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Metabolic Brain Disease

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05.07.2017 | Original Article

Beneficial effects of liraglutide (GLP1 analog) in the hippocampal inflammation

verfasst von: Andre R. C. Barreto-Vianna, Marcia B. Aguila, Carlos A. Mandarim-de-Lacerda

Erschienen in: Metabolic Brain Disease | Ausgabe 5/2017

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Abstract

The brain is very sensitive to metabolic dysfunctions induced by diets high in saturated fatty acids, leading to neuroinflammation. The liraglutide has been found to have neuroprotective effects. However, its neuroprotective action in a model of palmitate-induced neuroinflammation had not yet been evaluated. Mice were intracerebroventricular (ICV) infused with palmitate and received subcutaneous liraglutide. The hippocampal dentate gyrus and CA1 regions were analyzed (morphology and inflammation-related proteins in microglia and astrocyte by confocal microscopy). Also, a real-time PCR was performed to measure the levels of tumor necrosis factor (TNF) alpha and interleukin (IL) 6. Palmitate ICV infusion resulted in pronounced inflammation response in the hippocampus, reactive microgliosis, and astrogliosis, with hypertrophied IBA1 immunoreactive microglia, increased microglial density with ameboid shape, decreased in the number of branches and junctions and increased the major histocompatibility complex (MHC) II expression. Also, we observed in the hippocampus of ICV palmitate infused mice an elevation in the pro-inflammatory cytokine levels TNFalpha and IL6. Liraglutide induced the neuroprotective microglial phenotype, characterized by an increased microglia complexity (enlarged Feret’s diameter), an improved number of both cell junctions and processes, and lower circularity, accompanied by a significant reduction in TNFalpha and IL6 expressions. The study provides evidence that liraglutide may be a suitable treatment against the palmitate-induced neuroinflammation, which it is characterized by the reactive microgliosis and astrogliosis, as well as increased pro-inflammatory cytokines, which has been described as one of the primary causes of several pathologies of the central nervous system.

Allan SM, Rothwell NJ (2003) Inflammation in central nervous system injury. Philos Trans R Soc Lond Ser B Biol Sci 358:1669–1677. doi:10.1098/rstb.2003.1358 CrossRef

Athauda D, Foltynie T (2016) The glucagon-like peptide 1 (GLP) receptor as a therapeutic target in Parkinson's disease: mechanisms of action. Drug Discov Today 21:802–818. doi:10.1016/j.drudis.2016.01.013 CrossRefPubMed

Baron R, Babcock AA, Nemirovsky A, Finsen B, Monsonego A (2014) Accelerated microglial pathology is associated with Abeta plaques in mouse models of Alzheimer's disease. Aging Cell 13:584–595. doi:10.1111/acel.12210 CrossRefPubMedPubMedCentral

Barreto-Vianna AR, Aguila MB, Mandarim-de-Lacerda CA (2016) Effects of liraglutide in hypothalamic arcuate nucleus of obese mice. Obesity (Silver Spring) 24:626–633. doi:10.1002/oby.21387 CrossRef

Bays H, Pi-Sunyer X, Hemmingsson JU, Claudius B, Jensen CB, Van Gaal L (2016) Liraglutide 3.0 mg for weight management: weight-loss dependent and independent effects. Curr Med Res Opin:1–5. doi:10.1080/03007995.2016.1251892

Bruck D, Wenning GK, Stefanova N, Fellner L (2016) Glia and alpha-synuclein in neurodegeneration: a complex interaction. Neurobiol Dis 85:262–274. doi:10.1016/j.nbd.2015.03.003 CrossRefPubMed

Cano V, Valladolid-Acebes I, Hernandez-Nuno F, Merino B, Del Olmo N, Chowen JA, Ruiz-Gayo M (2014) Morphological changes in glial fibrillary acidic protein immunopositive astrocytes in the hippocampus of dietary-induced obese mice. Neuroreport 25:819–822. doi:10.1097/WNR.0000000000000180 CrossRef

Christou GA, Katsiki N, Kiortsis DN (2016) The current role of Liraglutide in the pharmacotherapy of obesity. Curr Vasc Pharmacol 14:201–207CrossRefPubMed

