12/15-Lipoxygenase inhibition counteracts MAPK phosphorylation in mouse and cell culture models of diabetic peripheral neuropathy

Roman Stavniichuk, Alexander A. Obrosov, Viktor R. Drel, Jerry L. Nadler, Irina G. Obrosova, Mark A. Yorek

Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, USA.
Department of Veterans Affairs Iowa City Health Care System and Department of Internal Medicine, University of Iowa, Iowa City, USA.
Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, USA.

DOI: 10.4236/jdm.2013.33015                

Abstract

Background: Increased mitogen-activated protein kinase (MAPK) phosphorylation has been detected in peripheral nerve of human subjects and animal models with diabetes as well as high-glucose exposed human Schwann cells, and have been implicated in diabetic peripheral neuropathy. In our recent studies, leukocytetype 12/15-lipoxygenase inhibition or gene deficiency alleviated large and small nerve fiber dysfunction, but not intraepidermal nerve fiber loss in streptozotocin-diabetic mice. Methods: To address a mechanism we evaluated the potential for pharmacological 12/15-lipoxygenase inhibition to counteract excessive MAPK phosphorylation in mouse and cell culture models of diabetic neuropathy. C57Bl6/J mice were made diabetic with streptozotocin and maintained with or without the 12/15-lipoxygenase inhibitor cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC). Human Schwann cells were cultured in5.5 mMor30 mMglucose with or without CDC. Results: 12(S) HETE concentrations (ELISA), as well as 12/15-lipoxygenase expression and p38 MAPK, ERK, and SAPK/JNK phosphorylation (all by Western blot analysis) were increased in the peripheral nerve and spinal cord of diabetic mice as well as in high glucose-exposed human Schwann cells. CDC counteracted diabetes-induced increase in 12(S)HETE concentrations (a measure of 12/15-lipoxygenase activity), but not 12/15-lipoxygenase overexpression, in sciatic nerve and spinal cord. The inhibitor blunted excessive p38 MAPK and ERK, but not SAPK/ JNK, phosphorylation in sciatic nerve and high glucose exposed human Schwann cells, but did not affect MAPK, ERK, and SAPK/JNK phosphorylation in spinal cord. Conclusion: 12/15-lipoxygenase inhibition counteracts diabetes related MAPK phosphorylation in mouse and cell culture models of diabetic neuropathy and implies that 12/15-lipoxygenase inhibitors may be an effective treatment for diabetic peripheral neuropathy.

Keywords

Diabetes; Lipoxygenase; Neuropathy; Schwann Cells; Mitogen-Activated Protein Kinase

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Boulton, A.J., Vinik, A.I., Arezzo, J.C., Bril, V., Feldman, E.L., Freeman, R., et al. (2005) Diabetic neuropathies: A statement by the American Diabetes Association. Diabetes Care, 28, 956-962. doi:10.2337/diacare.28.4.956
[2]	Sinnreich, M., Taylor, B.V. and Dyck, P.J. (2005) Diabetic neuropathies. Classification, clinical features, and pathophysiological basis. Neurologist, 11, 63-79. doi:10.1097/01.nrl.0000156314.24508.ed
[3]	Veves, A., Backonja, M. and Malik, R.A. (2008) Painful diabetic neuropathy: Epidemiology, natural history, early diagnosis, and treatment options. Pain Medicine, 9, 660-674. doi:10.1111/j.1526-4637.2007.00347.x
[4]	Tesfaye, S., Boulton, A.J., Dyck, P.J., Freeman, R., Horowitz, M., Kempler, P., et al. (2010) Diabetic neuropathies: Update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care, 33, 2285-2293. doi:10.2337/dc10-1303
[5]	Yagihashi, S., Yamagishi, S.I., Wada, R.R., Baba, M., Hohman, T.C., Yabe-Nishimura, C., et al. (2001) Neuropathy in diabetic mice overexpressing human aldose reductase and effects of aldose reductase inhibitor. Brain, 124, 2448-2458. doi:10.1093/brain/124.12.2448
[6]	Obrosova, I.G., Van Huysen, C., Fathallah, L., Cao, X.C., Greene, D.A. and Stevens, M.J. (2002) An aldose reductase inhibitor reverses early diabetes-induced changes in peripheral nerve function, metabolism, and antioxidative defense. The FASEB Journal, 16, 123-125.
