Abstract
Background
Minocycline a tetracycline antibiotic is known for anti-inflammatory and neuroprotective actions. Here we determine the therapeutic potential of minocycline against type 2 diabetes associated cognitive decline in rats.
Methods
High fat diet (HFD) and low dose streptozotocin (STZ; 25 mg/kg) were used to induce diabetes in Sprague-Dawley rats. Fasting blood glucose and haemoglobin (Hb) A1c were measured in these animals. Cognitive parameters were measured using passive avoidance and elevated plus maze test. Hippocampal Acetylcholine esterase (AchE), reduced glutathione (GSH), cytokines, chemokine levels were measured and histopathological evaluations were conducted. The diabetic animals were then given minocycline (50 mg/kg; 15 days) and the above parameters were reassessed. MTT and Lactate dehydrogenase (LDH) assays were conducted on neuronal cells in the presence of glucose with or without minocycline treatment.
Results
We induced diabetes using HFD and STZ in these animals. Animals showed high fasting blood glucose levels (>245 mg/dl) and HbA1c compared to control animals. Diabetes significantly lowered step down latency and increased transfer latency. Diabetic animals showed significantly higher AchE, Tumor necrosis factor (TNF)-α, Interleukin (IL)-1β and Monocyte chemoattractant protein (MCP)-1 and lower GSH levels and reduced both CA1 and CA3 neuronal density compared to controls. Minocycline treatment partially reversed the above neurobehavioral and biochemical changes and improved hippocampal neuronal density in diabetic animals. Cell line studies showed glucosemediated neuronal death, which was considerably reversed upon minocycline treatment.
Conclusions
Minocycline, primarily by its anti-inflammatory and antioxidant actions prevented hippocampal neuronal loss thus partially reversing the diabetes-associated cognitive decline in rats.
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References
Van den Berg E, Kloppenborg RP, Kessels RP, Kappelle LJ, Biessels GJ. Type 2 diabetes mellitus, hypertension, dyslipidemia and obesity: a systematic comparison of their impact on cognition. BBA-Mol Basis Dis 2009;1792:470–81.
Danesh J, Whincup P, Walker M, Lennon L, Thomson A, Appleby P, et al. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. Brit Med J 2000;321(7255):199–204.
Alexandraki KI, Piperi C, Ziakas PD, Apostolopoulos NV, Makrilakis K, Syriou V, et al. Cytokine secretion in long-standing diabetes mellitus type 1 and 2: associations with low-grade systemic inflammation. J Clin Immunol 2008;28(4):314–21.
Frances DEA, Ingaramo PI, Ronco MT, Carnovale CE. Diabetes, an inflammatory process: oxidative stress and TNF-alpha involved in hepatic complication. J Biomed Sci 2013;6(6):645–53.
Vikram A, Tripathi DN, Kumar A, Singh S. Oxidative stress and inflammation in diabetic complications. Int J Endocrinol 2014;2014:.
Kampoli A-M, Tousoulis D, Briasoulis A, Latsios G, Papageorgiou N, Stefanadis C. Potential pathogenic inflammatory mechanisms of endothelial dysfunction induced by type 2 diabetes mellitus. Curr Pharm Des 2011;17(37):4147–58.
Helmersson J, Vessby B, Larsson A, Basu S. Association of type 2 diabetes with cyclooxygenase-mediated inflammation and oxidative stress in an elderly population. Circulation 2004;109(14):1729–34.
Basta G, Schmidt AM, De Caterina R. Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes. Cardiovasc Res 2004;63(4):582–92.
Goldin A, Beckman JA, Schmidt AM, Creager MA. Advanced glycation end products. Circulation 2006;114(6):597–605.
Negrean M, Stirban A, Stratmann B, Gawlowski T, Horstmann T, Götting C, et al. Effects of low-and high-advanced glycation endproduct meals on macro-and microvascular endothelial function and oxidative stress in patients with type 2 diabetes mellitus. Am J Clin Nutr 2007;85(5):1236–43.
Biessels G-J, Kappelle A, Bravenboer B, Erkelens D, Gispen W. Cerebral function in diabetes mellitus. Diabetologia 1994;37(7):643–50.
