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Current Drug Metabolism

Editor-in-Chief

ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

Research Article

Pain Allaying Epalrestat-Loaded Lipid Nanoformulation for the Diabetic Neuropathic Pain Interventions: Design, Development, and Animal Study

Author(s): Vishal Kumar Vishwakarma, Shravan Kumar Paswan, Taruna Arora, Rahul Kumar Verma and Harlokesh Narayan Yadav*

Volume 23, Issue 7, 2022

Published on: 23 August, 2022

Page: [571 - 583] Pages: 13

DOI: 10.2174/1389200223666220810152633

Price: $65

Abstract

Background: Diabetic peripheral neuropathy is the most common complication of diabetes mellitus. Epalrestat, an aldose reductase inhibitor, has been approved for clinical therapy for diabetic peripheral neuropathic pain. In the present study, solid lipid-based nanoparticles are used for oral administration of epalrestat (E-SLN) and evaluated against diabetic neuropathic pain in a rat model.

Methods: Experimental diabetes in rats was induced by a single dose of streptozotocin (STZ) administration. The therapeutic efficiency of Epalrestat nanoparticles (0.25, 0.50, 1, and 5 mg/kg) in diabetic rats was studied. STZinduced diabetic rats were treated with different doses of E-SLN for 8 weeks. The nanoparticles were orally administered at a single dose in rats, and the various parameters related to peripheral neuropathy were evaluated and compared with the bare drug. The blood glucose level was estimated by standard glucometer, HbA1c, triglycerides, total cholesterol, and liver function test (ALT and AST) were analyzed by blood samples collected from retro-orbital plexus. Oxidative stress markers and Na+K+ATPase, TNF-α, and IL-1β levels were measured in the homogenate of sciatic nerves. Behavioral tests were also performed by the hot plate method and tail-flick method.

Results: E-SLN synthesized by the micro-emulsification method was 281 ± 60 nm in size, and encapsulation efficacy was found to be 88 ± 2%. Optimized E-SLN were characterized and found to be optimum in size, spherical shape, decent encapsulation efficiency, stable at acidic gastric pH, and suitable for oral delivery. E-SLNs did not significantly reverse the STZ-induced elevated blood glucose level (FBS and PPBS), HbA1c, triglycerides, and total cholesterol but significantly improved TNF-α, IL-1β, and increased Na+K+ATPase levels, oxidative stress marker and ALT, AST in the treated rat group as compared with the diabetic group. Doses of E-SLN, i.e. 0.5, 1.0, 2.5, and 5 mg/kg, significantly increased the tail-flick latency time and hot plate response time in a dose-dependent manner compared with the diabetic group.

Conclusion: Thus, it is suggested that E-SLN were equally effective and less hepatotoxic compared with the standard treatment of epalrestat. To the best of our knowledge, we, for the first time, propose the orally deliverable E-SLN that ameliorates STZ-induced diabetes neuropathic pain effectively as compared with conventional epalrestat.

Keywords: Diabetes mellitus, solid lipid nanoparticles, diabetic neuropathy, wistar rats, epalrestat, hyperglycemia.