[7]	Ho, E.C., Lam, K.S., Chen, Y.S. and Yip, J.C., Arvindakshan, M., Yamagishi, S., et al. (2006) Aldose reductasedeficient mice are protected from delayed motor nerve conduction velocity, increased c-Jun NH2-terminal kinase activation, depletion of reduced glutathione, increased superoxide accumulation, and DNA damage. Diabetes, 55, 1946-1953. doi:10.2337/db05-1497
[8]	Jack, M.M., Ryals, J.M. and Wright, D.E. (2011) Characterization of glyoxalase I in a streptozocin-induced mouse model of diabetes with painful and insensate neuropathy. Diabetologia, 54, 2174-2182. doi:10.1007/s00125-011-2196-3
[9]	Bierhaus, A., Fleming, T., Stoyanov, S., Leffler, A., Babes, A., Neacsu, C., et al. (2012) Methylglyoxal modification of Na(v)1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy. Nature Medicine, 18, 926-933. doi:10.1038/nm.2750
[10]	Bierhaus, A., Haslbeck, K.M., Humpert, P.M., Liliensiek, B., Dehmer, T., Morcos, M., et al. (2004) Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily. Journal Clinical Investigation, 114, 1741-1751.
[11]	Cameron, N.E., Gibson, T.M., Nangle, M.R. and Cotter, M.A. (2005) Inhibitors of advanced glycation end product formation and neurovascular dysfunction in experimental diabetes. Annuals New York Academy Science, 1043, 784-792. doi:10.1196/annals.1333.091
[12]	Nagamatsu, M., Nickander, K.K., Schmelzer, J.D., Raya, A., Wittrock, D.A., Tritschler, H., et al. (1995) Lipoic acid improves nerve blood flow, reduces oxidative stress, and improves distal nerve conduction in experimental diabetic neuropathy. Diabetes Care, 18, 1160-1167. doi:10.2337/dia care.18.8.1160
[13]	Cameron, N.E., Tuck, Z., McCabe, L. and Cotter, M.A. (2001) Effect of the hydroxyl radical scavenger, dimethylthiourea, on peripheral nerve tissue perfusion, conduction velocity and nociception in experimental diabetes. Diabetologia, 44, 1161-1169. doi:10.1007/s001250100626
[14]	Coppey, L.J., Gellett, J.S., Davidson, E.P., Dunlap, J.A., Lund, D.D. and Yorek, M.A. (2001) Effect of antioxidant treatment of streptozotocin-induced diabetic rats on endoneurial blood flow, motor nerve conduction velocity, and vascular reactivity of epineurial arterioles of the sciatic nerve. Diabetes, 50, 1927-1937. doi:10.2337/diabetes.50.8.1927
[15]	Obrosova, I.G., Mabley, J.G., Zsengellér, Z., Charniauskaya, T., Abatan, O.I., Groves, J.T., et al. (2005) Role for nitrosative stress in diabetic neuropathy: Evidence from studies with a peroxynitrite decomposition catalyst. FASEB Journal, 19, 401-403.
[16]	Lupachyk, S., Shevalye, H., Maksimchyk, Y., Drel, V.R. and Obrosova, I.G. (2011) PARP inhibition alleviates diabetes-induced systemic oxidative stress and neural tissue 4-hydroxynonenal adduct accumulation: Correlation with peripheral nerve function. Free Radical Biology Medicine, 50, 1400-1409. doi:10.1016/j.freeradbiomed.2011.01.037
[17]	Goss, J.R., Goins, W.F., Lacomis, D., Mata, M., Glorioso, J.C. and Fink, D.J. (2002) Herpes simplex-mediated gene transfer of nerve growth factor protects against peripheral neuropathy in streptozotocin-induced diabetes in the mouse. Diabetes, 51, 2227-2232. doi:10.2337/diab etes.51.7.2227
[18]	Bianchi, R., Buyukakilli, B., Brines, M., Savino, C., Cavaletti, G., Oggioni, N., et al. (2004) Erythropoietin both protects from and reverses experimental diabetic neuropathy. Proceedings National Academy Science, 101, 823-828. doi:10.1073/pnas.0307823100
