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Current Molecular Medicine


ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

Mini-Review Article

Diabetic Neuropathy: Review on Molecular Mechanisms

Author(s): Mrinal M. Sanaye* and Samruddhi A. Kavishwar

Volume 23, Issue 2, 2023

Published on: 18 March, 2022

Page: [97 - 110] Pages: 14

DOI: 10.2174/1566524021666210816093111

Price: $65


Diabetic mellitus is a worldwide endocrine and metabolic disorder with insulin insensitivity or deficiency or both whose prevalence could rise up to 592 million by 2035. Consistent hyperglycemia leads to one of the most common comorbidities like Diabetic Peripheral Neuropathy (DPN). DPN is underlined with unpleasant sensory experience, such as tingling and burning sensation, hyperalgesia, numbness, etc. Globally, 50-60% of the diabetic population is suffering from such symptoms as microvascular complications. Consistent hyperglycemia during DM causes activation/inhibition of various pathways playing important role in the homeostasis of neurons and other cells. Disruption of these pathways results into apoptosis and mitochondrial dysfunctions, causing neuropathy. Among these, pathways like Polyol and PARP are some of the most intensively studied ones whereas those like Wnt pathway, Mitogen activated protein kinase (MAPK), mTOR pathway are comparatively newly discovered. Understanding of these pathways and their role in pathophysiology of DN underlines a few molecules of immense therapeutic value. The inhibitors or activators of these molecules can be of therapeutic importance in the management of DPN. This review, hence, focuses on these underlying molecular mechanisms intending to provide therapeutically effective molecular targets for the treatment of DPN.

Keywords: Diabetic neuropathy, molecular mechanisms, therapeutic targets, mTOR, polyol.

Sandireddy R, Yerra VG, Areti A, Komirishetty P, Kumar A. Neuroinflammation and oxidative stress in diabetic neuropathy: futuristic strategies based on these targets. Int J Endocrinol 2014; 2014: 674987.
[] [PMID: 24883061]
Aslam A, Singh J, Rajbhandari S. Pathogenesis of painful diabetic neuropathy. Pain Res Treat 2014; 2014: 412041.
[] [PMID: 24891949]
Kumar KH, Elavarasi P. Definition of pain and classification of pain disorders. J Adv Clin Res Insights. 2016; 3: pp. 87-90.
Pasero C. Pathophysiology of neuropathic pain. Pain Manag Nurs 2004; 5(4) (Suppl. 1): 3-8.
[] [PMID: 15644854]
Baron R. Neuropathic pain: A clinical perspective. In: Canning BJ, Spina D, Eds. Handbook of experimental pharmacology. Berlin, Heidelberg: Springer Berlin Heidelberg 2009; 194: pp. 3-30. Sensory Nerves Available from: [Cited 2020 Apr 4]
Tesfaye S, Selvarajah D. Advances in the epidemiology, pathogenesis and management of diabetic peripheral neuropathy. Diabetes Metab Res Rev 2012; 28 (Suppl. 1): 8-14.
[] [PMID: 22271716]
Tan J-S, Lin C-C, Chen G-S. Vasomodulation of peripheral blood flow by focused ultrasound potentiates improvement of diabetic neuropathy. BMJ Open Diabetes Res Care 2020; 8(1): e001004.
[] [PMID: 32188594]
Srinivasan S, Stevens M, Wiley JW. Diabetic peripheral neuropathy: evidence for apoptosis and associated mitochondrial dysfunction. Diabetes 2000; 49(11): 1932-8.
[] [PMID: 11078462]
Cavalli E, Mammana S, Nicoletti F, Bramanti P, Mazzon E. The neuropathic pain: An overview of the current treatment and future therapeutic approaches. Int J Immunopathol Pharmacol 2019; 33: 2058738419838383.
[] [PMID: 30900486]
Román-Pintos LM, Villegas-Rivera G, Rodríguez-Carrizalez AD, Miranda-Díaz AG, Cardona-Muñoz EG. Diabetic polyneuropathy in type 2 diabetes mellitus: Inflammation, oxidative stress, and mitochondrial function. J Diabetes Res 2016; 2016: 3425617.