Contreras A, Del Rio D, Martinez A, Gil C, Morales L, Ruiz-Gayo M, Del Olmo N (2017) Inhibition of hippocampal long-term potentiation by HF diets: is it related to an effect of palmitic acid involving glycogen synthase kinase-3? Neuroreport 28:354–359. doi:10.1097/WNR.0000000000000774 CrossRefPubMed

Erion JR, Wosiski-Kuhn M, Dey A, Hao S, Davis CL, Pollock NK, Stranahan AM (2014) Obesity elicits interleukin 1-mediated deficits in hippocampal synaptic plasticity. J Neurosci 34:2618–2631. doi:10.1523/JNEUROSCI.4200-13.2014 CrossRefPubMedPubMedCentral

Femminella GD, Edison P (2014) Evaluation of neuroprotective effect of glucagon-like peptide 1 analogs using neuroimaging. Alzheimers Dement 10:S55–S61. doi:10.1016/j.jalz.2013.12.012 CrossRefPubMed

Gupta S, Knight AG, Gupta S, Keller JN, Bruce-Keller AJ (2012) Saturated long-chain fatty acids activate inflammatory signaling in astrocytes. J Neurochem 120:1060–1071. doi:10.1111/j.1471-4159.2012.07660.x PubMedPubMedCentral

Hao S, Dey A, Yu X, Stranahan AM (2016) Dietary obesity reversibly induces synaptic stripping by microglia and impairs hippocampal plasticity. Brain Behav Immun 51:230–239. doi:10.1016/j.bbi.2015.08.023 CrossRefPubMed

Holland WL et al (2011) Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid-induced ceramide biosynthesis in mice. J Clin Invest 121:1858–1870. doi:10.1172/JCI43378 CrossRefPubMedPubMedCentral

Holm TH, Draeby D, Owens T (2012) Microglia are required for astroglial toll-like receptor 4 response and for optimal TLR2 and TLR3 response. Glia 60:630–638. doi:10.1002/glia.22296 CrossRefPubMed

Hou J, Manaenko A, Hakon J, Hansen-Schwartz J, Tang J, Zhang JH (2012) Liraglutide, a long-acting GLP1 mimetic, and its metabolite attenuate inflammation after intracerebral hemorrhage. J Cereb Blood Flow Metab 32:2201–2210. doi:10.1038/jcbfm.2012.133 CrossRefPubMedPubMedCentral

Hunter K, Holscher C (2012) Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis. BMC Neurosci 13:33. doi:10.1186/1471-2202-13-33 CrossRefPubMedPubMedCentral

Iwai T, Ito S, Tanimitsu K, Udagawa S, Oka J (2006) Glucagon-like peptide-1 inhibits LPS-induced IL-1beta production in cultured rat astrocytes. Neurosci Res 55:352–360. doi:10.1016/j.neures.2006.04.008 CrossRefPubMed

Kanoski SE, Davidson TL (2011) Western diet consumption and cognitive impairment: links to hippocampal dysfunction and obesity. Physiol Behav 103:59–68. doi:10.1016/j.physbeh.2010.12.003 CrossRefPubMed

Karmi A et al (2010) Increased brain fatty acid uptake in metabolic syndrome. Diabetes 59:2171–2177. doi:10.2337/db09-0138 CrossRefPubMedPubMedCentral

Kleinridders A et al (2009) MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity. Cell Metab 10:249–259. doi:10.1016/j.cmet.2009.08.013 CrossRefPubMedPubMedCentral

Leal MC, Casabona JC, Puntel M, Pitossi FJ (2013) Interleukin-1beta and tumor necrosis factor-alpha: reliable targets for protective therapies in Parkinson's disease? Front Cell Neurosci 7:53. doi:10.3389/fncel.2013.00053 CrossRefPubMedPubMedCentral

Lee JY, Sohn KH, Rhee SH, Hwang D (2001) Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through toll-like receptor 4. J Biol Chem 276:16683–16689. doi:10.1074/jbc.M011695200 CrossRefPubMed

Lehnardt S et al (2003) Activation of innate immunity in the CNS triggers neurodegeneration through a toll-like receptor 4-dependent pathway. Proc Natl Acad Sci U S A 100:8514–8519. doi:10.1073/pnas.1432609100 CrossRefPubMedPubMedCentral