[19]	Nakamura, J., Kato, K., Hamada, Y., Nakayama, M., Chaya, S., Nakashima, E., et al. (1999) A protein kinase C-betaselective inhibitor ameliorates neural dysfunction in streptozotocin-induced diabetic rats. Diabetes, 48, 2090-2095. doi:10.2337/diabetes.48.10.2090
[20]	Cameron, N.E., Cotter, M.A., Jack, A.M., Basso, M.D. and Hohman, T.C. (1999) Protein kinase C effects on nerve function, perfusion, Na(+), K(+)-ATPase activity and glutathione content in diabetic rats. Diabetologia, 42, 1120-1130. doi:10.1007/s001250051280
[21]	Li, F., Drel, V.R., Szabó, C., Stevens, M.J. and Obrosova, I.G. (2005) Low-dose poly(ADP-ribose) polymerase inhibitor-containing combination therapies reverse early peripheral diabetic neuropathy. Diabetes, 54, 1514-1522. doi:10.2337/diabetes.54.5.1514
[22]	Obrosova, I.G., Xu, W., Lyzogubov, V.V., Ilnytska, O., Mashtalir, N., Vareniuk, I., et al. (2008) PARP inhibition or gene deficiency counteracts intraepidermal nerve fiber loss and neuropathic pain in advanced diabetic neuropathy. Free Radical Biology Medicine, 44, 972-981. doi:10.1016/j.freeradbiomed.2007.09.013
[23]	Kellogg, A.P., Wiggin, T.D., Larkin, D.D., Hayes, J.M., Stevens, M.J. and Pop-Busui, R. (2007) Protective effects of cyclooxygenase-2 gene inactivation against peripheral nerve dysfunction and intraepidermal nerve fiber loss in experimental diabetes. Diabetes, 56, 2997-3005. doi:10.2337/db07-0740
[24]	Stavniichuk, R., Drel, V.R., Shevalye, H., Vareniuk, I., Stevens, M.J., Nadler, J.L., et al. (2010) Role of 12/15-lipoxygenase in nitrosative stress and peripheral prediabetic and diabetic neuropathies. Free Radical Biology Medicine, 49, 1036-1045. doi:10.1016/j.freeradbiomed.2010.06.016
[25]	Obrosova, I.G., Stavniichuk, R., Drel, V.R., Shevalye, H., Vareniuk, I., Nadler, J.L., et al. (2010) Different roles of 12/15-lipoxygenase in diabetic large and small fiber peripheral and autonomic neuropathies. American Journal Pathology, 177, 1436-1447. doi:10.2353/ajpath.2010.100178
[26]	Purves, T., Middlemas, A., Agthong, S., Jude, E.B., Boulton, A.J., Fernyhough, P., et al. (2001) A role for mitogen-activated protein kinases in the etiology of diabetic neuropathy. FASEB Journal, 15, 2508-2514. doi:10.1096/fj.01-0253hyp
[27]	Price, S.A., Agthong, S., Middlemas, A.B. and Tomlinson, D.R. (2004) Mitogen-activated protein kinase p38 mediates reduced nerve conduction velocity in experimental diabetic neuropathy: Interactions with aldose reductase. Diabetes, 53, 1851-1856. doi:10.2337/diabetes.53.7.1851
[28]	Cheng, H.T., Dauch, J.R., Oh, S.S., Hayes, J.M., Hong, Y. and Feldman, E.L. (2010) p38 mediates mechanical allodynia in a mouse model of type 2 diabetes. Molecular Pain, 19, 6-28.
[29]	Stavniichuk, R., Drel, V.R., Shevalye, H., Maksimchyk, Y., Kuchmerovska, T.M., Nadler, J.L., et al. (2011) Baicalein alleviates diabetic peripheral neuropathy through inhibition of oxidative-nitrosative stress and p38 MAPK activation. Experimental Neurology, 230, 106-113. doi:10.1016/j.expn eurol.2011.04.002
[30]	Drel, V.R., Pacher, P., Stavniichuk, R., Xu, W., Zhang, J., Kuchmerovska, T.M., et al. (2011) Poly(ADP-ribose)polymerase inhibition counteracts renal hypertrophy and multiple manifestations of peripheral neuropathy in diabetic Akita mice. International Journal Molecular Medicine, 28, 629-635.