Hartge MM, Unger T, Kintscher U. The endothelium and vascular inflammation in diabetes. Diab Vasc Dis Res 2007;4(2):84–8.
Nagayach A, Patro N, Patro I. Astrocytic and microglial response in experimentally induced diabetic rat brain. Metab Brain Dis 2014;29(3):747–61.
Creager M, Goldin A, Beckman J, Schmidt A. Advanced glycation end products-Sparking the development of diabetic vascular injury. Circulation 2006;114:597–605.
Giulian D, Li J, Bartel S, Broker J, Li X, Kirkpatrick JB. Cell surface morphology identifies microglia as a distinct class of mononuclear phagocyte. J Neurosci 1995;15(11):7712–26.
Streit WJ, Graeber MB, Kreutzberg GW. Peripheral nerve lesion produces increased levels of major histocompatibility complex antigens in the central nervous system. J Neuroimmunol 1989;21(2):117–23.
Streit WJ, Kreutzberg GW. Response of endogenous glial cells to motor neuron degeneration induced by toxic ricin. J Comp Neurol 1988;268(2):248–63.
Gehrmann J, Matsumoto Y, Kreutzberg GW. Microglia: intrinsic immuneffector cell of the brain. Brain Res Rev 1995;20(3):269–87.
Colton CA, Gilbert DL. Production of superoxide anions by a CNS macrophage. the microglia. FEBS lett. 1987;223(2):284–8.
Banati R, Rothe G, Valet G, Kreutzberg G. Detection of lysosomal cysteine proteinases in microglia: flow cytometric measurement and histochemical localization of cathepsin B and L. Glia 1993;7(2):183–91.
Shen WH, Zhou J-H, Broussard SR, Johnson RW, Dantzer R, Kelley KW. Tumor necrosis factor α inhibits insulin-like growth factor I-induced hematopoietic cell survival and proliferation. Endocrinology 2004;145(7):3101–5.
Banerjee S, Walseth TF, Borgmann K, Wu L, Bidasee KR, Kannan MS, et al. CD38/cyclic ADP-ribose regulates astrocyte calcium signaling: implications for neuroinflammation and HIV-1-associated dementia. J Neuroimmune Pharmacol 2008;3(3):154.
Venters HD, Tang Q, Liu Q, VanHoy RW, Dantzer R, Kelley KW. A new mechanism of neurodegeneration: a proinflammatory cytokine inhibits receptor signaling by a survival peptide. P Natl Acad Sci-Biol. 1999;96(17):9879–84.
Reed M, Meszaros K, Entes L, Claypool M, Pinkett J, Gadbois T, et al. A new rat model of type 2 diabetes: the fat-fed, streptozotocin-treated rat. Metabolis 2000;49(11):1390–4.
Srinivasan K, Viswanad B, Asrat L, Kaul C, Ramarao P. Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening. Pharmacol Res 2005;52(4):313–20.
Greenwood CE, Winocur G. Learning and memory impairment in rats fed a high saturated fat diet. Behav Neural Biol 1990;53(1):74–87.
Schmatz R, Mazzanti CM, Spanevello R, Stefanello N, Gutierres J, Corrêa M, et al. Resveratrol prevents memory deficits and the increase in acetylcholinesterase activity in streptozotocin-induced diabetic rats. Eur J Pharmacol 2009;610(1):42–8.
Ghareeb DA, Hussen HM. Vanadium improves brain acetylcholinesterase activity on early stage alloxan-diabetic rats. Neurosci Lett 2008;436(1):44–7.
Pari L, Latha M. Protective role of Scoparia dulcis plant extract on brain antioxidant status and lipid peroxidation in STZ diabetic male Wistar rats. BMC Complement Altern Med 2004;4(1):16.
McNeilly AD, Williamson R, Sutherland C, Balfour DJ, Stewart CA. High fat feeding promotes simultaneous decline in insulin sensitivity and cognitive performance in a delayed matching and non-matching to position task. Behav Brain Res 2011;217(1):134–41.
Leite LM, Carvalho AGG, Ferreira PLT, Pessoa IX, Gonçalves DO, de Araújo Lopes A, et al. Anti-inflammatory properties of doxycycline and minocycline in experimental models: an in vivo and in vitro comparative study. Inflammopharmacology 2011;19(2):99–110.