Letra L, Santana I, Seiça R (2014) Obesity as a risk factor for Alzheimer’s disease: the role of adipocytokines. Metab Brain Dis 29:563–568. doi:10.1007/s11011-014-9501-z CrossRefPubMed

Liu L, Chan C (2014) The role of inflammasome in Alzheimer's disease. Ageing Res Rev 15:6–15. doi:10.1016/j.arr.2013.12.007 CrossRefPubMed

Liu L, Martin R, Chan C (2013) Palmitate-activated astrocytes via serine palmitoyltransferase increase BACE1 in primary neurons by sphingomyelinases. Neurobiol Aging 34:540–550. doi:10.1016/j.neurobiolaging.2012.05.017 CrossRefPubMed

Liu JT, Chen BY, Zhang JQ, Kuang F, Chen LW (2015) Lead exposure induced microgliosis and astrogliosis in hippocampus of young mice potentially by triggering TLR4-MyD88-NFkappaB signaling cascades. Toxicol Lett 239:97–107. doi:10.1016/j.toxlet.2015.09.015 CrossRefPubMed

Lull ME, Block ML (2010) Microglial activation and chronic neurodegeneration. Neurotherapeutics 7:354–365. doi:10.1016/j.nurt.2010.05.014 CrossRefPubMedPubMedCentral

Mandarim-de-Lacerda CA, Santos CF, Aguila MB (2010) Image analysis and quantitative morphology. Methods Mol Biol 611:211–225. doi:10.1007/978-1-60327-345-9_17 CrossRefPubMed

McClean PL, Holscher C (2014) Liraglutide can reverse memory impairment, synaptic loss and reduce plaque load in aged APP/PS1 mice, a model of Alzheimer's disease. Neuropharmacology 76 Pt A:57–67. doi:10.1016/j.neuropharm.2013.08.005

McClean PL, Jalewa J, Holscher C (2015) Prophylactic liraglutide treatment prevents amyloid plaque deposition, chronic inflammation and memory impairment in APP/PS1 mice. Behav Brain Res 293:96–106. doi:10.1016/j.bbr.2015.07.024 CrossRefPubMed

Michael-Titus AT, Priestley JV (2014) Omega-3 fatty acids and traumatic neurological injury: from neuroprotection to neuroplasticity? Trends Neurosci 37:30–38. doi:10.1016/j.tins.2013.10.005 CrossRefPubMed

Milanski M et al (2009) Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity. J Neurosci 29:359–370. doi:10.1523/JNEUROSCI.2760-08.2009 CrossRefPubMed

Morrison HW, Filosa JA (2013) A quantitative spatiotemporal analysis of microglia morphology during ischemic stroke and reperfusion. J Neuroinflammation 10:4. doi:10.1186/1742-2094-10-4 CrossRefPubMedPubMedCentral

Nair AB, Jacob S (2016) A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm 7:27–31. doi:10.4103/0976-0105.177703 CrossRefPubMedPubMedCentral

Oh H, Boghossian S, York DA, Park-York M (2013) The effect of high fat diet and saturated fatty acids on insulin signaling in the amygdala and hypothalamus of rats. Brain Res 1537:191–200. doi:10.1016/j.brainres.2013.09.025 CrossRefPubMed

Park S, Kang S, Kim DS, Moon BR (2017) Agrimonia pilosa Ledeb., Cinnamomum cassia Blume, and Lonicera japonica Thunb. protect against cognitive dysfunction and energy and glucose dysregulation by reducing neuroinflammation and hippocampal insulin resistance in beta-amyloid-infused rats. Nutr Neurosci 20:77–88. doi:10.1080/1028415X.2015.1135572 CrossRefPubMed

Parthsarathy V, Holscher C (2013) The type 2 diabetes drug liraglutide reduces chronic inflammation induced by irradiation in the mouse brain. Eur J Pharmacol 700:42–50. doi:10.1016/j.ejphar.2012.12.012 CrossRefPubMed

Paxinos GF, Franklin K (2001) KBJ: the mouse brain in stereotaxic coordinates. Academic Press, New York

