Login Register Cart 0
Generic placeholder image

Current Neurovascular Research

Editor-in-Chief

ISSN (Print): 1567-2026
ISSN (Online): 1875-5739

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Transient Receptor Potential Canonical 5 (TRPC5) Channels Activator, BTD [N-{3-(adamantan-2-yloxy)-propyl}-3-(6-methyl-1,1-dioxo-2H-1λ6,2,4- benzothiadiazin-3-yl)-propanamide)] Ameliorates Diabetic Cardiac Autonomic Neuropathy in Rats

Author(s): Pratik Adhya and Shyam Sunder Sharma*

Volume 20, Issue 1, 2023

Published on: 27 April, 2023

Page: [112 - 123] Pages: 12

DOI: 10.2174/1567202620666230403134627

Price: $65

Abstract

Background: Diabetic cardiac autonomic neuropathy (DCAN) is a serious diabetic complication with no approved pharmacological agents for its treatment. Parasympathetic system dysfunction characterized by vagal nerve damage is one of the major drivers of DCAN. The TRPC5 or transient receptor potential canonical 5 channel is a promising target in autonomic dysfunction; however, its role in vagal nerve damage and subsequent DCAN has not yet been elucidated. The present study investigated the role of the TRPC5 channel in DCAN using [N-{3-(adamantan-2-yloxy)-propyl}-3-(6-methyl-1,1-dioxo-2H-1λ6,2,4-benzothiadiazin-3-yl) propanamide)] or BTD, which is a potent TRPC5 activator.

Objectives: The role of the TRPC5 channel and its activator, BTD, was investigated in the treatment of parasympathetic dysfunction associated with DCAN.

Methods: Type 1 diabetes was induced in male Sprague-Dawley rats using streptozotocin. The alterations in cardiac autonomic parameters in diabetic animals were assessed by heart rate variability, hemodynamic parameters, and baroreflex sensitivity. TRPC5's role in DCAN was investigated by treating diseased rats with BTD (1 and 3 mg/kg, i.p. for 14 days). BTD's beneficial effects in parasympathetic dysfunction were assessed by western blotting, estimating oxidative stress and inflammatory markers in the vagus nerve.

Results: BTD treatment (3 mg/kg, i.p.) once daily for 14 days ameliorated heart rate variability, hemodynamic dysfunction, and baroreflex sensitivity in diseased rats. BTD treatment down regulated TRPC5 expression by increasing the activity of protein kinase C in the vagus nerve. It also down-regulated the apoptotic marker CASPASE-3 and also exerted potent anti-inflammatory action on pro-inflammatory cytokines levels in the vagus.

Conclusion: BTD ameliorated parasympathetic dysfunction associated with DCAN by virtue of its TRPC5 modulatory, anti-inflammatory, and anti-apoptotic properties.

Keywords: Diabetic cardiac autonomic neuropathy, TRPC5, BTD, diabetic complications, vagus nerve, TRPC5 activator, parasympathetic system.