[] [PMID: 28058263]
Schreiber AK, Nones CF, Reis RC, Chichorro JG, Cunha JM. Diabetic neuropathic pain: Physiopathology and treatment. World J Diabetes 2015; 6(3): 432-44.
[] [PMID: 25897354]
Grover M, Shah K, Khullar G, Gupta J, Behl T. Investigation of the utility of Curcuma caesia in the treatment of diabetic neuropathy. J Pharm Pharmacol 2019; 71(5): 725-32.
[] [PMID: 30767224]
Feldman EL, Nave K-A, Jensen TS, Bennett DLH. New horizons in diabetic neuropathy: mechanisms, bioenergetics, and pain. Neuron 2017; 93(6): 1296-313.
[] [PMID: 28334605]
Viader A, Sasaki Y, Kim S, et al. Aberrant Schwann cell lipid metabolism linked to mitochondrial deficits leads to axon degeneration and neuropathy. Neuron 2013; 77(5): 886-98.
[] [PMID: 23473319]
Vincent AM, Callaghan BC, Smith AL, Feldman EL. Diabetic neuropathy: cellular mechanisms as therapeutic targets. Nat Rev Neurol 2011; 7(10): 573-83.
[] [PMID: 21912405]
Vincent AM, Kato K, McLean LL, Soules ME, Feldman EL. Sensory neurons and schwann cells respond to oxidative stress by increasing antioxidant defense mechanisms. Antioxid Redox Signal 2009; 11(3): 425-38.
[] [PMID: 19072199]
Russell JW, Berent-Spillson A, Vincent AM, Freimann CL, Sullivan KA, Feldman EL. Oxidative injury and neuropathy in diabetes and impaired glucose tolerance. Neurobiol Dis 2008; 30(3): 420-9.
[] [PMID: 18424057]
Vincent AM, Edwards JL, Sadidi M, Feldman EL. The antioxidant response as a drug target in diabetic neuropathy. Curr Drug Targets 2008; 9(1): 94-100.
[] [PMID: 18220717]
Vincent AM, Calabek B, Roberts L, Feldman EL. Biology of diabetic neuropathy. Handb Clin Neurol 2013; 115: 591-606.
[] [PMID: 23931804]
Vincent AM, Russell JW, Low P, Feldman EL. Oxidative stress in the pathogenesis of diabetic neuropathy. Endocr Rev 2004; 25(4): 612-28.
[] [PMID: 15294884]
Fernyhough P. Mitochondrial dysfunction in diabetic neuropathy: A series of unfortunate metabolic events. Curr Diab Rep 2015; 15(11): 89.
[] [PMID: 26370700]
Fernyhough P, McGavock J. Mechanisms of disease: Mitochondrial dysfunction in sensory neuropathy and other complications in diabetes. Handb Clin Neurol 2014; 126: 353-77.
[] [PMID: 25410234]
Chowdhury SKR, Smith DR, Fernyhough P. The role of aberrant mitochondrial bioenergetics in diabetic neuropathy. Neurobiol Dis 2013; 51: 56-65.
[] [PMID: 22446165]
Bachewal P, Gundu C, Yerra VG, Kalvala AK, Areti A, Kumar A. Morin exerts neuroprotection via attenuation of ROS induced oxidative damage and neuroinflammation in experimental diabetic neuropathy. Biofactors 2018; 44(2): 109-22.
[] [PMID: 29193444]
Areti A, Yerra VG, Komirishetty P, Kumar A. Potential therapeutic benefits of maintaining mitochondrial health in peripheral neuropathies. Curr Neuropharmacol 2016; 14(6): 593-609.
[] [PMID: 26818748]
Ganesh Yerra V, Negi G, Sharma SS, Kumar A. Potential therapeutic effects of the simultaneous targeting of the Nrf2 and NF-κB pathways in diabetic neuropathy. Redox Biol 2013; 1(1): 394-7.
