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ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

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Research Article

Activation of Melanocortin-4 Receptor by a Synthetic Agonist Inhibits Ethanolinduced Neuroinflammation in Rats

Author(s): Osvaldo Flores-Bastías, Gonzalo I. Gómez, Juan A. Orellana and Eduardo Karahanian*

Volume 25, Issue 45, 2019

Page: [4799 - 4805] Pages: 7

DOI: 10.2174/1381612825666191216145153

Price: $65

Abstract

Background: High ethanol intake induces a neuroinflammatory response resulting in the subsequent maintenance of chronic alcohol consumption. The melanocortin system plays a pivotal role in the modulation of alcohol consumption. Interestingly, it has been shown that the activation of melanocortin-4 receptor (MC4R) in the brain decreases the neuroinflammatory response in models of brain damage other than alcohol consumption, such as LPS-induced neuroinflammation, cerebral ischemia, glutamate excitotoxicity, and spinal cord injury.

Objectives: In this work, we aimed to study whether MC4R activation by a synthetic MC4R-agonist peptide prevents ethanol-induced neuroinflammation, and if alcohol consumption produces changes in MC4R expression in the hippocampus and hypothalamus.

Methods: Ethanol-preferring Sprague Dawley rats were selected offering access to 20% ethanol on alternate days for 4 weeks (intermittent access protocol). After this time, animals were i.p. administered an MC4R agonist peptide in the last 2 days of the protocol. Then, the expression of the proinflammatory cytokines interleukin 6 (IL-6), interleukin 1-beta (IL-1β), and tumor necrosis factor-alpha (TNF-α) were measured in the hippocampus, hypothalamus and prefrontal cortex. It was also evaluated if ethanol intake produces alterations in the expression of MC4R in the hippocampus and the hypothalamus.

Results: Alcohol consumption increased the expression of MC4R in the hippocampus and the hypothalamus. The administration of the MC4R agonist reduced IL-6, IL-1β and TNF-α levels in hippocampus, hypothalamus and prefrontal cortex, to those observed in control rats that did not drink alcohol.

Conclusion: High ethanol consumption produces an increase in the expression of MC4R in the hippocampus and hypothalamus. The administration of a synthetic MC4R-agonist peptide prevents neuroinflammation induced by alcohol consumption in the hippocampus, hypothalamus, and prefrontal cortex. These results could explain the effect of α-MSH and other synthetic MC4R agonists in decreasing alcohol intake through the reduction of the ethanol-induced inflammatory response in the brain.

Keywords: MC4R, melanocortin, α-MSH, alcohol use disorder, neuroinflammation, hypothalamus.