« Previous Next »
[1]
Sudo SZ, Montagnoli TL, Rocha BS, Santos AD, de Sá MPL, Zapata-Sudo G. Diabetes-induced cardiac autonomic neuropathy: Impact on heart function and prognosis. Biomedicines 2022; 10(12): 3258.
[http://dx.doi.org/10.3390/biomedicines10123258] [PMID: 36552014]
[2]
Pop-Busui R. Cardiac autonomic neuropathy in diabetes: A clinical perspective. Diabetes Care 2010; 33(2): 434-41.
[http://dx.doi.org/10.2337/dc09-1294] [PMID: 20103559]
[3]
Vinik AI, Casellini C, Parson HK, Colberg SR, Nevoret ML. Cardiac autonomic neuropathy in diabetes: A predictor of cardiometabolic events. Front Neurosci 2018; 12: 591.
[http://dx.doi.org/10.3389/fnins.2018.00591] [PMID: 30210276]
[4]
Moţăţăianu A, Maier S, Bajko Z, Voidazan S, Bălaşa R, Stoian A. Cardiac autonomic neuropathy in type 1 and type 2 diabetes patients. BMC Neurol 2018; 18(1): 126.
[http://dx.doi.org/10.1186/s12883-018-1125-1] [PMID: 30149797]
[5]
Ang L, Dillon B, Mizokami-Stout K, Pop-Busui R. Cardiovascular autonomic neuropathy: A silent killer with long reach. Auton Neurosci 2020; 225: 102646.
[http://dx.doi.org/10.1016/j.autneu.2020.102646] [PMID: 32106052]
[6]
Agashe S, Petak S. Cardiac autonomic neuropathy in diabetes mellitus. Methodist DeBakey Cardiovasc J 2018; 14(4): 251-6.
[http://dx.doi.org/10.14797/mdcj-14-4-251] [PMID: 30788010]
[7]
Dimitropoulos G, Tahrani AA, Stevens MJ. Cardiac autonomic neuropathy in patients with diabetes mellitus. World J Diabet 2014; 5(1): 17-39.
[http://dx.doi.org/10.4239/wjd.v5.i1.17] [PMID: 24567799]
[8]
McCorry LK. Physiology of the autonomic nervous system. Am J Pharm Educ 2007; 71(4): 78.
[http://dx.doi.org/10.5688/aj710478] [PMID: 17786266]
[9]
Verrotti A, Prezioso G, Scattoni R, Chiarelli F. Autonomic neuropathy in diabetes mellitus. Front Endocrinol 2014; 5: 205.
[http://dx.doi.org/10.3389/fendo.2014.00205] [PMID: 25520703]
[10]
Fabiyi-Edebor TD. Vitamin C ameliorated cardiac autonomic neuropathy in type 2 diabetic rats. World J Diabet 2020; 11(3): 52-65.
[http://dx.doi.org/10.4239/wjd.v11.i3.52] [PMID: 32180894]
[11]
Sakaguchi R, Mori Y. Transient receptor potential (TRP) channels: Biosensors for redox environmental stimuli and cellular status. Free Radic Biol Med 2020; 146: 36-44.
[http://dx.doi.org/10.1016/j.freeradbiomed.2019.10.415] [PMID: 31682917]
[12]
Sharma S, Hopkins CR. Review of transient receptor potential canonical (TRPC5) channel modulators and diseases. J Med Chem 2019; 62(17): 7589-602.
[http://dx.doi.org/10.1021/acs.jmedchem.8b01954] [PMID: 30943030]
[13]
Du SL, Jia ZQ, Zhong JC, Wang LF. TRPC5 in cardiovascular diseases. Rev Cardiovasc Med 2021; 22(1): 127-35.
[http://dx.doi.org/10.31083/j.rcm.2021.01.212] [PMID: 33792254]
[14]
Zou Y, Chen M, Zhang S, et al. TRPC5 induced autophagy promotes the TMZ-resistance of glioma cells via the CAMMKβ/AMPKα/mTOR pathway. Oncol Rep 2019; 41(6): 3413-23.
[http://dx.doi.org/10.3892/or.2019.7095] [PMID: 30942446]
[15]
Wang X, Dande RR, Yu H, et al. TRPC5 Does not cause or aggravate glomerular disease. J Am Soc Nephrol 2018; 29(2): 409-15.
[http://dx.doi.org/10.1681/ASN.2017060682] [PMID: 29061651]
[16]
Zhu Y, Gao M, Zhou T, et al. The TRPC5 channel regulates angiogenesis and promotes recovery from ischemic injury in mice. J Biol Chem 2019; 294(1): 28-37.