[] [PMID: 24024177]
Negi G, Kumar A. S. Sharma S. Nrf2 and NF-κB modulation by sulforaphane counteracts multiple manifestations of diabetic neuropathy in rats and high glucose-induced changes. Curr Neurovasc Res 2011; 8(4): 294-304.
[] [PMID: 22023613]
Negi G, Kumar A, Sharma SS. Melatonin modulates neuroinflammation and oxidative stress in experimental diabetic neuropathy: Effects on NF-κB and Nrf2 cascades: Melatonin and NF-κB/Nrf2 in diabetic neuropathy. J Pineal Res 2010.
Sandireddy R, Yerra VG, Komirishetti P, Areti A, Kumar A. Fisetin imparts neuroprotection in experimental diabetic neuropathy by modulating nrf2 and nf-κb pathways. Cell Mol Neurobiol 2016; 36(6): 883-92.
[] [PMID: 26399251]
Edwards JL, Vincent AM, Cheng HT, Feldman EL. Diabetic neuropathy: Mechanisms to management. Pharmacol Ther 2008; 120(1): 1-34.
[] [PMID: 18616962]
Southan GJ, Szabó C. Poly(ADP-ribose) polymerase inhibitors. Curr Med Chem 2003; 10(4): 321-40.
[] [PMID: 12570705]
Venugopal S. Biochemical alterations in diabetic neuropathy. J Mol Genet Med 2014; 08(04) Available from: [Cited 2020 Apr 23]
Pacher P, Obrosova IG, Mabley JG, Szabó C. Role of nitrosative stress and peroxynitrite in the pathogenesis of diabetic complications. Emerging new therapeutical strategies. Curr Med Chem 2005; 12(3): 267-75.
[] [PMID: 15723618]
Obrosova IG, Julius UA. Role for poly(ADP-ribose) polymerase activation in diabetic nephropathy, neuropathy and retinopathy. Curr Vasc Pharmacol 2005; 3(3): 267-83.
[] [PMID: 16026323]
Li F, Drel VR, Szabó C, Stevens MJ, Obrosova IG. Low-dose poly(ADP-ribose) polymerase inhibitor-containing combination therapies reverse early peripheral diabetic neuropathy. Diabetes 2005; 54(5): 1514-22.
[] [PMID: 15855340]
Pacher P, Liaudet L, Soriano FG, Mabley JG, Szabó E, Szabó C. The role of poly(ADP-ribose) polymerase activation in the development of myocardial and endothelial dysfunction in diabetes. Diabetes 2002; 51(2): 514-21.
[] [PMID: 11812763]
Ilnytska O, Lyzogubov VV, Stevens MJ, et al. Poly(ADP-ribose) polymerase inhibition alleviates experimental diabetic sensory neuropathy. Diabetes 2006; 55(6): 1686-94.
[] [PMID: 16731831]
Zheng L, Szabó C, Kern TS. Poly(ADP-ribose) polymerase is involved in the development of diabetic retinopathy via regulation of nuclear factor-kappaB. Diabetes 2004; 53(11): 2960-7.
[] [PMID: 15504977]
Komirishetty P, Areti A, Sistla R, Kumar A. Morin mitigates chronic constriction injury (cci)-induced peripheral neuropathy by inhibiting oxidative stress induced parp over-activation and neuroinflammation. Neurochem Res 2016; 41(8): 2029-42.
[] [PMID: 27084773]
Sommer C, Kress M. Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia. Neurosci Lett 2004; 361(1-3): 184-7.
[] [PMID: 15135924]
Obrosova IG, Li F, Abatan OI, et al. Role of poly(ADP-ribose) polymerase activation in diabetic neuropathy. Diabetes 2004; 53(3): 711-20.
[] [PMID: 14988256]
Komirishetty P, Areti A, Gogoi R, Sistla R, Kumar A. Poly(ADP-ribose) polymerase inhibition reveals a potential mechanism to promote neuroprotection and treat neuropathic pain. Neural Regen Res 2016; 11(10): 1545-8.