Tikka T, Fiebich BL, Goldsteins G, Keinänen R, Minocycline Koistinaho J. A tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. J Neurosci 2001;21(8):2580–8.
Adlard PA, Engesser-Cesar C, Cotman CW. Mild stress facilitates learning and exercise improves retention in aged mice. Exp Gerontol 2011;46(1):53–9.
Blum D, Chtarto A, Tenenbaum L, Brotchi J, Levivier M. Clinical potential of minocycline for neurodegenerative disorders. Neurobiol Dis 2004;17(3):359–66.
Swanson RA, Ying W, Kauppinen TM. Astrocyte influences on ischemic neuronal death. Curr Mol Med 2004;4(2):193–205.
Cl Gabriel, Justicia C, Camins A, Planas AM. Activation of nuclear factor-κB in the rat brain after transient focal ischemia. Mol Brain Res. 1999;65(1):61–9.
Krady JK, Basu A, Allen CM, Xu Y, LaNoue KF, Gardner TW, et al. Minocycline reduces proinflammatory cytokine expression, microglial activation, and caspase-3 activation in a rodent model of diabetic retinopathy. Diabetes 2005;54(5):1559–65.
Yrjänheikki J, Tikka T, Keinänen 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-Biol 1999;96(23):13496–500.
Hunter CL, Bachman D, Granholm AC. Minocycline prevents cholinergic loss in a mouse model of Down’s syndrome. Ann Neurol 2004;56(5):675–88.
Xue M, Mikliaeva EI, Casha S, Zygun D, Demchuk A, Yong VW. Improving outcomes of neuroprotection by minocycline: guides from cell culture and intracerebral hemorrhage in mice. Am J Pathol 2010;176(3):1193–202.
Baydas G, Nedzvetskii VS, Nerush PA, Kirichenko SV, Yoldas T. Altered expression of NCAM in hippocampus and cortex may underlie memory and learning deficits in rats with streptozotocin-induced diabetes mellitus. Life Sci 2003;73:1907–16.
Dhingra DM, Parle M, Kulkarni SK. Memory enhancing activity of Glycyrrhiza glabra in mice. J Ethnopharmacol 2004;91(2–3):361–5.
Pocernich CB, Butterfield DA. Elevation of glutathione as a therapeutic strategy in Alzheimer disease. BBA-Mol Basis Dis. 2012;1822(5):625–30.
Sarter M, Bruno JP. Cognitive functions of cortical acetylcholine: toward a unifying hypothesis. Brain Res Rev 1997;23(1):28–46.
Ellman GL, Courtney KD, Andres V. Jr, Featherstone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 1961;7(2):88–95.
Zhang JM, An J. Cytokines, inflammation and pain. Int Anesthesiol Clin 2007;45(2):27–37.
Stranahan AM, Norman ED, Lee K, Cutler RG, Telljohann RS, Egan JM, et al. Diet-induced insulin resistance impairs hippocampal synaptic plasticity and cognition in middle-aged rats. Hippocampus 2008;18(11):1085–8.
Morrison CD, Pistell PJ, Ingram DK, Johnson WD, Liu Y, Fernandez-Kim SO, et al. High fat diet increases hippocampal oxidative stress and cognitive impairment in aged mice: implications for decreased Nrf2 signaling. J Neurochem 2010;114(6):1581–9.
Uranga RM, Bruce-Keller AJ, Morrison CD, Fernandez-Kim SO, Ebenezer PJ, Zhang L, et al. Intersection between metabolic dysfunction, high fat diet consumption, and brain aging. J Neurochem 2010;114(2):344–61.
Kalmijn S. Fatty acid intake and the risk of dementia and cognitive decline: a review of clinical and epidemiological studies. J Nutr Health Aging 2000;4(4):202–7.
Uranga RM, Keller JN. Diet and age interactions with regards to cholesterol regulation and brain pathogenesis. Curr Gerontol Geriatr Res 2010;219683.
Mehta BK, Banerjee S. Characterization of cognitive impairment in type 2 diabetic rats. Indian J Pharm Sci 2017;79(5):785–93.
