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Open Access 01-12-2012 | Research

Prevention of hypoglycemia-induced neuronal death by minocycline

Authors: Seok Joon Won, Jin Hee Kim, Byung Hoon Yoo, Min Sohn, Tiina M Kauppinen, Man-Seong Park, Hyung-Joo Kwon, Jialing Liu, Sang Won Suh

Published in: Journal of Neuroinflammation | Issue 1/2012

Abstract

Diabetic patients who attempt strict management of blood glucose levels frequently experience hypoglycemia. Severe and prolonged hypoglycemia causes neuronal death and cognitive impairment. There is no effective tool for prevention of these unwanted clinical sequelae. Minocycline, a second-generation tetracycline derivative, has been recognized as an anti-inflammatory and neuroprotective agent in several animal models such as stroke and traumatic brain injury. In the present study, we tested whether minocycline also has protective effects on hypoglycemia-induced neuronal death and cognitive impairment. To test our hypothesis we used an animal model of insulin-induced acute hypoglycemia. Minocycline was injected intraperitoneally at 6 hours after hypoglycemia/glucose reperfusion and injected once per day for the following 1 week. Histological evaluation for neuronal death and microglial activation was performed from 1 day to 1 week after hypoglycemia. Cognitive evaluation was conducted 6 weeks after hypoglycemia. Microglial activation began to be evident in the hippocampal area at 1 day after hypoglycemia and persisted for 1 week. Minocycline injection significantly reduced hypoglycemia-induced microglial activation and myeloperoxidase (MPO) immunoreactivity. Neuronal death was significantly reduced by minocycline treatment when evaluated at 1 week after hypoglycemia. Hypoglycemia-induced cognitive impairment is also significantly prevented by the same minocycline regimen when subjects were evaluated at 6 weeks after hypoglycemia. Therefore, these results suggest that delayed treatment (6 hours post-insult) with minocycline protects against microglial activation, neuronal death and cognitive impairment caused by severe hypoglycemia. The present study suggests that minocycline has therapeutic potential to prevent hypoglycemia-induced brain injury in diabetic patients.

Davis EA, Jones TW: Hypoglycemia in children with diabetes: incidence, counterregulation and cognitive dysfunction. J Pediatr Endocrinol Metab 1998,11(Suppl 1):177–182.PubMed

Ben-Ami H, Nagachandran P, Mendelson A, Edoute Y: Drug-induced hypoglycemic coma in 102 diabetic patients. Arch Intern Med 1999, 159:281–284.CrossRefPubMed

Cryer PE: Diverse causes of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med 2004, 350:2272–2279.CrossRefPubMed

Malouf R, Brust JC: Hypoglycemia: causes, neurological manifestations, and outcome. Ann Neurol 1985, 17:421–430.CrossRefPubMed

Golden MP, Ingersoll GM, Brack CJ, Russell BA, Wright JC, Huberty TJ: Longitudinal relationship of asymptomatic hypoglycemia to cognitive function in IDDM. Diabetes Care 1989, 12:89–93.CrossRefPubMed

Ryan CM, Atchison J, Puczynski S, Puczynski M, Arslanian S, Becker D: Mild hypoglycemia associated with deterioration of mental efficiency in children with insulin-dependent diabetes mellitus. J Pediatr 1990, 117:32–38.CrossRefPubMed

Cryer PE: Hypoglycemia-associated autonomic failure in diabetes. Am J Physiol Endocrinol Metab 2001, 281:E1115-E1121.PubMed

Kalimo H, Olsson Y: Effects of severe hypoglycemia on the human brain. Neuropathological case reports. Acta Neurol Scand 1980, 62:345–356.CrossRefPubMed

Langan SJ, Deary IJ, Hepburn DA, Frier BM: Cumulative cognitive impairment following recurrent severe hypoglycaemia in adult patients with insulin-treated diabetes mellitus. Diabetologia 1991, 34:337–344.CrossRefPubMed

10.

