A COMPARATIVE IN SILICO AND PRECLINICAL EVALUATION OF TWO STRUCTURAL ANALOGUES FOR DIABETIC NEUROPATHIC PAIN WITH FOCUS ON N-TYPE CALCIUM CHANNEL BLOCKADE AND OXIDATIVE STRESS PATHWAYS: A COMPREHENSIVE REVIEW
Main Article Content
Keywords
Diabetic neuropathy, N-type calcium channels, oxidative stress, in-silico, preclinical, structural analogues
Abstract
BACKGROUND: Diabetic neuropathic pain (DNP) is a major clinical issue with prevalence of about 50 per cent among patients with diabetes in the world. Existing treatment solutions are not very effective and are characterized by significant adverse effects. Calcium channels N type voltage-gated (Cav2.2) and oxidative stress pathways have become attractive therapeutic targets in the management of DNPs.
OBJECTIVE: This is a systematic review of the comparative effectiveness of N-type calcium channels and oxidative stress pathways structural analogues in diabetic neuropathic pain, including in-silico molecular docking research and preclinical research.
METHODS: A systematic literature search was conducted across PubMed, Scopus, and Web of Science databases for articles published between 2018-2024. Keywords were diabetic neuropathy, N-type calcium channels, oxidative stress, in-silico and structural analogues.
RESULTS: There is now new evidence showing that dual-targeting systems that incorporate both N-type calcium channel blockade with antioxidative mechanisms have better therapeutic potential than single-target therapies. In-silico analysis indicates that it has been found to be critical in binding with the cav2.2 channel subunits and preclinical model shows that it can cause reduced pain and neuroprotection effects.
CONCLUSION: Computational and preclinical methods have shown useful information in the design of next-generation therapeutics of diabetic neuropathic pain, and structural analogues have been promising dual-mechanism.
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3. Ziegler D, Papanas N, Vinik AI, Shaw JE. Epidemiology of polyneuropathy in diabetes and prediabetes. Handb Clin Neurol. 2014;126:3-22.
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5. Salvemini D, Little JW, Doyle T, Neumann WL. Roles of reactive oxygen and nitrogen species in pain. Free Radic Biol Med. 2011;51(5):951-966.
6. Zamponi GW, Lewis RJ, Todorovic SM, et al. Role of voltage-gated calcium channels in ascending pain pathways. Brain Res Rev. 2009;60(1):84-89.
7. Jagodic MM, Pathirathna S, Nelson MT, et al. Cell-specific alterations of T-type calcium current in painful diabetic neuropathy enhance excitability of sensory neurons. J Neurosci. 2007;27(12):3305-3316.
8. Vincent AM, Callaghan BC, Smith AL, Feldman EL. Diabetic neuropathy: cellular mechanisms as therapeutic targets. Nat Rev Neurol. 2011;7(10):573-583.
9. Lionta E, Spyrou G, Vassilatis DK, Cournia Z. Structure-based virtual screening for drug discovery: principles, applications and recent advances. Curr Top Med Chem. 2014;14(16):1923-1938.
10. Kitchen DB, Decornez H, Furr JR, Bajorath J. Docking and scoring in virtual screening for drug discovery: methods and applications. Nat Rev Drug Discov. 2004;3(11):935-949.
11. Edwards JL, Vincent AM, Cheng HT, Feldman EL. Diabetic neuropathy: mechanisms to management. Pharmacol Ther. 2008;120(1):1-34.
12. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414(6865):813-820.
13. Tomlinson DR, Gardiner NJ. Glucose neurotoxicity. Nat Rev Neurosci. 2008;9(1):36-45.
14. Singh R, Barden A, Mori T, Beilin L. Advanced glycation end-products: a review. Diabetologia. 2001;44(2):129-146.
15. Callaghan BC, Cheng HT, Stables CL, et al. Diabetic neuropathy: clinical manifestations and current treatments. Lancet Neurol. 2012;11(6):521-534.
16. Westenbroek RE, Hoskins L, Catterall WA. Localization of Ca2+ channel subtypes on rat spinal motor neurons, interneurons, and nerve terminals. J Neurosci. 1998;18(16):6319-6330.
17. Duzhyy DE, Viatchenko-Karpinski VY, Khomula EV, et al. Upregulation of T-type Ca2+ channels in long-term diabetes determines increased excitability of a specific type of capsaicin-insensitive DRG neurons. Mol Pain. 2015;11:29.
18. Bierhaus A, Haslbeck KM, Humpert PM, et al. Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily. J Clin Invest. 2004;114(12):1741-1751.
19. Calcutt NA, Jolivalt CG, Fernyhough P. Growth factors as therapeutics for diabetic neuropathy. Curr Drug Targets. 2008;9(1):47-59.
20. Shankarappa SA, Piedras-Rentería ES, Stubbs EB Jr. Forced-exercise delays neuropathy in experimental diabetes: effects on voltage-activated calcium channels. J Neurochem. 2005;94(4):1067-1078.