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[1]
Kuthati, Y.; Navakanth Rao, V.; Busa, P.; Tummala, S.; Davuluri Venkata Naga, G.; Wong, C.S. Scope and applications of nanomedicines for the management of neuropathic pain. Mol. Pharm., 2020, 17(4), 1015-1027.
[http://dx.doi.org/10.1021/acs.molpharmaceut.9b01027] [PMID: 32142287]
[2]
Grant, G.J.; Vermeulen, K.; Zakowski, M.I.; Stenner, M.; Turndorf, H.; Langerman, L. Prolonged analgesia and decreased toxicity with lipo-somal morphine in a mouse model. Anesth. Analg., 1994, 79(4), 706-709.
[http://dx.doi.org/10.1213/00000539-199410000-00015] [PMID: 7943779]
[3]
Alyautdin, R.N.; Petrov, V.E.; Langer, K.; Berthold, A.; Kharkevich, D.A.; Kreuter, J. Delivery of loperamide across the blood-brain barrier with polysorbate 80-coated polybutylcyanoacrylate nanoparticles. Pharm. Res., 1997, 14(3), 325-328.
[http://dx.doi.org/10.1023/A:1012098005098] [PMID: 9098875]
[4]
Malik, O.; Kaye, A.D.; Kaye, A.; Belani, K.; Urman, R.D. Emerging roles of liposomal bupivacaine in anesthesia practice. J. Anaesthesiol. Clin. Pharmacol., 2017, 33(2), 151-156.
[http://dx.doi.org/10.4103/joacp.JOACP_375_15] [PMID: 28781438]
[5]
Oates, P.J.; Mylari, B.L. Aldose reductase inhibitors: Therapeutic implications for diabetic complications. Expert Opin. Investig. Drugs, 1999, 8(12), 2095-2119.
[http://dx.doi.org/10.1517/13543784.8.12.2095] [PMID: 11139842]
[6]
Hotta, N. New concepts and insights on pathogenesis and treatment of diabetic complications: Polyol pathway and its inhibition. Nagoya J. Med. Sci., 1997, 60(3-4), 89-100.
[PMID: 9481088]
[7]
Ramirez, M.A.; Borja, N.L. Epalrestat: An aldose reductase inhibitor for the treatment of diabetic neuropathy. Pharmacotherapy, 2008, 28(5), 646-655.
[http://dx.doi.org/10.1592/phco.28.5.646] [PMID: 18447661]
[8]
Zhu, Y.; Sheng, Y. Sustained delivery of epalrestat to the retina using PEGylated solid lipid nanoparticles laden contact lens. Int. J. Pharm., 2020, 587, 119688.
[http://dx.doi.org/10.1016/j.ijpharm.2020.119688] [PMID: 32717281]
[9]
Alvi, Z.; Akhtar, M.; Rahman, N.U.; Hosny, K.M.; Sindi, A.M.; Khan, B.A.; Nazir, I.; Sadaquat, H. Utilization of gelling polymer to formulate nanoparticles loaded with epalrestat-cyclodextrin inclusion complex: Formulation, characterization, in-silico modelling and in-vivo toxicity evaluation. Polymers (Basel), 2021, 13(24), 4350.
[http://dx.doi.org/10.3390/polym13244350] [PMID: 34960901]
[10]
Schwarz, C.; Mehnert, W. Solid Lipid Nanoparticles (SLN) for controlled drug delivery. II. Drug incorporation and physicochemical charac-terization. J. Microencapsul., 1999, 16(2), 205-213.
[http://dx.doi.org/10.1080/026520499289185] [PMID: 10080114]
[11]
zur Mühlen, A.; Schwarz, C.; Mehnert, W. Solid Lipid Nanoparticles (SLN) for controlled drug delivery-drug release and release mechanism. Eur. J. Pharm. Biopharm., 1998, 45(2), 149-155.
[http://dx.doi.org/10.1016/S0939-6411(97)00150-1] [PMID: 9704911]
[12]
Mehnert, W.; Mäder, K. Solid lipid nanoparticles: Production, characterization and applications. Adv. Drug Deliv. Rev., 2001, 47(2-3), 165-196.
[http://dx.doi.org/10.1016/S0169-409X(01)00105-3] [PMID: 11311991]
[13]
Kaur, I.P.; Bhandari, R.; Bhandari, S.; Kakkar, V. Potential of solid lipid nanoparticles in brain targeting. J. Control. Release, 2008, 127(2), 97-109.
[http://dx.doi.org/10.1016/j.jconrel.2007.12.018] [PMID: 18313785]
[14]