[] [PMID: 27904474]
Tentori L, Portarena I, Graziani G. Potential clinical applications of poly(ADP-ribose) polymerase (PARP) inhibitors. Pharmacol Res 2002; 45(2): 73-85.
[] [PMID: 11846617]
Dewanjee S, Das S, Das AK, et al. Molecular mechanism of diabetic neuropathy and its pharmacotherapeutic targets. Eur J Pharmacol 2018; 833: 472-523.
[] [PMID: 29966615]
Lupachyk S, Shevalye H, Maksimchyk Y, Drel VR, Obrosova IG. PARP inhibition alleviates diabetes-induced systemic oxidative stress and neural tissue 4-hydroxynonenal adduct accumulation: correlation with peripheral nerve function. Free Radic Biol Med 2011; 50(10): 1400-9.
[] [PMID: 21300148]
Li F, Szabó C, Pacher P, et al. Evaluation of orally active poly(ADP-ribose) polymerase inhibitor in streptozotocin-diabetic rat model of early peripheral neuropathy. Diabetologia 2004; 47(4): 710-7.
[] [PMID: 15298348]
Assaf N, El-Shamarka ME, Salem NA, Khadrawy YA, El Sayed NS. Neuroprotective effect of PPAR alpha and gamma agonists in a mouse model of amyloidogenesis through modulation of the Wnt/beta catenin pathway via targeting alpha- and beta-secretases. Prog Neuropsychopharmacol Biol Psychiatry 2020; 97: 109793.
[] [PMID: 31669201]
Rosso SB, Inestrosa NC. WNT signaling in neuronal maturation and synaptogenesis. Front Cell Neurosci 2013; 7 Available from: [Cited 2020 May 2]
Liu W, Liang X, Yang D. The effects of chinese medicine on activation of wnt/β-catenin signal pathway under high glucose condition. Evid Based Complement Alternat Med 2015; 2015: 295135.
[] [PMID: 26495008]
Katoh M, Katoh M. WNT signaling pathway and stem cell signaling network. Clin Cancer Res 2007; 13(14): 4042-5.
[] [PMID: 17634527]
Clevers H, Nusse R. Wnt/β-catenin signaling and disease. Cell 2012; 149(6): 1192-205.
[] [PMID: 22682243]
Chong ZZ, Shang YC, Maiese K. Vascular injury during elevated glucose can be mitigated by erythropoietin and Wnt signaling. Curr Neurovasc Res 2007; 4(3): 194-204.
[] [PMID: 17691973]
Yang KM, Hu HJYAD, Li XS. MX Li. The changes of Wnt/β-catenin pathway in diabetic rat pancrease and its role in regulating the differentiation and proliferation of pancreatic stem cells. Chin J Diabetes 2011; 19(2): 149-51.
Hong QX, Xu SY. Expression profiling of spinal genes in peripheral neuropathy model rats with type 2 diabetes mellitus. Int J Clin Exp Med 2016; 9(3): 6376-84.
Folestad A, Ålund M, Asteberg S, et al. Role of Wnt/β-catenin and RANKL/OPG in bone healing of diabetic Charcot arthropathy patients. Acta Orthop 2015; 86(4): 415-25.
[] [PMID: 25811776]
Ng LF, Kaur P, Bunnag N, et al. WNT signaling in disease. Cells 2019; 8(8): 826.
[] [PMID: 31382613]
Morfini G, Szebenyi G, Elluru R, Ratner N, Brady ST. Glycogen synthase kinase 3 phosphorylates kinesin light chains and negatively regulates kinesin-based motility. EMBO J 2002; 21(3): 281-93.
[] [PMID: 11823421]
Cohen P, Frame S. The renaissance of GSK3. Nat Rev Mol Cell Biol 2001; 2(10): 769-76.