Wieloch T: Hypoglycemia-induced neuronal damage prevented by an N-methyl-D- aspartate antagonist. Science 1985, 230:681–683.CrossRefPubMed

11.

Suh SW, Garnier P, Aoyama K, Chen Y, Swanson RA: Zinc release contributes to hypoglycemia-induced neuronal death. Neurobiol Dis 2004, 16:538–545.CrossRefPubMed

12.

Suh SW, Gum ET, Hamby AM, Chan PH, Swanson RA: Hypoglycemic neuronal death is triggered by glucose reperfusion and activation of neuronal NADPH oxidase. J Clin Invest 2007, 117:910–918.CrossRefPubMedPubMedCentral

13.

Moller JC, Klein MA, Haas S, Jones LL, Kreutzberg GW, Raivich G: Regulation of thrombospondin in the regenerating mouse facial motor nucleus. Glia 1996, 17:121–132.CrossRefPubMed

14.

Vilhardt F: Microglia: phagocyte and glia cell. Int J Biochem Cell Biol 2005, 37:17–21.CrossRefPubMed

15.

Jin R, Yang G, Li G: Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J Leukoc Biol 2010, 87:779–789.CrossRefPubMedPubMedCentral

16.

Festoff BW, Ameenuddin S, Arnold PM, Wong A, Santacruz KS, Citron BA: Minocycline neuroprotects, reduces microgliosis, and inhibits caspase protease expression early after spinal cord injury. J Neurochem 2006, 97:1314–1326.CrossRefPubMed

17.

Wang Q, Tang XN, Yenari MA: The inflammatory response in stroke. J Neuroimmunol 2007, 184:53–68.CrossRefPubMed

18.

Shin BS, Won SJ, Yoo BH, Kauppinen TM, Suh SW: Prevention of hypoglycemia-induced neuronal death by hypothermia. J Cereb Blood Flow Metab 2010, 30:390–402.CrossRefPubMed

19.

Du Y, Ma Z, Lin S, Dodel RC, Gao F, Bales KR, Triarhou LC, Chernet E, Perry KW, Nelson DL, Luecke S, Phebus LA, Bymaster FP, Paul SM: Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease. Proc Natl Acad Sci USA 2001, 98:1466914674.

20.

Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S, Bian J, Guo L, Farrell LA, Hersch SM, Hobbs W, Vonsattel JP, Cha JH, Friedlander RM: Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med 2000, 6:797–801.CrossRefPubMed

21.

Ryu JK, Franciosi S, Sattayaprasert P, Kim SU, McLarnon JG: Minocycline inhibits neuronal death and glial activation induced by beta-amyloid peptide in rat hippocampus. Glia 2004, 48:85–90.CrossRefPubMed

22.

Yrjanheikki J, Keinanen R, Pellikka M, Hokfelt T, Koistinaho J: Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci USA 1998, 95:15769–15774.CrossRefPubMedPubMedCentral

23.

Yrjanheikki J, Tikka T, Keinanen R, Goldsteins G, Chan PH, Koistinaho J: A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci USA 1999, 96:13496–13500.CrossRefPubMedPubMedCentral

24.

Lee SM, Yune TY, Kim SJ, Park DW, Lee YK, Kim YC, Oh YJ, Markelonis GJ, Oh TH: Minocycline reduces cell death and improves functional recovery after traumatic spinal cord injury in the rat. J Neurotrauma 2003, 20:1017–1027.CrossRefPubMed

25.

Auer RN, Olsson Y, Siesjo BK: Hypoglycemic brain injury in the rat. Correlation of density of brain damage with the EEG isoelectric time: a quantitative study. Diabetes 1984, 33:1090–1098.CrossRefPubMed

26.

Suh SW, Aoyama K, Chen Y, Garnier P, Matsumori Y, Gum E, Liu J, Swanson RA: Hypoglycemic neuronal death and cognitive impairment are prevented by poly(ADP-ribose) polymerase inhibitors administered after hypoglycemia. J Neurosci 2003, 23:10681–10690.PubMed

27.