Pistell PJ, Morrison CD, Gupta S, Knight AG, Keller JN, Ingram DK, Bruce-Keller AJ (2010) Cognitive impairment following high fat diet consumption is associated with brain inflammation. J Neuroimmunol 219:25–32. doi:10.1016/j.jneuroim.2009.11.010 CrossRefPubMed

Posey KA et al (2009) Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a HF diet. Am J Physiol Endocrinol Metab 296:E1003–E1012. doi:10.1152/ajpendo.90377.2008 CrossRefPubMed

Proctor C, Thiennimitr P, Chattipakorn N, Chattipakorn SC (2017) Diet, gut microbiota and cognition. Metab Brain Dis 32:1–17. doi:10.1007/s11011-016-9917-8 CrossRefPubMed

Reeves PG, Nielsen FH, Fahey GC Jr (1993) AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J Nutr 123:1939–1951PubMed

Rodriguez-Navas C, Morselli E, Clegg DJ (2016) Sexually dimorphic brain fatty acid composition in low and high fat diet-fed mice. Mol Metab 5:680–689. doi:10.1016/j.molmet.2016.06.014 CrossRefPubMedPubMedCentral

Sabin MA et al (2007) Fasting nonesterified fatty acid profiles in childhood and their relationship with adiposity, insulin sensitivity, and lipid levels. Pediatrics 120:e1426–e1433. doi:10.1542/peds.2007-0189 CrossRefPubMed

Sahin TD, Karson A, Balci F, Yazir Y, Bayramgurler D, Utkan T (2015) TNFalpha inhibition prevents cognitive decline and maintains hippocampal BDNF levels in the unpredictable chronic mild stress rat model of depression. Behav Brain Res 292:233–240. doi:10.1016/j.bbr.2015.05.062 CrossRefPubMed

Santiago JA, Potashkin JA (2013) Shared dysregulated pathways lead to Parkinson's disease and diabetes. Trends Mol Med 19:176–186. doi:10.1016/j.molmed.2013.01.002 CrossRefPubMed

Secher A et al (2014) The arcuate nucleus mediates GLP1 receptor agonist liraglutide-dependent weight loss. J Clin Invest 124:4473–4488. doi:10.1172/JCI75276 CrossRefPubMedPubMedCentral

Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 116:3015–3025. doi:10.1172/JCI28898 CrossRefPubMedPubMedCentral

Srodulski S et al (2014) Neuroinflammation and neurologic deficits in diabetes linked to brain accumulation of amylin. Mol Neurodegener 9:30. doi:10.1186/1750-1326-9-30 CrossRefPubMedPubMedCentral

Stranahan AM (2015) Models and mechanisms for hippocampal dysfunction in obesity and diabetes. Neuroscience 309:125–139. doi:10.1016/j.neuroscience.2015.04.045 CrossRefPubMedPubMedCentral

Valladolid-Acebes I et al (2012) HF diets induce changes in hippocampal glutamate metabolism and neurotransmission. Am J Physiol Endocrinol Metab 302:E396–E402. doi:10.1152/ajpendo.00343.2011 CrossRefPubMed

Vinet J et al (2012) Neuroprotective function for ramified microglia in hippocampal excitotoxicity. J Neuroinflammation 9:27. doi:10.1186/1742-2094-9-27 CrossRefPubMedPubMedCentral

Zanier ER, Fumagalli S, Perego C, Pischiutta F, De Simoni MG (2015) Shape descriptors of the "never resting" microglia in three different acute brain injury models in mice. Intensive Care Med Exp 3:39. doi:10.1186/s40635-015-0039-0 CrossRefPubMed

Zhang W, Li P, Hu X, Zhang F, Chen J, Gao Y (2011) Omega-3 polyunsaturated fatty acids in the brain: metabolism and neuroprotection. Front Biosci (Landmark Ed) 16:2653–2670CrossRef

Titel: Beneficial effects of liraglutide (GLP1 analog) in the hippocampal inflammation
verfasst von: Andre R. C. Barreto-Vianna
Marcia B. Aguila
Carlos A. Mandarim-de-Lacerda
Publikationsdatum: 05.07.2017
Verlag: Springer US
Erschienen in: Metabolic Brain Disease / Ausgabe 5/2017
Print ISSN: 0885-7490
Elektronische ISSN: 1573-7365
DOI: https://doi.org/10.1007/s11011-017-0059-4

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