[http://dx.doi.org/10.1074/jbc.RA118.005392] [PMID: 30413532]
[17]
He Z, Jia C, Feng S, et al. TRPC5 channel is the mediator of neurotrophin-3 in regulating dendritic growth via CaMKIIα in rat hippocampal neurons. J Neurosci 2012; 32(27): 9383-95.
[http://dx.doi.org/10.1523/JNEUROSCI.6363-11.2012] [PMID: 22764246]
[18]
Kozai D, Ogawa N, Mori Y. Redox regulation of transient receptor potential channels. Antioxid Redox Signal 2014; 21(6): 971-86.
[http://dx.doi.org/10.1089/ars.2013.5616] [PMID: 24161127]
[19]
Sadler KE, Moehring F, Shiers SI, et al. Transient receptor potential canonical 5 mediates inflammatory mechanical and spontaneous pain in mice. Sci Transl Med 2021; 13(595): eabd7702.
[http://dx.doi.org/10.1126/scitranslmed.abd7702] [PMID: 34039739]
[20]
Bernal L, Sotelo-Hitschfeld P, König C, et al. Odontoblast TRPC5 channels signal cold pain in teeth. Sci Adv 2021; 7(13): eabf5567.
[http://dx.doi.org/10.1126/sciadv.abf5567] [PMID: 33771873]
[21]
Zimmermann K, Lennerz JK, Hein A, et al. Transient receptor potential cation channel, subfamily C, member 5 (TRPC5) is a cold-transducer in the peripheral nervous system. Proc Natl Acad Sci USA 2011; 108(44): 18114-9.
[http://dx.doi.org/10.1073/pnas.1115387108] [PMID: 22025699]
[22]
Lau OC, Shen B, Wong CO, et al. TRPC5 channels participate in pressure-sensing in aortic baroreceptors. Nat Commun 2016; 7(1): 11947.
[http://dx.doi.org/10.1038/ncomms11947] [PMID: 27411851]
[23]
Sharma SS, Kumar A, Kaundal RK. Protective effects of 4-amino1,8-napthalimide, a poly (ADP-ribose) polymerase inhibitor in experimental diabetic neuropathy. Life Sci 2008; 82(11-12): 570-6.
[http://dx.doi.org/10.1016/j.lfs.2007.11.031] [PMID: 18262571]
[24]
Addepalli V, Suryavanshi SV. Catechin attenuates diabetic autonomic neuropathy in streptozotocin induced diabetic rats. Biomed Pharmacother 2018; 108: 1517-23.
[http://dx.doi.org/10.1016/j.biopha.2018.09.179] [PMID: 30372853]
[25]
Kumar A, Sharma SS. NF-κB inhibitory action of resveratrol: A probable mechanism of neuroprotection in experimental diabetic neuropathy Biochem Biophys Res Commun 2010; 394(2): 360-5.
[http://dx.doi.org/10.1016/j.bbrc.2010.03.014] [PMID: 20211601]
[26]
Beckmann H, Richter J, Hill K, Urban N, Lemoine H, Schaefer M. A benzothiadiazine derivative and methylprednisolone are novel and selective activators of transient receptor potential canonical 5 (TRPC5) channels. Cell Calcium 2017; 66: 10-8.
[http://dx.doi.org/10.1016/j.ceca.2017.05.012] [PMID: 28807145]
[27]
Rubaiy HN. Treasure troves of pharmacological tools to study transient receptor potential canonical 1/4/5 channels. Br J Pharmacol 2019; 176(7): 832-46.
[http://dx.doi.org/10.1111/bph.14578] [PMID: 30656647]
[28]
Turner PV, Brabb T, Pekow C, Vasbinder MA. Administration of substances to laboratory animals: Routes of administration and factors to consider. J Am Assoc Lab Anim Sci 2011; 50(5): 600-13.
[PMID: 22330705]
[29]
Xuan YL, Wang Y, Xue M, et al. In rats the duration of diabetes influences its impact on cardiac autonomic innervations and electrophysiology. Auton Neurosci 2015; 189: 31-6.
[http://dx.doi.org/10.1016/j.autneu.2015.01.003] [PMID: 25655058]
[30]
Bulani Y, Srinivasan K, Sharma SS. Attenuation of type-1 diabetes-induced cardiovascular dysfunctions by direct thrombin inhibitor in rats: A mechanistic study. Mol Cell Biochem 2019; 451(1-2): 69-78.
