scholarly journals Transient Receptor Potential Melastatin 8 Contributes to Cystitis-Induced Neuronal Sprouting and Pain Hypersensitivity Through AKT/Mtor Signaling Pathway in Interstitial Cystitis/ Bladder Pain Syndrome

2021 ◽  
Author(s):  
Liyang Wu ◽  
Fei Zhou ◽  
Jianzhong Zhang ◽  
Ran Chang ◽  
Fei Wang ◽  
...  
Keyword(s):  
Interstitial Cystitis ◽  
Transient Receptor Potential ◽  
Pain Syndrome ◽  
Receptor Potential ◽  
Bladder Pain Syndrome ◽  
Control Group ◽  
Mtor Signaling Pathway ◽  
Bladder Pain ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor

Abstract Transient receptor potential melastatin 8 (TRPM8) is associated with the pathophysiology of interstitial cystitis (IC)/ bladder pain syndrome (BPS). We investigated the mechanism of TRPM8 in neuroproliferation and pain, as well as the relevance of the Akt/mTOR signaling pathway in mice with IC/BPS. The model of IC/BPS was established in wild and TRPM8-/- mice. The mechanical sensitivity was measured. The number of neurite segments, length of neurites, and density of neurites were all counted. IL-6 and norepinephrine levels were detected by ELISA, Western blot was used to detect protein levels of TRPM8, Akt, p-Akt, mTOR, p-mTOR. Immunofluorescence was used to detect TRPM8 expression and distribution in neurites, neurons, and sensory nerves in mouse bladder tissue. Pain threshold in the IC / BPS group was decreased, and neurite segments, length, and density were all significantly enhanced when compared to the control group. The parameters in the TRPM8 agonists(menthol)+IC/BPS group were more statistically significant. Neurite number and density were lower in TRPM8-/-+IC/BPS mice than in IC/BPS mice. The expression of TRPM8 and the ratios of p-Akt/Akt and p-mTOR/mTOR rose in the IC/BPS group. In TRPM8-/-+IC/BPS mice, the ratios of p-Akt/Akt and p-mTOR/mTOR were not substantially different from those in the control group. TRPM8-/-+IC/BPS mice had considerably lower levels of serum IL-6 and urine norepinephrine than wild-type IC/BPS mice. TRPM8 can induce pain hypersensitivity and sensory nerve proliferation by activating Akt/mTOR pathway and raising the expression of IL-6 and norepinephrine in IC/BPS models. These findings offer new perspectives on IC/BPS treatment.

scholarly journals Risk of Urinary Tract Carcinoma among Subjects with Bladder Pain Syndrome/Interstitial Cystitis: A Nationwide Population-Based Study

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Ming Ping Wu ◽  
Hao Lun Luo ◽  
Shih Feng Weng ◽  
Chung-Han Ho ◽  
Michael B. Chancellor ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Interstitial Cystitis ◽  
Subsequent Development ◽  
Pain Syndrome ◽  
Population Based ◽  
Bladder Pain Syndrome ◽  
Control Group ◽  
Bladder Pain ◽  
Comorbidity Index

Objective. To investigate the subsequent risks of urinary tract cancers among individuals with bladder pain syndrome/interstitial cystitis (BPS/IC), and gender differences, as well as the effect of associated comorbidity using a population-based administrative database in Taiwan. Patients and Methods. BPS/IC subjects (10192) and their age- and sex-matched non-BPS/IC control subjects (30576), who had no previous upper urinary tract cancer (UUC), bladder cancer (BC), and prostate cancer (PC), subsequently developed these disorders from the recruited date between 2002 and 2008 and the end of follow-up 2011. A Cox proportional hazards regression model was constructed to estimate the risk of subsequent UUC, BC, and PC following a diagnosis of IC/BPS. The effect of associated comorbidities was measured by Charlson Comorbidity Index (CCI). The risk of outcomes was assessed with Kaplan-Meier curves. Results. In the BPS/IC subjects, 37 (0.36%) received a diagnosis of BC, and 22 (0.22%) received a diagnosis of UUC; both were significantly higher than the control group, 19 (0.06%) for BC and 30 (0.10%) for UUC. Cox proportional analysis revealed that the adjusted HR for BC and UUC during the follow-up period for patients with IC/BPS was 5.44 (95% CI: 3.10-9.54) and 1.97 (95% CI: 1.13-3.45) than that of comparison subjects. The HRs went up to 5.66 (95% CI: 3.21-9.99) and 2.01 (95% CI: 1.14-3.55) after adjusted by Comorbidity Index (CCI). The male BPS/IC patients have a higher adjusted HR for BC; however, female patients have a higher adjusted HR for both BC and UUC. The adjusted HR for PC has no difference between BPS/IC and control group. Conclusion. Patients with BPS/IC are at risk of developing BC in both males and females, and UUC in females. This result reminds physicians to evaluate the potential risk of subsequent development of BC and UUC among individuals with BPS/IC.

scholarly journals A Systematic Review of Therapeutic Approaches Used in Experimental Models of Interstitial Cystitis/Bladder Pain Syndrome

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 865
Author(s):  
Tadeja Kuret ◽  
Dominika Peskar ◽  
Andreja Erman ◽  
Peter Veranič
Keyword(s):  
Interstitial Cystitis ◽  
Methodological Quality ◽  
Transient Receptor Potential ◽  
Pain Syndrome ◽  
Therapeutic Agents ◽  
Bladder Pain Syndrome ◽  
Experimental Models ◽  
Transient Receptor Potential Channels ◽  
Therapeutic Approaches ◽  
Bladder Pain