Beaty HN. Rifampin and minocycline in meningococcal disease. Rev Infect Dis 1983;5(Supplement 3):S451–58.
Fraser A, Gafter-Gvili A, Paul M, Leibovici L. Prophylactic use of antibiotics for prevention of meningococcal infections: systematic review and meta-analysis of randomised trials. Eur J Clin Microbiol 2005;24(3):172–81.
Raghavendra V, Tanga F, DeLeo JA. Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J Pharmacol Exp Ther 2003;306(2):624–30.
Kielian T, Esen N, Liu S, Phulwani NK, Syed MM, Phillips N, et al. Minocycline modulates neuroinflammation independently of its antimicrobial activity in Staphylococcus aureus-induced brain abscess. Am J Pathol 2007;171(4):1199–214.
Kim H-S, Suh Y-H. Minocycline and neurodegenerative diseases. Behav Brain Res 2009;196(2):168–79.
Zink MC, Uhrlaub J, DeWitt J, Voelker T, Bullock B, Mankowski J, et al. Neuroprotective and anti-human immunodeficiency virus activity of minocycline. JAMA 2005;293(16):2003–11.
Kou W, Banerjee S, Eudy J, Smith LM, Persidsky R, Borgmann K, et al. CD38 regulation in activated astrocytes: implications for neuroinflammation and HIV-1 brain infection. J Neurosci Res 2009;87(10):2326–39.
Tangpong J, Sompol P, Vore M, Clair WS, Butterfield D, Clair DS. Tumor necrosis factor alpha-mediated nitric oxide production enhances manganese superoxide dismutase nitration and mitochondrial dysfunction in primary neurons: an insight into the role of glial cells. Neuroscience 2008;151(2):622–9.
K-j Min, Jou I, Joe E. Plasminogen-induced IL-1β and TNF-α production in microglia is regulated by reactive oxygen species. Biochem Bioph Res Co 2003;312(4):969–74.
Conti G, Scarpini E, Baron P, Livraghi S, Tiriticco M, Bianchi R, et al. Macrophage infiltration and death in the nerve during the early phases of experimental diabetic neuropathy: a process concomitant with endoneurial induction of IL-1β and p75NTR. J Neurol Sci 2002;195(1):35–40.
Ledeboer A, Sloane EM, Milligan ED, Frank MG, Mahony JH, Maier SF, et al. Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain 2005;115(1):71–83.
Mukherjee A, Mehta BK, Sen KK, Banerjee S. Metabolic syndrome-associated cognitive decline in mice: role of minocycline. Indian J Pharmacol 2018;50(2):61–5.
Kraus RL, Pasieczny R, Lariosa-Willingham K, Turner MS, Jiang A, Trauger JW. Antioxidant properties of minocycline: neuroprotection in an oxidative stress assay and direct radical-scavenging activity. J Neurochem 2005;94(3):819–27.
Yenari MA, Xu L, Tang XN, Qiao Y, Giffard RG. Microglia potentiate damage to blood-brain barrier constituents. Stroke 2006;37(4):1087–93.
Bigl K, Schmitt A, Meiners I, Münch G, Arendt T. Comparison of results of the CellTiter Blue, the tetrazolium (3-[4, 5-dimethylthioazol-2-yl]-2, 5-diphenyl tetrazolium bromide), and the lactate dehydrogenase assay applied in brain cells after exposure to advanced glycation endproducts. Toxicol In Vitro 2007;21(5):962–71.
Lobner D. Comparison of the LDH and MTT assays for quantifying cell death: validity for neuronal apoptosis? J Neurosci Meth. 2000;96(2):147–52.
Kupsch K, Hertel S, Kreutzmann P, Wolf G, Wallesch CW, Siemen D, et al. Impairment of mitochondrial function by minocycline. FEBS J 2009;276(6):1729–32.
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Mehta, B.K., Banerjee, S. Minocycline reverses diabetes-associated cognitive impairment in rats. Pharmacol. Rep 71, 713–720 (2019). https://doi.org/10.1016/j.pharep.2019.03.012
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DOI: https://doi.org/10.1016/j.pharep.2019.03.012