[http://dx.doi.org/10.1007/s11010-018-3394-9] [PMID: 29971544]
[31]
Bulani Y, Sharma SS. Argatroban attenuates diabetic cardiomyopathy in rats by reducing fibrosis, Inflammation, apoptosis, and protease-activated receptor expression. Cardiovasc Drugs Ther 2017; 31(3): 255-67.
[http://dx.doi.org/10.1007/s10557-017-6732-3] [PMID: 28695302]
[32]
Liu IM, Chang CK, Juang SW, et al. Role of hyperglycaemia in the pathogenesis of hypotension observed in type-1 diabetic rats. Int J Exp Pathol 2008; 89(4): 292-300.
[http://dx.doi.org/10.1111/j.1365-2613.2008.00595.x] [PMID: 18715473]
[33]
Amara VR, Surapaneni SK, Tikoo K. Dysregulation of microRNAs and renin-angiotensin system in high salt diet-induced cardiac dysfunction in uninephrectomized rats. PLoS One 2017; 12(7): e0180490.
[http://dx.doi.org/10.1371/journal.pone.0180490] [PMID: 28727756]
[34]
Resham K, Khare P, Bishnoi M, Sharma SS. Neuroprotective effects of isoquercitrin in diabetic neuropathy via Wnt/β‐catenin signaling pathway inhibition. Biofactors 2020; 46(3): 411-20.
[http://dx.doi.org/10.1002/biof.1615] [PMID: 31960520]
[35]
Negi G, Kumar A, Kaundal RK, Gulati A, Sharma SS. Functional and biochemical evidence indicating beneficial effect of Melatonin and Nicotinamide alone and in combination in experimental diabetic neuropathy. Neuropharmacology 2010; 58(3): 585-92.
[http://dx.doi.org/10.1016/j.neuropharm.2009.11.018] [PMID: 20005237]
[36]
Kharatmal SB, Singh JN, Sharma SS. Calpain inhibitor, MDL 28170 confer electrophysiological, nociceptive and biochemical improvement in diabetic neuropathy. Neuropharmacology 2015; 97: 113-21.
[http://dx.doi.org/10.1016/j.neuropharm.2015.05.040] [PMID: 26087461]
[37]
Suryavanshi SV, Kulkarni YA. Attenuation of cardiac autonomic neuropathy by escin in diabetic rats. Pharmacology 2021; 106(3-4): 211-7.
[http://dx.doi.org/10.1159/000509730] [PMID: 32877906]
[38]
Negi G, Kumar A, Sharma SS. Concurrent targeting of nitrosative stress–PARP pathway corrects functional, behavioral and biochemical deficits in experimental diabetic neuropathy. Biochem Biophys Res Commun 2010; 391(1): 102-6.
[http://dx.doi.org/10.1016/j.bbrc.2009.11.010] [PMID: 19900402]
[39]
Negi G, Kumar A, Sharma SS. Melatonin modulates neuroinflammation and oxidative stress in experimental diabetic neuropathy: Effects on NF-κB and Nrf2 cascades. J Pineal Res 2011; 50(2): 124-31.
[PMID: 21062351]
[40]
Bass JJ, Wilkinson DJ, Rankin D, et al. An overview of technical considerations for Western blotting applications to physiological research. Scand J Med Sci Sports 2017; 27(1): 4-25.
[http://dx.doi.org/10.1111/sms.12702] [PMID: 27263489]
[41]
Vaidya B, Kaur H, Thapak P, Sharma SS, Singh JN. Pharmacological Modulation of TRPM2 Channels via PARP Pathway Leads to Neuroprotection in MPTP-induced Parkinson’s Disease in Sprague Dawley Rats. Mol Neurobiol 2022; 59(3): 1528-42.
[http://dx.doi.org/10.1007/s12035-021-02711-4] [PMID: 34997907]
[42]
Kahya MC, Nazıroğlu M, Övey İS. Modulation of diabetes-induced oxidative stress, apoptosis, and Ca2+ entry through TRPM2 and TRPV1 channels in dorsal root ganglion and hippocampus of diabetic rats by melatonin and selenium. Mol Neurobiol 2017; 54(3): 2345-60.
[http://dx.doi.org/10.1007/s12035-016-9727-3] [PMID: 26957303]
