrial depolarization. Furthermore, microglia derived from TRPV1‐KO mice showed delayed Ca2+ efflux compared with microglia derived from wild‐type mice. Capsaicin‐induced microglial migration was inhibited by membrane‐permeable antioxidants and MAPK inhibitors, suggesting that mitochondrial TRPV1 activation induced Ca2+‐dependent production of ROS followed by MAPK activation, which correlated with an augmented migration of microglia. Moreover, a mixture of three endovanilloids augmented microglial migration via TRPV1 activation. Together, these results indicate that mitochondrial TRPV1 plays an important role in inducing microglial migration. Activation of TRPV1 triggers an increase in intramitochondrial Ca2+ concentration and following depolarization of mitochondria, which results in mtROS production, MAPK activation, and enhancement of chemotactic activity in microglia. GLIA 2015;63:1870–1882
Main Points
Activation of TRPV1 triggers an increase i Main points; n intramitochondrial Ca2+ concentration and following depolarization of mitochondria, which results in mtROS production, MAPK activation, and enhancement of chemotactic activity in microglia.
Background:
Oxaliplatin, a platinum-based chemotherapeutic agent, causes an unusual acute peripheral neuropathy. Oxaliplatin-induced acute peripheral neuropathy appears in almost all patients rapidly ...after infusion, and is triggered or exacerbated by cold, while its mechanisms are poorly understood. In this study, the involvement of thermosensitive transient receptor potential channels (TRPA1, TRPM8 and TRPV1) in oxaliplatin-induced acute hypersensitivity was investigated in mice.
Results:
A single intraperitoneal administration of oxaliplatin (1–10 mg/kg) induced cold but not mechanical hypersensitivity within 2 h in a dose-dependent manner. Infusion of the oxaliplatin metabolite, oxalate (1.7 mg/kg), also induced acute cold hypersensitivity, while another platinum-based chemotherapeutic agent, cisplatin (5 mg/kg), or the non-platinum-containing chemotherapeutic agent, paclitaxel (6 mg/kg) failed to induce mechanical or cold hypersensitivity. The oxaliplatin-induced acute cold hypersensitivity was abolished by the TRPA1 antagonist HC-030031 (100 mg/kg) and by TRPA1 deficiency. The nocifensive behaviors evoked by intraplantar injections of allyl-isothiocyanate (AITC; TRPA1 agonist) were significantly enhanced in mice treated for 2 h with oxaliplatin (1–10 mg/kg) in a dose-dependent manner, while capsaicin (TRPV1 agonist)-evoked nocifensive behaviors were not affected. Menthol (TRPM8/TRPA1 agonist)-evoked nocifensive-like behaviors were also enhanced by oxaliplatin pretreatment, which were inhibited by TRPA1 deficiency. Similarly, oxalate enhanced, but neither cisplatin nor paclitaxel affected AITC-evoked nocifensive behaviors. Pretreatment of cultured mouse dorsal root ganglia (DRG) neurons with oxaliplatin (30–300 μM) for 1, 2, or 4 h significantly increased the number of AITC-sensitive neurons in a concentration-dependent manner whereas there was no change in the number of menthol- or capsaicin-sensitive neurons.
Conclusions:
Taken together, these results suggest that a brief treatment with oxaliplatin or its metabolite oxalate is sufficient to enhance the responsiveness of TRPA1 but not that of TRPM8 and TRPV1 expressed by DRG neurons, which may contribute to the characteristic acute peripheral neuropathy induced by oxaliplatin.