« Previous Next »
[1]
World Health Organization Global Status Report on Alcohol and Health 2014.Available at: . www.who.int/substance_abuse/publications/global_alcohol_report/en/
[2]
Lim SS, Vos T, Flaxman AD, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380(9859): 2224-60.
[http://dx.doi.org/10.1016/S0140-6736(12)61766-8] [PMID: 23245609]
[3]
Nutt DJ, King LA, Phillips LD. Drug harms in the UK: a multicriteria decision analysis. Lancet 2010; 376(9752): 1558-65.
[http://dx.doi.org/10.1016/S0140-6736(10)61462-6] [PMID: 21036393]
[4]
Baan R, Straif K, Grosse Y, et al. Carcinogenicity of alcoholic beverages. Lancet Oncol 2007; 8(4): 292-3.
[http://dx.doi.org/10.1016/S1470-2045(07)70099-2] [PMID: 17431955]
[5]
Shield KD, Parry C, Rehm J. Chronic diseases and conditions related to alcohol use. Alcohol Res 2013; 35(2): 155-73.
[PMID: 24881324]
[6]
Crews FT, Nixon K. Mechanisms of neurodegeneration and regeneration in alcoholism. Alcohol Alcohol 2009; 44(2): 115-27.
[http://dx.doi.org/10.1093/alcalc/agn079] [PMID: 18940959]
[7]
Peterson JB, Rothfleisch J, Zelazo PD, Pihl RO. Acute alcohol intoxication and cognitive functioning. J Stud Alcohol 1990; 51(2): 114-22.
[http://dx.doi.org/10.15288/jsa.1990.51.114] [PMID: 2308348]
[8]
Whiteford HA, Degenhardt L, Rehm J, et al. Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet 2013; 382(9904): 1575-86.
[http://dx.doi.org/10.1016/S0140-6736(13)61611-6] [PMID: 23993280]
[9]
Kushner MG, Abrams K, Borchardt C. The relationship between anxiety disorders and alcohol use disorders: a review of major perspectives and findings. Clin Psychol Rev 2000; 20(2): 149-71.
[http://dx.doi.org/10.1016/S0272-7358(99)00027-6] [PMID: 10721495]
[10]
Rose ME, Grant JE. Alcohol-induced blackout. Phenomenology, biological basis, and gender differences. J Addict Med 2010; 4(2): 61-73.
[http://dx.doi.org/10.1097/ADM.0b013e3181e1299d] [PMID: 21769024]
[11]
Israel Y, Karahanian E, Ezquer F, et al. Acquisition, maintenance and relapse-like alcohol drinking: lessons from the UChB rat line. Front Behav Neurosci 2017; 11: 57.
[http://dx.doi.org/10.3389/fnbeh.2017.00057] [PMID: 28420969]
[12]
Coller JK, Hutchinson MR. Implications of central immune signaling caused by drugs of abuse: mechanisms, mediators and new therapeutic approaches for prediction and treatment of drug dependence. Pharmacol Ther 2012; 134(2): 219-45.
[http://dx.doi.org/10.1016/j.pharmthera.2012.01.008] [PMID: 22316499]
[13]
Flores-Bastías O, Karahanian E. Neuroinflammation produced by heavy alcohol intake is due to loops of interactions between Toll-like 4 and TNF receptors, peroxisome proliferator-activated receptors and the central melanocortin system: a novel hypothesis and new therapeutic avenues. Neuropharmacology 2018; 128: 401-7.
[http://dx.doi.org/10.1016/j.neuropharm.2017.11.003] [PMID: 29113896]
[14]
Crews FT, Zou J, Qin L. Induction of innate immune genes in brain create the neurobiology of addiction. Brain Behav Immun 2011; 25(Suppl. 1): S4-S12.
[http://dx.doi.org/10.1016/j.bbi.2011.03.003] [PMID: 21402143]
[15]
Orellana JA, Cerpa W, Carvajal MF, et al. New implications for the melanocortin system in alcohol drinking behavior in adolescents: the glial dysfunction hypothesis. Front Cell Neurosci 2017; 11: 90.
[http://dx.doi.org/10.3389/fncel.2017.00090] [PMID: 28424592]
[16]
Blanco AM, Guerri C. Ethanol intake enhances inflammatory mediators in brain: role of glial cells and TLR4/IL-1RI receptors. Front Biosci 2007; 12: 2616-30.
[http://dx.doi.org/10.2741/2259] [PMID: 17127267]
[17]