Kakkar, V.; Muppu, S.K.; Chopra, K.; Kaur, I.P. Curcumin loaded solid lipid nanoparticles: An efficient formulation approach for cerebral ischemic reperfusion injury in rats. Eur. J. Pharm. Biopharm., 2013, 85(3 Pt A), 339-345.
[http://dx.doi.org/10.1016/j.ejpb.2013.02.005] [PMID: 23454202]
[15]
Manjunath, K.; Reddy, J.S.; Venkateswarlu, V. Solid lipid nanoparticles as drug delivery systems. Methods Find. Exp. Clin. Pharmacol., 2005, 27(2), 127-144.
[http://dx.doi.org/10.1358/mf.2005.27.2.876286] [PMID: 15834465]
[16]
Senduran, N.; Yadav, H.N.; Vishwakarma, V.K.; Bhatnagar, P.; Gupta, P.; Bhatia, J.; Dinda, A.K. Orally deliverable nanoformulation of lirag-lutide against type 2 diabetic rat model. J. Drug Deliv. Sci. Technol., 2020, 56, 101513.
[http://dx.doi.org/10.1016/j.jddst.2020.101513]
[17]
Possover, M.; Chiantera, V. Isolated infiltrative endometriosis of the sciatic nerve: A report of three patients. Fertil. Steril., 2007, 87(2), 417.e17-417.e19.
[http://dx.doi.org/10.1016/j.fertnstert.2006.05.084] [PMID: 17276152]
[18]
Ohkawa, H.; Ohishi, N.; Yagi, K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal. Biochem., 1979, 95(2), 351-358.
[http://dx.doi.org/10.1016/0003-2697(79)90738-3] [PMID: 36810]
[19]
Marklund, S.; Marklund, G. Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for super-oxide dismutase. Eur. J. Biochem., 1974, 47(3), 469-474.
[http://dx.doi.org/10.1111/j.1432-1033.1974.tb03714.x] [PMID: 4215654]
[20]
Vishwakarma, V.K.; Goyal, A.; Gupta, J.K.; Upadhyay, P.K.; Yadav, H.N. Involvement of atrial natriuretic peptide in abrogated cardioprotec-tive effect of ischemic preconditioning in ovariectomized rat heart. Hum. Exp. Toxicol., 2018, 37(7), 704-713.
[http://dx.doi.org/10.1177/0960327117730878] [PMID: 28920462]
[21]
Ali, S.; Maiti, A.; Vishwakarma, V.K. Effects of Anethum graveolense Linn. Extract on bile duct ligation induced hepatic fibrosis in rats. Int. J. Pharm. Sci. Res., 2019, 31, 1795-1803.
[22]
Sawynok, J.; Esser, M.J.; Reid, A.R. Peripheral antinociceptive actions of desipramine and fluoxetine in an inflammatory and neuropathic pain test in the rat. Pain, 1999, 82(2), 149-158.
[http://dx.doi.org/10.1016/S0304-3959(99)00043-3] [PMID: 10467920]
[23]
Jawaid, T.; Shakya, A.K.; Kamal, M.; Hussain, S. Amitriptyline and sertraline in diabetic neuropathy: A comparative view. Int. J. Heal. Res, 2009, 1(2), 73-78.
[http://dx.doi.org/10.4314/ijhr.v1i2.47918]
[24]
Samaddar, S.; Koneri, R. Polyphenols of marine red macroalga Symphyocladia latiuscula ameliorate diabetic peripheral neuropathy in exper-imental animals. Heliyon, 2019, 5(5), e01781.
[http://dx.doi.org/10.1016/j.heliyon.2019.e01781] [PMID: 31193485]
[25]
Yang, B.B.; Hong, Z.W.; Zhang, Z.; Yu, W.; Song, T.; Zhu, L.L.; Jiang, H.S.; Chen, G.T.; Chen, Y.; Dai, Y.T. Epalrestat, an aldose reductase inhibitor, restores erectile function in streptozocin-induced diabetic rats. Int. J. Impot. Res., 2019, 31(2), 97-104.
[http://dx.doi.org/10.1038/s41443-018-0075-x] [PMID: 30214006]
[26]
Li, Q.R.; Wang, Z.; Zhou, W.; Fan, S.R.; Ma, R.; Xue, L.; Yang, L.; Li, Y.S.; Tan, H.L.; Shao, Q.H.; Yang, H.Y. Epalrestat protects against diabetic peripheral neuropathy by alleviating oxidative stress and inhibiting polyol pathway. Neural Regen. Res., 2016, 11(2), 345-351.
[http://dx.doi.org/10.4103/1673-5374.177745] [PMID: 27073391]
[27]
Kany, S.; Vollrath, J.T.; Relja, B. Cytokines in inflammatory disease. Int. J. Mol. Sci., 2019, 20(23), 6008.