[43]
Resham K, Sharma SS. Pharmacological interventions targeting Wnt/β-catenin signaling pathway attenuate paclitaxel-induced peripheral neuropathy. Eur J Pharmacol 2019; 864: 172714.
[http://dx.doi.org/10.1016/j.ejphar.2019.172714] [PMID: 31586636]
[44]
Furman BL. Streptozotocin-induced diabetic models in mice and rats. Curr Protoc Pharmacol 2015; 70(5.47): 1-20.
[http://dx.doi.org/10.1002/0471141755.ph0547s70]
[45]
Mostafavinia A, Amini A, Ghorishi SK, Pouriran R, Bayat M. The effects of dosage and the routes of administrations of streptozotocin and alloxan on induction rate of type1 diabetes mellitus and mortality rate in rats. Lab Anim Res 2016; 32(3): 160-5.
[http://dx.doi.org/10.5625/lar.2016.32.3.160] [PMID: 27729932]
[46]
Xie F, Sun C, Sun L, et al. Influence of fluvastatin on cardiac function and baroreflex sensitivity in diabetic rats. Acta Pharmacol Sin 2011; 32(3): 321-8.
[http://dx.doi.org/10.1038/aps.2010.221] [PMID: 21372824]
[47]
Khaliq F, Parveen A, Singh S, Hussain ME, Fahim M. Terminalia arjuna improves cardiovascular autonomic neuropathy in streptozotocin-induced diabetic rats. Cardiovasc Toxicol 2013; 13(1): 68-76.
[http://dx.doi.org/10.1007/s12012-012-9187-6] [PMID: 23001577]
[48]
Goldberger JJ, Arora R, Buckley U, Shivkumar K. Autonomic Nervous System Dysfunction. J Am Coll Cardiol 2019; 73(10): 1189-206.
[http://dx.doi.org/10.1016/j.jacc.2018.12.064] [PMID: 30871703]
[49]
Serhiyenko VA, Serhiyenko AA. Cardiac autonomic neuropathy: Risk factors, diagnosis and treatment. World J Diabet 2018; 9(1): 1-24.
[http://dx.doi.org/10.4239/wjd.v9.i1.1] [PMID: 29359025]
[50]
Gao Y, Yao T, Deng Z, et al. TrpC5 Mediates acute leptin and serotonin effects via pomc neurons. Cell Rep 2017; 18(3): 583-92.
[http://dx.doi.org/10.1016/j.celrep.2016.12.072] [PMID: 28099839]
[51]
de Sousa Valente J, Alawi KM, Keringer P, et al. Examining the role of transient receptor potential canonical 5 (TRPC5) in osteoarthritis. Osteoarthrit Cartilage Open 2020; 2(4): 100119.
[http://dx.doi.org/10.1016/j.ocarto.2020.100119] [PMID: 33381767]
[52]
Oda M, Yamamoto H, Matsumoto H, Ishizaki Y, Shibasaki K. TRPC5 regulates axonal outgrowth in developing retinal ganglion cells. Lab Invest 2020; 100(2): 297-310.
[http://dx.doi.org/10.1038/s41374-019-0347-1] [PMID: 31844148]
[53]
Michlig S, Merlini JM, Beaumont M, et al. Effects of TRP channel agonist ingestion on metabolism and autonomic nervous system in a randomized clinical trial of healthy subjects. Sci Rep 2016; 6(1): 20795.
[http://dx.doi.org/10.1038/srep20795] [PMID: 26883089]
[54]
Alawi KM, Aubdool AA, Liang L, et al. The sympathetic nervous system is controlled by transient receptor potential vanilloid 1 in the regulation of body temperature. FASEB J 2015; 29(10): 4285-98.
[http://dx.doi.org/10.1096/fj.15-272526] [PMID: 26136480]
[55]
Müller M, Niemeyer K, Urban N, et al. BTDAzo: A Photoswitchable TRPC5 Channel Activator**. Angew Chem Int Ed 2022; 61(36): e202201565.
[http://dx.doi.org/10.1002/anie.202201565] [PMID: 35713469]
[56]
Ningoo M, Plant LD, Greka A, Logothetis DE. PIP2 regulation of TRPC5 channel activation and desensitization. J Biol Chem 2021; 296: 100726.
[http://dx.doi.org/10.1016/j.jbc.2021.100726] [PMID: 33933453]
[57]