Walker DW, Barnes DE, Zornetzer SF, Hunter BE, Kubanis P. Neuronal loss in hippocampus induced by prolonged ethanol consumption in rats. Science 1980; 209(4457): 711-3.
[http://dx.doi.org/10.1126/science.7394532] [PMID: 7394532]
[18]
Franke H, Kittner H, Berger P, Wirkner K, Schramek J. The reaction of astrocytes and neurons in the hippocampus of adult rats during chronic ethanol treatment and correlations to behavioral impairments. Alcohol 1997; 14(5): 445-54.
[http://dx.doi.org/10.1016/S0741-8329(96)00209-1] [PMID: 9305459]
[19]
He J, Crews FT. Increased MCP-1 and microglia in various regions of the human alcoholic brain. Exp Neurol 2008; 210(2): 349-58.
[http://dx.doi.org/10.1016/j.expneurol.2007.11.017] [PMID: 18190912]
[20]
Ward RJ, Colivicchi MA, Allen R, et al. Neuro-inflammation induced in the hippocampus of ‘binge drinking’ rats may be mediated by elevated extracellular glutamate content. J Neurochem 2009; 111(5): 1119-28.
[http://dx.doi.org/10.1111/j.1471-4159.2009.06389.x] [PMID: 19765190]
[21]
Zou J, Crews F. Induction of innate immune gene expression cascades in brain slice cultures by ethanol: key role of NF-κB and proinflammatory cytokines. Alcohol Clin Exp Res 2010; 34(5): 777-89.
[http://dx.doi.org/10.1111/j.1530-0277.2010.01150.x] [PMID: 20201932]
[22]
Chandel NS, Trzyna WC, McClintock DS, Schumacker PT. Role of oxidants in NF-kappa B activation and TNF-alpha gene transcription induced by hypoxia and endotoxin. J Immunol 2000; 165(2): 1013-21.
[http://dx.doi.org/10.4049/jimmunol.165.2.1013] [PMID: 10878378]
[23]
Lieber CS. Microsomal ethanol-oxidizing system (MEOS): the first 30 years (1968-1998) - a review. Alcohol Clin Exp Res 1999; 23(6): 991-1007.
[http://dx.doi.org/10.1097/00000374-199906000-00006] [PMID: 10397283]
[24]
Cao Q, Mak KM, Lieber CS. Cytochrome P4502E1 primes macrophages to increase TNF-alpha production in response to lipopolysaccharide. Am J Physiol Gastrointest Liver Physiol 2005; 289(1): G95-G107.
[http://dx.doi.org/10.1152/ajpgi.00383.2004] [PMID: 15961886]
[25]
Crews FT, Sarkar DK, Qin L, Zou J, Boyadjieva N, Vetreno RP. Neuroimmune function and the consequences of alcohol exposure. Alcohol Res 2015; 37(2): 331-341, 344-351.
[PMID: 26695754]
[26]
Barson JR, Leibowitz SF. Hypothalamic neuropeptide signaling in alcohol addiction. Prog Neuropsychopharmacol Biol Psychiatry 2016; 65: 321-9.
[http://dx.doi.org/10.1016/j.pnpbp.2015.02.006] [PMID: 25689818]
[27]
Rada P, Avena NM, Leibowitz SF, Hoebel BG. Ethanol intake is increased by injection of galanin in the paraventricular nucleus and reduced by a galanin antagonist. Alcohol 2004; 33(2): 91-7.
[http://dx.doi.org/10.1016/S0741-8329(04)00097-7] [PMID: 15528006]
[28]
Schneider ER, Rada P, Darby RD, Leibowitz SF, Hoebel BG. Orexigenic peptides and alcohol intake: differential effects of orexin, galanin, and ghrelin. Alcohol Clin Exp Res 2007; 31(11): 1858-65.
[http://dx.doi.org/10.1111/j.1530-0277.2007.00510.x] [PMID: 17850217]
[29]
Barson JR, Carr AJ, Soun JE, et al. Opioids in the hypothalamic paraventricular nucleus stimulate ethanol intake. Alcohol Clin Exp Res 2010; 34(2): 214-22.
[http://dx.doi.org/10.1111/j.1530-0277.2009.01084.x] [PMID: 19951300]
[30]
Navarro M, Cubero I, Knapp DJ, Breese GR, Thiele TE. Decreased immunoreactivity of the melanocortin neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH) after chronic ethanol exposure in Sprague-Dawley rats. Alcohol Clin Exp Res 2008; 32(2): 266-76.
[http://dx.doi.org/10.1111/j.1530-0277.2007.00578.x] [PMID: 18162070]
[31]