[31]	Stavniichuk, R., Shevalye, H., Hirooka, H., Nadler, J.L. and Obrosova, I.G. (2012) Interplay of sorbitol pathway of glucose metabolism, 12/15-lipoxygenase, and mitogen-activated protein kinases in the pathogenesis of diabetic peripheral neuropathy. Biochemical Pharmacology, 83, 932-940. doi:10.1016/j.bcp.2012.01.015
[32]	Askwith, T., Zeng, W., Eggo, M.C. and Stevens, M.J. (2012) Taurine reduces nitrosative stress and nitric oxide synthase expression in high glucose-exposed human Schwann cells. Experimental Neurology, 233, 154-162. doi:10.1016/j.expneurol.2011.09.010
[33]	Roberts, P.J. and Der, C.J. (2007) Targeting the RafMEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene, 26, 3291-3310. doi:10.1038/sj.onc.1210422
[34]	Lehmann, H.C. and Hoke, A. (2010) Schwann cells as a therapeutic target for peripheral neuropathies. CNS Neurology Disorders Drug Targets, 9, 801-816. doi:10.2174/187152 710793237412
[35]	Lehmann, H.C., Chen, W., Mi, R., Wang, S., Liu, Y., Rao, M., et al. (2012) Human Schwann cells retain essential phenotype characteristics after immortalization. Stem Cells Development, 21, 423-431. doi:10.1089/scd.2010.0513
[36]	Obrosova, I.G., Drel, V.R., Pacher, P., Ilnytska, O., Wang, Z.Q., Stevens, M.J., et al. (2005) Oxidative-nitrosative stress and poly(ADP-ribose) polymerase (PARP) activition in experimental diabetic neuropathy: The relation is revisited. Diabetes, 54, 3435-3441. doi:10.2337/diabetes.54.12.3435
[37]	Stevens, M.J., Li, F., Drel, V.R., Abatan, O.I., Kim, H., Burnett, D., et al. (2007) Nicotinamide reverses neurological and neurovascular deficits in streptozotocin diabetic rats. The Journal of Pharmacology and Experimental Therapeutics, 320, 458-464. doi:10.1124/jpet.106.109702
[38]	Askwith, T., Zeng, W., Eggo, M.C. and Stevens, M.J. (2009) Oxidative stress and dysregulation of the taurine transporter in high-glucose-exposed human Schwann cells: Implications for pathogenesis of diabetic neuropathy. American Journal of Physiology Endocrinology and Metabolism, 297, 620-628. doi:10.1152/ajpendo.00287.2009
[39]	Pop-Busui, R., Marinescu, V., Van Huysen, C., Li, F., Sullivan, K., Greene, D.A., et al. (2002) Dissection of metabolic, vascular, and nerve conduction interrelationships in experimental diabetic neuropathy by cyclooxygenase inhibition and acetyl-L-carnitine administration. Diabetes, 51, 2619-2628. doi:10.2337/diabetes.51.8.2619
[40]	Kellogg, A.P., Converso, K., Wiggin, T., Stevens, M. and Pop-Busui, R. (2009) Effects of cyclooxygenase-2 gene inactivation on cardiac autonomic and left ventricular function in experimental diabetes. American Journal of Physiology Heart and Circulation Physiology, 296, 453-461. doi:10.1152/ajpheart.00678.2008
[41]	Reddy, M.A., Thimmalapura, P.R., Lanting, L., Nadler, J.L., Fatima, S. and Natarajan, R. (2002) The oxidized lipid and lipoxygenase product 12(S)-hydroxyeicosa-tetraenoic acid induces hypertrophy and fibronectin transcription in vascular smooth muscle cells via p38 MAPK and cAMP response element-binding protein activation. Mediation of angiotensin II effects. Journal of Biological Chemistry, 277, 9920-9928. doi:10.1074/jbc.M111305200
[42]	Dwarakanath, R.S., Sahar, S., Reddy, M.A., Castanotto, D., Rossi, J.J. and Natarajan, R. (2004) Regulation of monocyte chemoattractant protein-1 by the oxidized lipid, 13-hydroperoxyoctadecadienoic acid, in vascular smooth muscle cells via nuclear factor-kappa B (NF-kappa B). Journal of Molecular and Cell Cardiology, 36, 585-595. doi:10.1016/j.yjmcc.2004.02.007
[43]	Reilly, K.B., Srinivasan, S., Hatley, M.E., Patricia, M.K., Lannigan, J., Bolick, D.T., et al. (2004) 12/15-Lipoxygenase activity mediates inflammatory monocyte/endothelial interactions and atherosclerosis in vivo. The Journal of Biological Chemistry, 279, 9440-9450. doi:10.1074/jbc.M303857200