Schmued LC, Hopkins KJ, Fluoro-Jade B: A high affinity fluorescent marker for the localization of neuronal degeneration. Brain Res 2000, 874:123–130.CrossRefPubMed

28.

Kauppinen TM, Higashi Y, Suh SW, Escartin C, Nagasawa K, Swanson RA: Zinc triggers microglial activation. J Neurosci 2008, 28:5827–5835.CrossRefPubMedPubMedCentral

29.

Barnes CA: Memory deficits associated with senescence: a neurophysiological and behavioral study in the rat. J Comp Physiol Psychol 1979, 93:74–104.CrossRefPubMed

30.

Biagas KV, Uhl MW, Schiding JK, Nemoto EM, Kochanek PM: Assessment of posttraumatic polymorphonuclear leukocyte accumulation in rat brain using tissue myeloperoxidase assay and vinblastine treatment. J Neurotrauma 1992, 9:363–371.CrossRefPubMed

31.

Matsuo Y, Onodera H, Shiga Y, Nakamura M, Ninomiya M, Kihara T, Kogure K: Correlation between myeloperoxidase-quantified neutrophil accumulation and ischemic brain injury in the rat. Effects of neutrophil depletion. Stroke 1994, 25:1469–1475.CrossRefPubMed

32.

Auer RN, Siesjo BK: Hypoglycaemia: brain neurochemistry and neuropathology. Baillieres Clin Endocrinol Metab 1993, 7:611–625.CrossRefPubMed

33.

Suh SW, Hamby AM, Swanson RA: Hypoglycemia, brain energetics, and hypoglycemic neuronal death. Glia 2007, 55:1280–1286.CrossRefPubMed

34.

Dereski MO, Chopp M, Knight RA, Rodolosi LC, Garcia JH: The heterogeneous temporal evolution of focal ischemic neuronal damage in the rat. Acta Neuropathol 1993, 85:327–333.CrossRefPubMed

35.

Auer RN, Kalimo H, Olsson Y, Siesjo BK: The temporal evolution of hypoglycemic brain damage. I. Light- and electron-microscopic findings in the rat cerebral cortex. Acta Neuropathol 1985, 67:13–24.CrossRefPubMed

36.

Feuerstein GZ, Wang X, Barone FC: Inflammatory gene expression in cerebral ischemia and trauma. Potential new therapeutic targets. Ann NY Acad Sci 1997, 825:179–193.CrossRefPubMed

37.

Iadecola C, Zhang F, Casey R, Nagayama M, Ross ME: Delayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene. J Neurosci 1997, 17:9157–9164.PubMed

38.

Nogawa S, Zhang F, Ross ME, Iadecola C: Cyclo-oxygenase-2 gene expression in neurons contributes to ischemic brain damage. J Neurosci 1997, 17:2746–2755.PubMed

39.

Suh SW, Hamby AM, Gum ET, Shin BS, Won SJ, Sheline CT, Chan PH, Swanson RA: Sequential release of nitric oxide, zinc, and superoxide in hypoglycemic neuronal death. J Cereb Blood Flow Metab 2008, 28:1697–1706.CrossRefPubMed

40.

Scholz M, Cinatl J, Schadel-Hopfner M, Windolf J: Neutrophils and the blood–brain barrier dysfunction after trauma. Med Res Rev 2007, 27:401–416.CrossRefPubMed

41.

Takizawa S, Aratani Y, Fukuyama N, Maeda N, Hirabayashi H, Koyama H, Shinohara Y, Nakazawa H: Deficiency of myeloperoxidase increases infarct volume and nitrotyrosine formation in mouse brain. J Cereb Blood Flow Metab 2002, 22:50–54.CrossRefPubMed

42.

Johnson EA, Dao TL, Guignet MA, Geddes CE, Koemeter-Cox AI, Kan RK: Increased expression of the chemokines CXCL1 and MIP-1alpha by resident brain cells precedes neutrophil infiltration in the brain following prolonged soman-induced status epilepticus in rats. J Neuroinflammation 2011, 8:41–50.CrossRefPubMedPubMedCentral

43.