[] [PMID: 11584304]
Hanger DP, Hughes K, Woodgett JR, Brion J-P, Anderton BH. Glycogen synthase kinase-3 induces Alzheimer’s disease-like phosphorylation of tau: generation of paired helical filament epitopes and neuronal localisation of the kinase. Neurosci Lett 1992; 147(1): 58-62.
[] [PMID: 1336152]
Mazzardo-Martins L, Martins DF, Stramosk J, Cidral-Filho FJ, Santos ARS. Glycogen synthase kinase 3-specific inhibitor AR-A014418 decreases neuropathic pain in mice: evidence for the mechanisms of action. Neuroscience 2012; 226: 411-20.
[] [PMID: 23000630]
Song B, Lai B, Zheng Z, et al. Inhibitory phosphorylation of GSK-3 by CaMKII couples depolarization to neuronal survival. J Biol Chem 2010; 285(52): 41122-34.
[] [PMID: 20841359]
Li Z, Ma L, Chen X, et al. Glycogen synthase kinase-3: A key kinase in retinal neuron apoptosis in early diabetic retinopathy. Chin Med J (Engl) 2014; 127(19): 3464-70.
[PMID: 25269915]
Jolivalt CG, Calcutt NA, Masliah E. Similar pattern of peripheral neuropathy in mouse models of type 1 diabetes and Alzheimer’s disease. Neuroscience 2012; 202: 405-12.
[] [PMID: 22178988]
Zhao Y, Yang Z. Effect of Wnt signaling pathway on pathogenesis and intervention of neuropathic pain. Exp Ther Med 2018. Available from: [Cited 2020 May 3]
Yuan S, Shi Y, Tang S-J. Wnt signaling in the pathogenesis of multiple sclerosis-associated chronic pain. J Neuroimmune Pharmacol 2012; 7(4): 904-13.
[] [PMID: 22547300]
Zhang Y-K, Huang Z-J, Liu S, Liu Y-P, Song AA, Song X-J. WNT signaling underlies the pathogenesis of neuropathic pain in rodents. J Clin Invest 2013; 123(5): 2268-86.
[] [PMID: 23585476]
Banerjee S, Biehl A, Gadina M, Hasni S, Schwartz DM. JAK-STAT Signaling as a Target for Inflammatory and Autoimmune Diseases: Current and Future Prospects. Drugs 2017; 77(5): 521-46.
[] [PMID: 28255960]
Li C-D, Zhao J-Y, Chen J-L, et al. Mechanism of the JAK2/STAT3-CAV-1-NR2B signaling pathway in painful diabetic neuropathy. Endocrine 2019; 64(1): 55-66.
[] [PMID: 30830585]
Bousoik E, Montazeri Aliabadi H. “Do We Know Jack” about JAK? A closer look at JAK/STAT signaling pathway. Front Oncol 2018; 8: 287.
[] [PMID: 30109213]
Mazière C, Conte MA, Mazière JC. Activation of JAK2 by the oxidative stress generated with oxidized low-density lipoprotein. Free Radic Biol Med 2001; 31(11): 1334-40.
[] [PMID: 11728804]
O’Shea JJ, Plenge R. JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity 2012; 36(4): 542-50.
[] [PMID: 22520847]
Hur J, O’Brien PD, Nair V, et al. Transcriptional networks of murine diabetic peripheral neuropathy and nephropathy: common and distinct gene expression patterns. Diabetologia 2016; 59(6): 1297-306.
[] [PMID: 27000313]
Simon AR, Rai U, Fanburg BL, Cochran BH. Activation of the JAK-STAT pathway by reactive oxygen species. Am J Physiol 1998; 275(6): C1640-52.
[] [PMID: 9843726]
Chowdhury SR, Saleh A, Akude E, et al. Ciliary neurotrophic factor reverses aberrant mitochondrial bioenergetics through the JAK/STAT pathway in cultured sensory neurons derived from streptozotocin-induced diabetic rodents. Cell Mol Neurobiol 2014; 34(5): 643-9.