Thorsell A, Slawecki CJ, Ehlers CL. Effects of neuropeptide Y and corticotropin-releasing factor on ethanol intake in Wistar rats: interaction with chronic ethanol exposure. Behav Brain Res 2005; 161(1): 133-40.
[http://dx.doi.org/10.1016/j.bbr.2005.01.016] [PMID: 15904720]
[32]
Hadley ME, Haskell-Luevano C. The proopiomelanocortin system. Ann N Y Acad Sci 1999; 885: 1-21.
[http://dx.doi.org/10.1111/j.1749-6632.1999.tb08662.x] [PMID: 10816638]
[33]
Mountjoy KG. Distribution and function of melanocortin receptors within the brain. Adv Exp Med Biol 2010; 681: 29-48.
[http://dx.doi.org/10.1007/978-1-4419-6354-3_3] [PMID: 21222258]
[34]
Olney JJ, Navarro M, Thiele TE. Targeting central melanocortin receptors: a promising novel approach for treating alcohol abuse disorders. Front Neurosci 2014; 8: 128.
[http://dx.doi.org/10.3389/fnins.2014.00128] [PMID: 24917782]
[35]
Navarro M, Cubero I, Knapp DJ, Thiele TE. MTII-induced reduction of voluntary ethanol drinking is blocked by pretreatment with AgRP-(83-132). Neuropeptides 2003; 37(6): 338-44.
[http://dx.doi.org/10.1016/j.npep.2003.10.003] [PMID: 14698676]
[36]
Ploj K, Roman E, Kask A, et al. Effects of melanocortin receptor ligands on ethanol intake and opioid peptide levels in alcohol-preferring AA rats. Brain Res Bull 2002; 59(2): 97-104.
[http://dx.doi.org/10.1016/S0361-9230(02)00844-4] [PMID: 12379439]
[37]
Navarro M, Lerma-Cabrera JM, Carvajal F, Lowery EG, Cubero I, Thiele TE. Assessment of voluntary ethanol consumption and the effects of a melanocortin (MC) receptor agonist on ethanol intake in mutant C57BL/6J mice lacking the MC-4 receptor. Alcohol Clin Exp Res 2011; 35(6): 1058-66.
[http://dx.doi.org/10.1111/j.1530-0277.2011.01438.x] [PMID: 21332528]
[38]
Lerma-Cabrera JM, Carvajal F, de la Torre L, et al. Control of food intake by MC4-R signaling in the lateral hypothalamus, nucleus accumbens shell and ventral tegmental area: interactions with ethanol. Behav Brain Res 2012; 234(1): 51-60.
[http://dx.doi.org/10.1016/j.bbr.2012.06.006] [PMID: 22713514]
[39]
Rainero I, De Gennaro T, Visentin G, et al. Effects of chronic ethanol treatment on alpha-MSH concentrations in rat brain and pituitary. Neuropeptides 1990; 15(3): 139-41.
[http://dx.doi.org/10.1016/0143-4179(90)90145-O] [PMID: 2174518]
[40]
Lerma-Cabrera JM, Carvajal F, Alcaraz-Iborra M, et al. Adolescent binge-like ethanol exposure reduces basal α-MSH expression in the hypothalamus and the amygdala of adult rats. Pharmacol Biochem Behav 2013; 110: 66-74.
[http://dx.doi.org/10.1016/j.pbb.2013.06.006] [PMID: 23792540]
[41]
Sprow GM, Rinker JA, Lowery-Gointa EG, Sparrow AM, Navarro M, Thiele TE. Lateral hypothalamic melanocortin receptor signaling modulates binge-like ethanol drinking in C57BL/6J mice. Addict Biol 2016; 21(4): 835-46.
[http://dx.doi.org/10.1111/adb.12264] [PMID: 25975524]
[42]
Shelkar GP, Kale AD, Singh U, Singru PS, Subhedar NK, Kokare DM. Alpha-melanocyte stimulating hormone modulates ethanol self-administration in posterior ventral tegmental area through melanocortin-4 receptors. Addict Biol 2015; 20(2): 302-15.
[http://dx.doi.org/10.1111/adb.12126] [PMID: 24635847]
[43]
Macaluso A, McCoy D, Ceriani G, et al. Antiinflammatory influences of alpha-MSH molecules: central neurogenic and peripheral actions. J Neurosci 1994; 14(4): 2377-82.
[http://dx.doi.org/10.1523/JNEUROSCI.14-04-02377.1994] [PMID: 8158274]
[44]
Benjamins JA, Nedelkoska L, Bealmear B, Lisak RP. ACTH protects mature oligodendroglia from excitotoxic and inflammation-related damage in vitro. Glia 2013; 61(8): 1206-17.
[http://dx.doi.org/10.1002/glia.22504] [PMID: 23832579]
[45]