Elewa HF, Hilali H, Hess DC, Machado LS, Fagan SC: Minocycline for short-term neuroprotection. Pharmacotherapy 2006, 26:515–521.CrossRefPubMedPubMedCentral

44.

Metz LM, Zhang Y, Yeung M, Patry DG, Bell RB, Stoian CA, Yong VW, Patten SB, Duquette P, Antel JP, Mitchell JR: Minocycline reduces gadolinium-enhancing magnetic resonance imaging lesions in multiple sclerosis. Ann Neurol 2004, 55:756.CrossRefPubMed

45.

Keck T, Balcom JH, Fernandez-del Castillo C, Antoniu BA, Warshaw AL: Matrix metalloproteinase-9 promotes neutrophil migration and alveolar capillary leakage in pancreatitis-associated lung injury in the rat. Gastroenterology 2002, 122:188–201.CrossRefPubMed

46.

Brundula V, Rewcastle NB, Metz LM, Bernard CC, Yong VW: Targeting leukocyte MMPs and transmigration: minocycline as a potential therapy for multiple sclerosis. Brain 2002, 125:1297–1308.CrossRefPubMed

47.

Zemke D, Majid A: The potential of minocycline for neuroprotection in human neurologic disease. Clin Neuropharmacol 2004, 27:293–298.CrossRefPubMed

48.

Lampl Y, Boaz M, Gilad R, Lorberboym M, Dabby R, Rapoport A, Anca-Hershkowitz M, Sadeh M: Minocycline treatment in acute stroke: an open-label, evaluator-blinded study. Neurology 2007, 69:1404–1410.CrossRefPubMed

49.

Rovet J, Alvarez M: Attentional functioning in children and adolescents with IDDM. Diabetes Care 1997, 20:803–810.CrossRefPubMed

50.

Hershey T, Perantie DC, Warren SL, Zimmerman EC, Sadler M, White NH: Frequency and timing of severe hypoglycemia affects spatial memory in children with type 1 diabetes. Diabetes Care 2005, 28:2372–2377.CrossRefPubMed

51.

Ennis K, Tran PV, Seaquist ER, Rao R: Postnatal age influences hypoglycemia-induced neuronal injury in the rat brain. Brain Res 2008, 1224:119–126.CrossRefPubMedPubMedCentral

52.

Liu Z, Fan Y, Won SJ, Neumann M, Hu D, Zhou L, Weinstein PR, Liu J: Chronic treatment with minocycline preserves adult new neurons and reduces functional impairment after focal cerebral ischemia. Stroke 2007, 38:146–152.CrossRefPubMed

53.

Fan R, Xu F, Previti ML, Davis J, Grande AM, Robinson JK, Van Nostrand WE: Minocycline reduces microglial activation and improves behavioral deficits in a transgenic model of cerebral microvascular amyloid. J Neurosci 2007, 27:3057–3063.CrossRefPubMed

54.

Hunter CL, Bachman D, Granholm AC: Minocycline prevents cholinergic loss in a mouse model of Down's syndrome. Ann Neurol 2004, 56:675–688.CrossRefPubMed

55.

Mizoguchi H, Takuma K, Fukakusa A, Ito Y, Nakatani A, Ibi D, Kim HC, Yamada K: Improvement by minocycline of methamphetamine-induced impairment of recognition memory in mice. Psychopharmacology (Berl) 2008, 196:233–241.CrossRef

Title: Prevention of hypoglycemia-induced neuronal death by minocycline
Authors: Seok Joon Won
Jin Hee Kim
Byung Hoon Yoo
Min Sohn
Tiina M Kauppinen
Man-Seong Park
Hyung-Joo Kwon
Jialing Liu
Sang Won Suh
Publication date: 01-12-2012
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2012
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/1742-2094-9-225

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Prevention of hypoglycemia-induced neuronal death by minocycline

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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