[44]	Dwarakanath, R.S., Sahar, S., Lanting, L., Wang, N., Stemerman, M.B., Natarajan, R., et al. (2008) Viral vector-mediated 12/15-lipoxygenase overexpression in vascular smooth muscle cells enhances inflammatory gene expression and migration. Journal of Vascular Research, 45, 132-142. doi:10.1159/000109966
[45]	Reddy, M.A., Sahar, S., Villeneuve, L.M., Lanting, L. and Natarajan, R. (2009) Role of src tyrosine kinase in the atherogenic effects of the 12/15-lipoxygenase pathway in vascular smooth muscle cells. Arteriosclerosis, Thrombosis and Vascular Biology, 29, 387-393. doi:10.1161/ATVB AHA.108.179150
[46]	Kim, Y.S., Reddy, M.A., Lanting, L., Adler, S.G. and Natarajan, R. (2003) Differential behavior of mesangial cells derived from 12/15-lipoxygenase knockout mice relative to control mice. Kidney International, 64, 1702-1714. doi:10.1046/j.1523-1755.2003.00286.x
[47]	Nangle, M.R., Cotter, M.A. and Cameron, N.E. (2006) Correction of nitrergic neurovascular dysfunction in diabetic mouse corpus cavernosum by p38 mitogen-activated protein kinase inhibition. International Journal of Impotence Research, 18, 258-263. doi:10.1038/sj.ijir.3901414
[48]	Daulhac, L., Mallet, C., Courteix, C., Etienne, M., Duroux, E., Privat, A.M., et al. (2006) Diabetes-induced mechanical hyperalgesia involves spinal mitogen-activated protein kinase activation in neurons and microglia via N-methyl-D-aspartate-dependent mechanisms. Molecular Pharmacology, 70, 1246-1254. doi:10.1124/mol.106.025478
[49]	Du, Y., Tang, J., Li, G., Berti-Mattera, L., Lee, C.A., Bartkowski, D., et al. (2010) Effects of p38 MAPK inhibition on early stages of diabetic retinopathy and sensory nerve function. Investigative Ophthalmology & Visual Science, 51, 2158-2164. doi:10.1167/iovs.09-3674
[50]	Daulhac, L., Maffre, V., Mallet, C., Etienne, M., Privat, A.M., Kowalski-Chauvel, A., et al. (2011) Phosphorylation of spinal N-methyl-d-aspartate receptor NR1 subunits by extracellular signal-regulated kinase in dorsal horn neurons and microglia contributes to diabetes-induced painful neuropathy. European Journal of Pain, 15, 169.e1-169.e12.
[51]	Tsuda, M., Ueno, H., Kataoka, A., Tozaki-Saitoh, H. and Inoue, K. (2008) Activation of dorsal horn microglia contributes to diabetes-induced tactile allodynia via extracellular signal-regulated protein kinase signaling. Glia, 56, 378-386. doi:10.1002/glia.20623
[52]	Price, S.A., Gardiner, N.J., Duran-Jimenez, B., Zeef, L.A., Obrosova, I.G. and Tomlinson, D.R. (2006) Thioredoxin interacting protein is increased in sensory neurons in experimental diabetes. Brain Research, 1116, 206-214. doi:10.1016/j.brainres.2006.07.109
[53]	Bürger, F., Krieg, P., Marks, F. and Fürstenberger, G. (2000) Positionaland stereo-selectivity of fatty acid oxygenation catalysed by mouse (12S)-lipoxygenase iso-enzymes. Biochemical Journal, 348, 329-335. doi:10.1042/0264-6021:3480329
[54]	Gong, Y.Z., Ding, W.G., Wu, J., Tsuji, K., Horie, M. and Matsuura, H. (2008) Cinnamyl-3,4-dihydroxy-alpha cyanocinnamate and nordihydroguaiaretic acid inhibit human Kv1.5 currents independently of lipoxygenase. European Journal of Pharmacology, 600, 18-25. doi:10.1016/j.ejphar.2008.10.010
[55]	Pergola, C., Jazzar, B., Rossi, A., Buehring, U., Luderer, S., Dehm, F., et al. (2011) Cinnamyl-3,4-dihydroxy-αcyanocinnamate is a potent inhibitor of 5-lipoxygenase. Journal of Pharmacology and Experimental Therapeutics, 338, 205-213. doi:10.1124/jpet.111.180794
[56]	Wen, Y., Scott, S., Liu, Y., Gonzales, N. and Nadler, J.L. (1997) Evidence that angiotensin II and lipoxygenase products activate c-Jun NH2-terminal kinase. Circulation Research, 81, 651-655.doi:10.1161/01.RES.81.5.651