[] [PMID: 24682898]
Saleh A, Chowdhury SK, Smith DR, et al. Diabetes impairs an interleukin-1β-dependent pathway that enhances neurite outgrowth through JAK/STAT3 modulation of mitochondrial bioenergetics in adult sensory neurons. Mol Brain 2013; 6(1): 45.
[] [PMID: 24152426]
Dominguez E, Rivat C, Pommier B, Mauborgne A, Pohl M. JAK/STAT3 pathway is activated in spinal cord microglia after peripheral nerve injury and contributes to neuropathic pain development in rat. J Neurochem 2008; 107(1): 50-60.
[] [PMID: 18636982]
Liu S, Mi W-L, Li Q, et al. Spinal IL-33/ST2 signaling contributes to neuropathic pain via neuronal camkii-creb and astroglial jak2-stat3 cascades in mice. Anesthesiology 2015; 123(5): 1154-69.
[] [PMID: 26352378]
Xie J-D, Chen S-R, Pan H-L. Presynaptic mGluR5 receptor controls glutamatergic input through protein kinase C-NMDA receptors in paclitaxel-induced neuropathic pain. J Biol Chem 2017; 292(50): 20644-54.
[] [PMID: 29074619]
Huang JS, Guh JY, Hung WC, et al. Role of the Janus kinase (JAK)/signal transducters and activators of transcription (STAT) cascade in advanced glycation end-product-induced cellular mitogenesis in NRK-49F cells. Biochem J 1999; 342(Pt 1): 231-8.
[] [PMID: 10432321]
Park S-K, Dahmer MK, Quasney MW. MAPK and JAK-STAT signaling pathways are involved in the oxidative stress-induced decrease in expression of surfactant protein genes. Cell Physiol Biochem 2012; 30(2): 334-46.
[] [PMID: 22739240]
Bhattacharjee N, Barma S, Konwar N, Dewanjee S, Manna P. Mechanistic insight of diabetic nephropathy and its pharmacotherapeutic targets: An update. Eur J Pharmacol 2016; 791: 8-24.
[] [PMID: 27568833]
Lu T-C, Wang Z-H, Feng X, et al. Knockdown of Stat3 activity in vivo prevents diabetic glomerulopathy. Kidney Int 2009; 76(1): 63-71.
[] [PMID: 19357722]
Wang X, Shaw S, Amiri F, Eaton DC, Marrero MB. Inhibition of the Jak/STAT signaling pathway prevents the high glucose-induced increase in tgf-beta and fibronectin synthesis in mesangial cells. Diabetes 2002; 51(12): 3505-9.
[] [PMID: 12453907]
Berthier CC, Zhang H, Schin M, et al. Enhanced expression of Janus kinase-signal transducer and activator of transcription pathway members in human diabetic nephropathy. Diabetes 2009; 58(2): 469-77.
[] [PMID: 19017763]
Soares-Silva M, Diniz FF, Gomes GN, Bahia D. The mitogen-activated protein kinase (MAPK) pathway: Role in immune evasion by trypanosomatids. Front Microbiol 2016; 7 Available from: [Cited 2020 May 5]
Johnson GL, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 2002; 298(5600): 1911-2.
[] [PMID: 12471242]
Peti W, Page R. Molecular basis of MAP kinase regulation. Protein Sci 2013; 22(12): 1698-710.
[] [PMID: 24115095]
Arthur JSC, Ley SC. Mitogen-activated protein kinases in innate immunity. Nat Rev Immunol 2013; 13(9): 679-92.
[] [PMID: 23954936]
Liu Y, Shepherd EG, Nelin LD. MAPK phosphatases--regulating the immune response. Nat Rev Immunol 2007; 7(3): 202-12.
[] [PMID: 17318231]
Dong C, Davis RJ, Flavell RA. MAP kinases in the immune response. Annu Rev Immunol 2002; 20(1): 55-72.
[] [PMID: 11861597]
Pimienta G, Pascual J. Canonical and alternative MAPK signaling. Cell Cycle 2007; 6(21): 2628-32.