Gada KD, Logothetis DE. PKC regulation of ion channels: The involvement of PIP2. J Biol Chem 2022; 298(6): 102035.
[http://dx.doi.org/10.1016/j.jbc.2022.102035] [PMID: 35588786]
[58]
Venkatachalam K, Zheng F, Gill DL. Regulation of canonical transient receptor potential (TRPC) channel function by diacylglycerol and protein kinase C. J Biol Chem 2003; 278(31): 29031-40.
[http://dx.doi.org/10.1074/jbc.M302751200] [PMID: 12721302]
[59]
Standaert ML, Bandyopadhyay G, Kanoh Y, Sajan MP, Farese RV. Insulin and PIP3 activate PKC-zeta by mechanisms that are both dependent and independent of phosphorylation of activation loop (T410) and autophosphorylation (T560) sites. Biochemistry 2001; 40(1): 249-55.
[http://dx.doi.org/10.1021/bi0018234] [PMID: 11141077]
[60]
AL-Shawaf E, Naylor J, Taylor H, et al. Short-term stimulation of calcium-permeable transient receptor potential canonical 5-containing channels by oxidized phospholipids. Arterioscler Thromb Vasc Biol 2010; 30(7): 1453-9.
[http://dx.doi.org/10.1161/ATVBAHA.110.205666] [PMID: 20378846]
[61]
Schwarz Y, Oleinikov K, Schindeldecker B, et al. TRPC channels regulate Ca2+-signaling and short-term plasticity of fast glutamatergic synapses. PLoS Biol 2019; 17(9): e3000445.
[http://dx.doi.org/10.1371/journal.pbio.3000445] [PMID: 31536487]
[62]
Puram SV, Riccio A, Koirala S, et al. A TRPC5-regulated calcium signaling pathway controls dendrite patterning in the mammalian brain. Genes Dev 2011; 25(24): 2659-73.
[http://dx.doi.org/10.1101/gad.174060.111] [PMID: 22135323]
[63]
Huo S, Ren J, Ma Y, et al. Upregulation of TRPC5 in hippocampal excitatory synapses improves memory impairment associated with neuroinflammation in microglia knockout IL-10 mice. J Neuroinflammat 2021; 18(1): 275.
[http://dx.doi.org/10.1186/s12974-021-02321-w] [PMID: 34836549]
[64]
Skelding KA, Suzuki T, Gordon S, et al. Regulation of CaMKII by phospho-Thr253 or phospho-Thr286 sensitive targeting alters cellular function. Cell Signal 2010; 22(5): 759-69.
[http://dx.doi.org/10.1016/j.cellsig.2009.12.011] [PMID: 20060891]
[65]
Hong C, Seo H, Kwak M, et al. Increased TRPC5 glutathionylation contributes to striatal neuron loss in Huntington’s disease. Brain 2015; 138(10): 3030-47.
[http://dx.doi.org/10.1093/brain/awv188] [PMID: 26133660]
[66]
Li K, Li W, Yin H, Cheong YK, Ren G, Yang Z. Pretreatment-Etidronate Alleviates CoCl2 Induced-SH-SY5Y Cell Apoptosis via Decreased HIF-1α and TRPC5 Channel Proteins. Neurochem Res 2019; 44(2): 428-40.
[http://dx.doi.org/10.1007/s11064-018-2696-3] [PMID: 30539408]
[67]
Porter AG, Jänicke RU. Emerging roles of caspase-3 in apoptosis. Cell Death Differ 1999; 6(2): 99-104.
[http://dx.doi.org/10.1038/sj.cdd.4400476] [PMID: 10200555]
[68]
Kolb H. Mouse models of insulin dependent diabetes: Low-dose streptozocin-induced diabetes and nonobese diabetic (NOD) mice. Diabetes Metab Rev 1987; 3(3): 751-78.
[http://dx.doi.org/10.1002/dmr.5610030308] [PMID: 2956075]
[69]
Baro A, Bhuyan AK, Sarma D, Choudhury B. A study of cardiac autonomic neuropathy in patients with type 2 diabetes mellitus: A Northeast India experience. Indian J Endocrinol Metab 2019; 23(2): 246-50.
[http://dx.doi.org/10.4103/ijem.IJEM_336_18] [PMID: 31161112]

Rights & Permissions Print Cite
Article Metrics
29
2
© 2024 Bentham Science Publishers | Privacy Policy