Caruso C, Durand D, Schiöth HB, Rey R, Seilicovich A, Lasaga M. Activation of melanocortin 4 receptors reduces the inflammatory response and prevents apoptosis induced by lipopolysaccharide and interferon-gamma in astrocytes. Endocrinology 2007; 148(10): 4918-26.
[http://dx.doi.org/10.1210/en.2007-0366] [PMID: 17595227]
[46]
Selkirk JV, Nottebaum LM, Lee J, Yang W, Foster AC, Lechner SM. Identification of differential melanocortin 4 receptor agonist profiles at natively expressed receptors in rat cortical astrocytes and recombinantly expressed receptors in human embryonic kidney cells. Neuropharmacology 2007; 52(2): 459-66.
[http://dx.doi.org/10.1016/j.neuropharm.2006.08.015] [PMID: 17095023]
[47]
Caruso C, Mohn C, Karara AL, et al. α-melanocyte-stimulating hormone through melanocortin-4 receptor inhibits nitric oxide synthase and cyclooxygenase expression in the hypothalamus of male rats. Neuroendocrinology 2004; 79(5): 278-86.
[http://dx.doi.org/10.1159/000079321] [PMID: 15218320]
[48]
Ichiyama T, Zhao H, Catania A, Furukawa S, Lipton JM. α-melanocyte-stimulating hormone inhibits NF-kappaB activation and IkappaBalpha degradation in human glioma cells and in experimental brain inflammation. Exp Neurol 1999; 157(2): 359-65.
[http://dx.doi.org/10.1006/exnr.1999.7064] [PMID: 10364447]
[49]
Ichiyama T, Sakai T, Catania A, Barsh GS, Furukawa S, Lipton JM. Systemically administered alpha-melanocyte-stimulating peptides inhibit NF-kappaB activation in experimental brain inflammation. Brain Res 1999; 836(1-2): 31-7.
[http://dx.doi.org/10.1016/S0006-8993(99)01584-X] [PMID: 10415402]
[50]
Muceniece R, Zvejniece L, Kirjanova O, et al. β-MSH inhibits brain inflammation via MC(3)/(4) receptors and impaired NF-kappaB signaling. J Neuroimmunol 2005; 169(1-2): 13-9.
[http://dx.doi.org/10.1016/j.jneuroim.2005.07.024] [PMID: 16154641]
[51]
Giuliani D, Mioni C, Altavilla D, et al. Both early and delayed treatment with melanocortin 4 receptor-stimulating melanocortins produces neuroprotection in cerebral ischemia. Endocrinology 2006; 147(3): 1126-35.
[http://dx.doi.org/10.1210/en.2005-0692] [PMID: 16254026]
[52]
Spaccapelo L, Bitto A, Galantucci M, et al. Melanocortin MC4 receptor agonists counteract late inflammatory and apoptotic responses and improve neuronal functionality after cerebral ischemia. Eur J Pharmacol 2011; 670(2-3): 479-86.
[http://dx.doi.org/10.1016/j.ejphar.2011.09.015] [PMID: 21946115]
[53]
Forslin Aronsson A, Spulber S, Oprica M, Winblad B, Post C, Schultzberg M. α-MSH rescues neurons from excitotoxic cell death. J Mol Neurosci 2007; 33(3): 239-51.
[http://dx.doi.org/10.1007/s12031-007-0019-2] [PMID: 17952633]
[54]
van de Meent H, Hamers FP, Lankhorst AJ, Joosten EA, Gispen WH. Beneficial effects of the melanocortin alpha-melanocyte-stimulating hormone on clinical and neurophysiological recovery after experimental spinal cord injury. Neurosurgery 1997; 40(1): 122-30.
[PMID: 8971834]
[55]
Lankhorst AJ, Duis SE, ter Laak MP, Joosten EA, Hamers FP, Gispen WH. Functional recovery after central infusion of alpha-melanocyte-stimulating hormone in rats with spinal cord contusion injury. J Neurotrauma 1999; 16(4): 323-31.
[http://dx.doi.org/10.1089/neu.1999.16.323] [PMID: 10225218]
[56]
Catania A. Neuroprotective actions of melanocortins: a therapeutic opportunity. Trends Neurosci 2008; 31(7): 353-60.
[http://dx.doi.org/10.1016/j.tins.2008.04.002] [PMID: 18550183]
[57]
Delgado R, Carlin A, Airaghi L, et al. Melanocortin peptides inhibit production of proinflammatory cytokines and nitric oxide by activated microglia. J Leukoc Biol 1998; 63(6): 740-5.