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a multifactorial, chronic bladder disorder with limited therapeutic options currently available. The present review provides an extensive overview of therapeutic approaches used in in vitro, ex vivo, and in vivo experimental models of IC/BPS. Publications were identified by electronic search of three online databases. Data were extracted for study design, type of treatment, main findings, and outcome, as well as for methodological quality and the reporting of measures to avoid bias. A total of 100 full-text articles were included. The majority of identified articles evaluated therapeutic agents currently recommended to treat IC/BPS by the American Urological Association guidelines (21%) and therapeutic agents currently approved to treat other diseases (11%). More recently published articles assessed therapeutic approaches using stem cells (11%) and plant-derived agents (10%), while novel potential drug targets identified were proteinase-activated (6%) and purinergic (4%) receptors, transient receptor potential channels (3%), microRNAs (2%), and activation of the cannabinoid system (7%). Our results show that the reported methodological quality of animal studies could be substantially improved, and measures to avoid bias should be more consistently reported in order to increase the value of preclinical research in IC/BPS for potential translation to a clinical setting.

The TRPM7 Channel in the Nervous and Cardiovascular Systems

2020 ◽  
Vol 21 (10) ◽  
pp. 985-992 ◽  
Author(s):  
Koichi Inoue ◽  
Zhi-Gang Xiong ◽  
Takatoshi Ueki
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Kinase Domain ◽  
Cellular Functions ◽  
Transient Receptor Potential Melastatin ◽  
Cation Permeability ◽  
Cardiovascular Systems ◽  
Transient Receptor ◽  
Excitatory Responses ◽  
Dual Operations

: Transient receptor potential melastatin 7 (TRPM7), along with the closely related TRPM6, are unique channels that have dual operations: cation permeability and kinase activity. In contrast to the limited tissue distribution of TRPM6, TRPM7 is widely expressed among tissues and is therefore implicated in a variety of cellular functions physiologically and pathophysiologically. The discovery of TRPM7’s unique structure imparting dual ion channel and kinase activities shed light onto novel and peculiar biological functions, such as Mg2+ homeostasis, cellular Ca2+ flickering, and even intranuclear transcriptional regulation by a cleaved kinase domain translocated to nuclei. Interestingly, at a higher level, TRPM7 participates in several biological processes in the nervous and cardiovascular systems, in which excitatory responses in neurons and cardiomyocytes are critical for their function. Here, we review the roles of TRPM7 in cells involved in the nervous and cardiovascular systems and discuss its potential as a future therapeutic target.

Pharmacological Inhibition of Transient Receptor Potential Melastatin 2 (TRPM2) Channels Attenuates Diabetes-induced Cognitive Deficits in Rats: A Mechanistic Study

2020 ◽  
Vol 17 (3) ◽  
pp. 249-258 ◽  
Author(s):  
Pavan Thapak ◽  
Mahendra Bishnoi ◽  
Shyam S. Sharma
Keyword(s):  
Cognitive Impairment ◽  
Cognitive Deficits ◽  
Ache Activity ◽  
Transient Receptor Potential ◽  
Mrna Level ◽  
Receptor Potential ◽  
Transient Receptor Potential Melastatin ◽  
Trpm2 Channels ◽  
Transient Receptor ◽  
Gsk 3Β

Background: Diabetes is a chronic metabolic disorder affecting the central nervous system. A growing body of evidence has depicted that high glucose level leads to the activation of the transient receptor potential melastatin 2 (TRPM2) channels. However, there are no studies targeting TRPM2 channels in diabetes-induced cognitive decline using a pharmacological approach. Objective: The present study intended to investigate the effects of 2-aminoethoxydiphenyl borate (2-APB), a TRPM2 inhibitor, in diabetes-induced cognitive impairment. Methods: Streptozotocin (STZ, 50 mg/kg, i.p.) was used to induce diabetes in rats. Animals were randomly divided into the treatment group, model group and age-matched control and pre se group. 2-APB treatment was given for three weeks to the animals. After 10 days of behavioural treatment, parameters were performed. Animals were sacrificed at 10th week of diabetic induction and the hippocampus and cortex were isolated. After that, protein and mRNA expression study was performed in the hippocampus. Acetylcholinesterase (AchE) activity was done in the cortex. Results: : Our study showed the 10th week diabetic animals developed cognitive impairment, which was evident from the behavioural parameters. Diabetic animals depicted an increase in the TRPM2 mRNA and protein expression in the hippocampus as well as increased AchE activity in the cortex. However, memory associated proteins were down-regulated, namely Ca2+/calmodulin-dependent protein kinase II (CaMKII-Thr286), glycogen synthase kinase 3 beta (GSK-3β-Ser9), cAMP response element-binding protein (CREB-Ser133), and postsynaptic density protein 95 (PSD-95). Gene expression of parvalbumin, calsequestrin and brain-derived neurotrophic factor (BDNF) were down-regulated while mRNA level of calcineurin A/ protein phosphatase 3 catalytic subunit alpha (PPP3CA) was upregulated in the hippocampus of diabetic animals. A three-week treatment with 2-APB significantly ameliorated the alteration in behavioural cognitive parameters in diabetic rats. Moreover, 2-APB also down-regulated the expression of TRPM2 mRNA and protein in the hippocampus as well as AchE activity in the cortex of diabetic animals as compared to diabetic animals. Moreover, the 2-APB treatment also upregulated the CaMKII (Thr-286), GSK-3β (Ser9), CREB (Ser133), and PSD-95 expression and mRNA levels of parvalbumin, calsequestrin, and BDNF while mRNA level of calcineurin A was down-regulated in the hippocampus of diabetic animals. Conclusion: : This study confirms the ameliorative effect of TRPM2 channel inhibitor in the diabetes- induced cognitive deficits. Inhibition of TRPM2 channels reduced the calcium associated downstream signaling and showed a neuroprotective effect of TRPM2 channels in diabetesinduced cognitive impairment.

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