Opioid-induced respiratory depression is a potentially life-threatening adverse drug event. The purpose of this study was to evaluate the incidence of respiratory depression using the Japanese ...Adverse Drug Event Report (JADER) Database to obtain data to promote proper use of opioids. The JADER database from April 2004 to March 2017 was obtained from the Pharmaceuticals and Medical Devices Agency. We calculated the reporting odds ratios (RORs) of suspected opioids (morphine, fentanyl, oxycodone, tapentadol, methadone, tramadol, pentazocine, buprenorphine, and codeine phosphate hydrate), analyzed the daily dose at first appearance and the time-to-onset profile, and assessed the hazard type using the Weibull shape parameter. ROR analysis detected adverse event signals for all opioids. Morphine showed a large ROR value with statistical significance in elderly (≥70 years old) patients. The median daily doses of oral morphine and oxycodone for inducing respiratory depression were comparably low (30 mg/d as oral morphine equivalent dose), while that of transdermal fentanyl was 120 mg/d (oral morphine equivalent dose). On time-to-onset analysis using the Weibull distribution, those opioids were classified as the early failure type. The median time-to-onset of oral morphine, oral oxycodone and transdermal fentanyl was 5.5, 11 and 12.5 d, respectively, and almost 50% of cases were reported within 30 d. Taken together, our results suggest that it is important to monitor patients carefully for at least the first one week to one month, even if opioids are administered at a relatively low dose, especially in elderly patients administered morphine.
Riboflavin (vitamin B2) plays an important role in cellular growth and function. Riboflavin transporter 2 (RFVT2) is widely expressed in several tissues, especially in the brain and salivary glands, ...and plays an important role in the tissue disruption of riboflavin. During the last 10 years, mutations in SLC52A2 have been documented in patients with a rare neurological disorder known as Brown–Vialetto–Van Laere syndrome. However, no suitable animal model of this disease has been reported. Here, we aimed to clarify the physiological role of RFVT2 using Slc52a2-mutant mice. The appearance, body weight, and plasma riboflavin concentration of Slc52a2 heterozygous mutant (Slc52a2+/−) mice were similar to those of wild-type (WT) mice. However, intercrossing between Slc52a2+/− mice failed to generate Slc52a2 homozygous mutant (Slc52a2−/−) mice. This suggested that Slc52a2 gene deficiency results in early embryonic lethality. Our findings suggested that RFVT2 is essential for growth and development, and its deletion may influence embryonic survival.
Tissue engineering using the chondrogenic potential of mesenchymal stem cells (MSCs) is a promising approach for cartilage regenerative therapy. Although dogs are widely used as an animal model for ...cartilage regeneration, chondrogenic differentiation of canine MSCs is still challenging. In this study, we aimed at establishing the optimal conditions for canine MSC chondrogenesis. Our results demonstrated that preconditioning with fibroblast growth factor-2 and serum-free induction medium enabled robust chondrogenesis of canine MSCs. These findings will allow effective generation of cartilage tissue from canine MSCs and advance research of cartilage regeneration in both dogs and humans.
The long non-coding RNA HOTAIR has been reported to be a poor prognostic biomarker in a variety of malignant tumors. However, little is known about the association of HOTAIR with gastric cancer. We ...examined the expression of HOTAIR in 68 gastric cancer samples using quantitative real-time RT-PCR and analyzed its correlation with the clinical parameters. The functional role of HOTAIR was examined by generating human gastric cancer cell lines with increased or suppressed HOTAIR expression. The anchorage -independent growth was assessed by soft agar assay. The increased or suppressed HOTAIR expressing gastric cancer cells were injected into the tail vein or peritoneal cavity of immunodeficient mice to examine the effect of this molecule on metastasis and peritoneal dissemination. The expression of HOTAIR was significantly higher in cancer lesions than in adjacent non-cancerous tissues in human gastric cancers. In the diffuse type of gastric cancer, the High-HOTAIR group (HOTAIR/GAPDH > 1) showed significantly more venous invasion, frequent lymph node metastases and a lower overall survival rate compared to the Low-HOTAIR group (HOTAIR/GAPDH < 1). Colony formation on the soft agar was enhanced in a HOTAIR-dependent manner. HOTAIR-expressing MKN74 formed more liver metastasis compared to control when they were injected into the tail vein of mice. In addition, reduced expression of HOTAIR in KATO III suppressed peritoneal dissemination. These results suggest that HOTAIR plays a pivotal role in the development of gastric cancer.
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