[http://dx.doi.org/10.3390/ijms20236008] [PMID: 31795299]
[28]
Schreiber, A.K.; Nones, C.F.; Reis, R.C.; Chichorro, J.G.; Cunha, J.M. Diabetic neuropathic pain: Physiopathology and treatment. World J. Diabetes, 2015, 6(3), 432-444.
[http://dx.doi.org/10.4239/wjd.v6.i3.432] [PMID: 25897354]
[29]
Rahman, M.M.; Chakraborti, R.R.; Potol, M.A.; Abir, A.H.; Sharmin, O.; Alam, M.; Khan, M.F.R.; Afrin, R.; Jannat, H.; Wadud, R.; Habib, Z.F. Epalrestat improves motor symptoms by reducing oxidative stress and inflammation in the reserpine induced mouse model of Parkin-son’s disease. Animal Model. Exp. Med., 2019, 3(1), 9-21.
[http://dx.doi.org/10.1002/ame2.12097] [PMID: 32318655]
[30]
Dawane, J.S.; Pandit, V.A.; Bhosale, M.S.; Khatavkar, P.S. Evaluation of effect of nishamalaki on STZ and HFHF diet induced diabetic neu-ropathy in wistar rats. J. Clin. Diagn. Res., 2016, 10(10), FF01-FF05.
[http://dx.doi.org/10.7860/JCDR/2016/21011.8752] [PMID: 27891351]
[31]
Singh, R.; Kishore, L.; Kaur, N. Diabetic peripheral neuropathy: Current perspective and future directions. Pharmacol. Res., 2014, 80, 21-35.
[http://dx.doi.org/10.1016/j.phrs.2013.12.005] [PMID: 24373831]
[32]
Vlassara, H.; Cai, W.; Crandall, J.; Goldberg, T.; Oberstein, R.; Dardaine, V.; Peppa, M.; Rayfield, E.J. Inflammatory mediators are induced by dietary glycotoxins, a major risk factor for diabetic angiopathy. Proc. Natl. Acad. Sci. USA, 2002, 99(24), 15596-15601.
[http://dx.doi.org/10.1073/pnas.242407999] [PMID: 12429856]
[33]
Samaddar, S.U.; Balwanth, R.K.; Sah, S.K.; Chandrasekhar, K.B. Protective effect of saponin of Momordica cymbalaria fenzl on high-glucose induced neuropathy in NB-41A3 mouse neuroblastoma cells. Int. J. Pharm. Pharm. Sci., 2016, 8(4), 229-235.
[34]
Kowluru, R.; Bitensky, M.W.; Kowluru, A.; Dembo, M.; Keaton, P.A.; Buican, T. Reversible sodium pump defect and swelling in the diabetic rat erythrocyte: Effects on filterability and implications for microangiopathy. Proc. Natl. Acad. Sci. USA, 1989, 86(9), 3327-3331.
[http://dx.doi.org/10.1073/pnas.86.9.3327] [PMID: 2541440]
[35]
Suzuki, H.; Shimosegawa, T.; Ohara, S.; Toyota, T. Epalrestat prevents the decrease in gastric mucosal blood flow and protects the gastric mucosa in streptozotocin diabetic rats. J. Gastroenterol., 1999, 34(2), 172-177.
[http://dx.doi.org/10.1007/s005350050239] [PMID: 10213114]
[36]
Gomes, R.M.; de Paulo, L.F.; Bonato Panizzon, C.P.D.N.; Neves, C.Q.; Cordeiro, B.C.; Zanoni, J.N.; Francisco, F.A.; Piovan, S.; de Freitas Mathias, P.C.; Longhini, R.; de Mello, J.C.P.; de Oliveira, J.C.; Pedrino, G.R.; da Silva Reis, A.A.; Cecchini, A.L.; Marçal Natali, M.R. Anti-diabetic effects of the ethyl-acetate fraction of Trichilia catigua in streptozo-tocin-induced type 1 diabetic rats. Cell. Physiol. Biochem., 2017, 42(3), 1087-1097.
[http://dx.doi.org/10.1159/000478761] [PMID: 28662504]
[37]
Raz, I.; Hasdai, D.; Seltzer, Z.; Melmed, R.N. Effect of hyperglycemia on pain perception and on efficacy of morphine analgesia in rats. Diabetes, 1988, 37(9), 1253-1259.
[http://dx.doi.org/10.2337/diab.37.9.1253] [PMID: 3410166]
[38]
Bargoni, A.; Cavalli, R.; Caputo, O.; Fundarò, A.; Gasco, M.R.; Zara, G.P. Solid lipid nanoparticles in lymph and plasma after duodenal ad-ministration to rats. Pharm. Res., 1998, 15(5), 745-750.
[http://dx.doi.org/10.1023/A:1011975120776] [PMID: 9619784]

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