[] [PMID: 17957138]
Turjanski AG, Vaqué JP, Gutkind JS. MAP kinases and the control of nuclear events. Oncogene 2007; 26(22): 3240-53.
[] [PMID: 17496919]
Kyriakis JM, Avruch J. Mammalian MAPK signal transduction pathways activated by stress and inflammation: A 10-year update. Physiol Rev 2012; 92(2): 689-737.
[] [PMID: 22535895]
Johnson GL. Defining MAPK interactomes. ACS Chem Biol 2011; 6(1): 18-20.
[] [PMID: 21128644]
Owens DM, Keyse SM. Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases. Oncogene 2007; 26(22): 3203-13.
[] [PMID: 17496916]
Raman M, Chen W, Cobb MH. Differential regulation and properties of MAPKs. Oncogene 2007; 26(22): 3100-12.
[] [PMID: 17496909]
Zhang Y, Dong C. Regulatory mechanisms of mitogen-activated kinase signaling. Cell Mol Life Sci 2007; 64(21): 2771-89.
[] [PMID: 17726577]
Huang Y-H, Hou S-Y, Cheng J-K, Wu C-H, Lin C-R. Pulsed radiofrequency attenuates diabetic neuropathic pain and suppresses formalin-evoked spinal glutamate release in rats. Int J Med Sci 2016; 13(12): 984-91.
[] [PMID: 27994505]
Rahn EJ, Guzman-Karlsson MC, David Sweatt J. Cellular, molecular, and epigenetic mechanisms in non-associative conditioning: implications for pain and memory. Neurobiol Learn Mem 2013; 105: 133-50.
[] [PMID: 23796633]
Daulhac L, Mallet C, Courteix C, et al. Diabetes-induced mechanical hyperalgesia involves spinal mitogen-activated protein kinase activation in neurons and microglia viaN-methyl-D-aspartate-dependent mechanisms. Mol Pharmacol 2006; 70(4): 1246-54.
[] [PMID: 16868181]
Wang H, Zhang H, Cao F, Lu J, Tang J, Li H, et al. Protection of insulin-like growth factor 1 on experimental peripheral neuropathy in diabetic mice. Mol Med Rep 2018.
Nam YH, Moon HW, Lee YR, et al. Panax ginseng (Korea Red Ginseng) repairs diabetic sensorineural damage through promotion of the nerve growth factor pathway in diabetic zebrafish. J Ginseng Res 2019; 43(2): 272-81.
[] [PMID: 30976165]
Wang Q, Zhai C, Wahafu A, Zhu Y, Liu Y, Sun L. Salvianolic acid B inhibits the development of diabetic peripheral neuropathy by suppressing autophagy and apoptosis. J Pharm Pharmacol 2018.
Jiang Y, Wang J, Li H, Xia L. IL-35 alleviates inflammation progression in a rat model of diabetic neuropathic pain via inhibition of JNK signaling. J Inflamm (Lond) 2019; 16(1): 19.
[] [PMID: 31367192]
Zhang T-T, Xue R, Fan S-Y, et al. Ammoxetine attenuates diabetic neuropathic pain through inhibiting microglial activation and neuroinflammation in the spinal cord. J Neuroinflammation 2018; 15(1): 176.
[] [PMID: 29879988]
Sehgal SN. Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc 2003; 35(3) (Suppl.): 7S-14S.
[] [PMID: 12742462]
Fingar DC, Blenis J. Target of rapamycin (TOR): An integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene 2004; 23(18): 3151-71.
[] [PMID: 15094765]
Cork GK, Thompson J, Slawson C. Real talk: The inter-play between the mtor, ampk, and hexosamine biosynthetic pathways in cell signaling. Front Endocrinol (Lausanne) 2018; 9: 522.
[] [PMID: 30237786]
Zhu L, Hao J, Cheng M, Zhang C, Huo C, Liu Y, et al. Hyperglycemia-induced Bcl-2/Bax-mediated apoptosis of Schwann cells via mTORC1/S6K1 inhibition in diabetic peripheral neuropathy. Exp Cell Res 2018; 367(2): 186-95.