21. Figueroa-Romero C, Sadidi M, Feldman EL. Mechanisms of disease: the oxidative stress theory of diabetic neuropathy. Rev Endocr Metab Disord. 2008;9(4):301-314.
22. Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005;54(6):1615-1625.
23. Russell JW, Golovoy D, Vincent AM, et al. High glucose-induced oxidative stress and mitochondrial dysfunction in neurons. FASEB J. 2002;16(13):1738-1748.
24. Niedowicz DM, Daleke DL. The role of oxidative stress in diabetic complications. Cell Biochem Biophys. 2005;43(2):289-330.
25. Obrosova IG. Diabetic painful and insensate neuropathy: pathogenesis and potential treatments. Neurotherapeutics. 2009;6(4):638-647.
26. Bril V, England J, Franklin GM, et al. Evidence-based guideline: Treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology. 2011;76(20):1758-1765.
27. Taylor CP, Angelotti T, Fauman E. Pharmacology and mechanism of action of pregabalin: the calcium channel alpha2-delta (alpha2-delta) subunit as a target for antiepileptic drug discovery. Epilepsy Res. 2007;73(2):137-150.
28. Moore RA, Straube S, Wiffen PJ, et al. Pregabalin for acute and chronic pain in adults. Cochrane Database Syst Rev. 2009;(3):CD007076.
29. Max MB, Lynch SA, Muir J, et al. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med. 1992;326(19):1250-1256.
30. Watson CP, Vernich L, Chipman M, Reed K. Nortriptyline versus amitriptyline in postherpetic neuralgia: a randomized trial. Neurology. 1998;51(4):1166-1171.
31. Staats PS, Yearwood T, Charapata SG, et al. Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: a randomized controlled trial. JAMA. 2004;291(1):63-70.
32. Scott DA, Wright CE, Angus JA. Actions of intrathecal omega-conotoxins CVID, GVIA, MVIIA, and morphine in acute and neuropathic pain in the rat. Eur J Pharmacol. 2002;451(3):279-286.
33. Ziegler D, Nowak H, Kempler P, et al. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis. Diabet Med. 2004;21(2):114-121.
34. Papanas N, Ziegler D. Efficacy of α-lipoic acid in diabetic neuropathy. Expert Opin Pharmacother. 2014;15(18):2721-2731.
35. Meng XY, Zhang HX, Mezei M, Cui M. Molecular docking: a powerful approach for structure-based drug discovery. Curr Comput Aided Drug Des. 2011;7(2):146-157.
36. Wu J, Yan Z, Li Z, et al. Structure of the voltage-gated calcium channel Ca(v)1.1 at 3.6 Å resolution. Nature. 2016;537(7619):191-196.
37. Zhao Y, Huang G, Wu Q, et al. Molecular basis for ligand modulation of a mammalian voltage-gated Ca²⁺ channel. Cell. 2019;177(6):1495-1506.
38. Lipkind GM, Fozzard HA. Molecular modeling of local anesthetic drug binding by voltage-gated sodium channels. Mol Pharmacol. 2005;68(6):1611-1622.
39. Yamakage M, Namiki A. Calcium channels--basic aspects of their structure, function and gene encoding; anesthetic action on the channels--a review. Can J Anaesth. 2002;49(2):151-164.
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Sep 30, 2025
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Krutarth Akhani, Dr. Pragnesh Patani, Mr Milan Jadav, & Dr. Nishkruti R. Mehta. (2025). A COMPARATIVE IN SILICO AND PRECLINICAL EVALUATION OF TWO STRUCTURAL ANALOGUES FOR DIABETIC NEUROPATHIC PAIN WITH FOCUS ON N-TYPE CALCIUM CHANNEL BLOCKADE AND OXIDATIVE STRESS PATHWAYS: A COMPREHENSIVE REVIEW. Journal of Population Therapeutics and Clinical Pharmacology, 32(8), 1192-1204. https://doi.org/10.53555/e7k75b17
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Author Biographies
Krutarth Akhani
Student, Khyati College of Pharmacy, Palodiya, Ahmedabad
Dr. Pragnesh Patani
Principal, Khyati College of Pharmacy, Palodiya, Ahmedabad
Mr Milan Jadav
Assitant Professor, Department of Pharmacology, Khyati College of Pharmacy, Palodiya, Ahmedabad
Dr. Nishkruti R. Mehta
Professor & Head, Department of Pharmacology, Khyati College of Pharmacy, Palodiya, Ahmedabad
How to Cite
Krutarth Akhani, Dr. Pragnesh Patani, Mr Milan Jadav, & Dr. Nishkruti R. Mehta. (2025). A COMPARATIVE IN SILICO AND PRECLINICAL EVALUATION OF TWO STRUCTURAL ANALOGUES FOR DIABETIC NEUROPATHIC PAIN WITH FOCUS ON N-TYPE CALCIUM CHANNEL BLOCKADE AND OXIDATIVE STRESS PATHWAYS: A COMPREHENSIVE REVIEW. Journal of Population Therapeutics and Clinical Pharmacology, 32(8), 1192-1204. https://doi.org/10.53555/e7k75b17