[http://dx.doi.org/10.1002/jlb.63.6.740] [PMID: 9620667]
[58]
Rajora N, Boccoli G, Burns D, Sharma S, Catania AP, Lipton JM. α-MSH modulates local and circulating tumor necrosis factor-α in experimental brain inflammation. J Neurosci 1997; 17(6): 2181-6.
[http://dx.doi.org/10.1523/JNEUROSCI.17-06-02181.1997] [PMID: 9045742]
[59]
Wong KY, Rajora N, Boccoli G, Catania A, Lipton JM. A potential mechanism of local anti-inflammatory action of alpha-melanocyte-stimulating hormone within the brain: modulation of tumor necrosis factor-alpha production by human astrocytic cells. Neuroimmunomodulation 1997; 4(1): 37-41.
[http://dx.doi.org/10.1159/000097313] [PMID: 9326743]
[60]
Muceniece R, Zvejniece L, Liepinsh E, et al. The MC3 receptor binding affinity of melanocortins correlates with the nitric oxide production inhibition in mice brain inflammation model. Peptides 2006; 27(6): 1443-50.
[http://dx.doi.org/10.1016/j.peptides.2005.12.002] [PMID: 16414147]
[61]
Galimberti D, Baron P, Meda L, et al. Alpha-MSH peptides inhibit production of nitric oxide and tumor necrosis factor-alpha by microglial cells activated with beta-amyloid and interferon gamma. Biochem Biophys Res Commun 1999; 263(1): 251-6.
[http://dx.doi.org/10.1006/bbrc.1999.1276] [PMID: 10486285]
[62]
Carniglia L, Durand D, Caruso C, Lasaga M. Effect of NDP-α-MSH on PPAR-γ and -β expression and anti-inflammatory cytokine release in rat astrocytes and microglia. PLoS One 2013; 8(2): e57313.
[http://dx.doi.org/10.1371/journal.pone.0057313] [PMID: 23468969]
[63]
Simms JA, Steensland P, Medina B, et al. Intermittent access to 20% ethanol induces high ethanol consumption in Long-Evans and Wistar rats. Alcohol Clin Exp Res 2008; 32(10): 1816-23.
[http://dx.doi.org/10.1111/j.1530-0277.2008.00753.x] [PMID: 18671810]
[64]
Moorman DE, Aston-Jones G. Orexin-1 receptor antagonism decreases ethanol consumption and preference selectively in high-ethanol-preferring Sprague-Dawley rats. Alcohol 2009; 43(5): 379-86.
[http://dx.doi.org/10.1016/j.alcohol.2009.07.002] [PMID: 19671464]
[65]
Carnicella S, Ron D, Barak S. Intermittent ethanol access schedule in rats as a preclinical model of alcohol abuse. Alcohol 2014; 48(3): 243-52.
[http://dx.doi.org/10.1016/j.alcohol.2014.01.006] [PMID: 24721195]
[66]
Liu D, Zhang HG, Zhao ZA, et al. Melanocortin MC4 receptor agonists alleviate brain damage in abdominal compartment syndrome in the rat. Neuropeptides 2015; 49: 55-61.
[http://dx.doi.org/10.1016/j.npep.2014.12.003] [PMID: 25616531]
[67]
Tang J, Youngentob SL, Glendinning JI. Postnatal exposure to ethanol increases its oral acceptability to adolescent rats. Chem Senses 2018; 43(8): 655-64.
[http://dx.doi.org/10.1093/chemse/bjy056] [PMID: 30169758]
[68]
Horrobin DF. Essential fatty acids, prostaglandins, and alcoholism: an overview. Alcohol Clin Exp Res 1987; 11(1): 2-9.
[http://dx.doi.org/10.1111/j.1530-0277.1987.tb01250.x] [PMID: 3032012]
[69]
Caruso C, Carniglia L, Durand D, Gonzalez PV, Scimonelli TN, Lasaga M. Melanocortin 4 receptor activation induces brain-derived neurotrophic factor expression in rat astrocytes through cyclic AMP-protein kinase A pathway. Mol Cell Endocrinol 2012; 348(1): 47-54.
[http://dx.doi.org/10.1016/j.mce.2011.07.036] [PMID: 21803120]
[70]
Xu D, Lian D, Wu J, et al. Brain-derived neurotrophic factor reduces inflammation and hippocampal apoptosis in experimental Streptococcus pneumoniae meningitis. J Neuroinflammation 2017; 14(1): 156.
[http://dx.doi.org/10.1186/s12974-017-0930-6] [PMID: 28778220]

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