Dong J, Li H, Bai Y, Wu C. Muscone ameliorates diabetic peripheral neuropathy through activating AKT/mTOR signalling pathway. J Pharm Pharmacol 2019; 71(11): 1706-13.
[] [PMID: 31468549]
Banko JL, Poulin F, Hou L, DeMaria CT, Sonenberg N, Klann E. The translation repressor 4E-BP2 is critical for eIF4F complex formation, synaptic plasticity, and memory in the hippocampus. J Neurosci 2005; 25(42): 9581-90.
[] [PMID: 16237163]
Costa-Mattioli M, Sossin WS, Klann E, Sonenberg N. Translational control of long-lasting synaptic plasticity and memory. Neuron 2009; 61(1): 10-26.
[] [PMID: 19146809]
Géranton SM, Jiménez-Díaz L, Torsney C, et al. A rapamycin-sensitive signaling pathway is essential for the full expression of persistent pain states. J Neurosci 2009; 29(47): 15017-27.
[] [PMID: 19940197]
Price TJ, Rashid MH, Millecamps M, Sanoja R, Entrena JM, Cervero F. Decreased nociceptive sensitization in mice lacking the fragile X mental retardation protein: role of mGluR1/5 and mTOR. J Neurosci 2007; 27(51): 13958-67.
[] [PMID: 18094233]
Xu Q, Fitzsimmons B, Steinauer J, et al. Spinal phosphinositide 3-kinase-Akt-mammalian target of rapamycin signaling cascades in inflammation-induced hyperalgesia. J Neurosci 2011; 31(6): 2113-24.
[] [PMID: 21307248]
Fumarola C, Bonelli MA, Petronini PG, Alfieri RR. Targeting PI3K/AKT/mTOR pathway in non small cell lung cancer. Biochem Pharmacol 2014; 90(3): 197-207.
[] [PMID: 24863259]
Zhang C-H, Lv X, Du W, et al. The Akt/mTOR cascade mediates high glucose-induced reductions in BDNF via DNMT1 in Schwann cells in diabetic peripheral neuropathy. Exp Cell Res 2019; 383(1): 111502.
[] [PMID: 31323191]
He WY, Zhang B, Zhao WC, et al. Contributions of mtor activation-mediated upregulation of synapsin ii and neurite outgrowth to hyperalgesia in stz-induced diabetic rats. ACS Chem Neurosci 2019; 10(5): 2385-96.
[] [PMID: 30785256]
Schmidtko A, Del Turco D, Coste O, et al. Essential role of the synaptic vesicle protein synapsin II in formalin-induced hyperalgesia and glutamate release in the spinal cord. Pain 2005; 115(1-2): 171-81.
[] [PMID: 15836980]
Schmidtko A, Luo C, Gao W, Geisslinger G, Kuner R, Tegeder I. Genetic deletion of synapsin II reduces neuropathic pain due to reduced glutamate but increased GABA in the spinal cord dorsal horn. Pain 2008; 139(3): 632-43.
[] [PMID: 18701217]
Hobson S-A, Holmes FE, Kerr NCH, Pope RJP, Wynick D. Mice deficient for galanin receptor 2 have decreased neurite outgrowth from adult sensory neurons and impaired pain-like behaviour. J Neurochem 2006; 99(3): 1000-10.
[] [PMID: 17076662]
Wilson SM, Xiong W, Wang Y, et al. Prevention of posttraumatic axon sprouting by blocking collapsin response mediator protein 2-mediated neurite outgrowth and tubulin polymerization. Neuroscience 2012; 210: 451-66.
[] [PMID: 22433297]
Evans LJ, Loescher AR, Boissonade FM, Whawell SA, Robinson PP, Andrew D. Temporal mismatch between pain behaviour, skin nerve growth factor and intra-epidermal nerve fibre density in trigeminal neuropathic pain. BMC Neurosci 2014; 15(1): 1.
[] [PMID: 24380503]

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