Abstract
As the innate immune cells that permanently reside in the central nervous system (CNS), microglia play an increasingly important role in maintaining brain function. Normally, microglia act as resting phenotype, which can be activated by various types of stimuli and release a variety of inflammatory mediators. Melatonin is an endogenous rhythmic hormone secreted principally by the pineal gland. Increasing evidence suggests that melatonin can detoxify reactive oxygen species (ROS) and prevent microglia from over-activation. This review summarizes the mechanisms of melatonin in inhibiting excessive activation of microglia and demonstrates the feasibility of melatonin in the treatment of diseases related to microglial over-activation.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ali T, Rehman SU, Shah FA, Kim MO (2018) Acute dose of melatonin via Nrf2 dependently prevents acute ethanol-induced neurotoxicity in the developing rodent brain. J Neuroinflammation 15:119. https://doi.org/10.1186/s12974-018-1157-x
Amaral FGD, Cipolla-Neto J (2018) A brief review about melatonin, a pineal hormone archives of endocrinology and metabolism. Arch Endocrinol Metab 62:472–479. https://doi.org/10.20945/2359-3997000000066
Amati AL et al (2017) Chemokines (CCL3, CCL4, and CCL5) inhibit ATP-induced release of IL-1beta by monocytic cells. Mediators Inflamm 2017:1434872. https://doi.org/10.1155/2017/1434872
Ano Y, Ikado K, Uchida K, Nakayama H (2020) Amyloid beta-induced mesenteric inflammation in an Alzheimer’s disease transgenic mouse model. Curr Alzheimer Res https://doi.org/10.2174/1567205017666200212160343
Arioz BI et al (2019) Melatonin attenuates LPS-induced acute depressive-like behaviors and microglial NLRP3 Inflammasome activation through the SIRT1/Nrf2 pathway. Front Immunol 10:1511. https://doi.org/10.3389/fimmu.2019.01511
Biber K, Zuurman MW, Dijkstra IM, Boddeke HW (2002) Chemokines in the brain: neuroimmunology and beyond. Curr Opin Pharmacol 2:63–68
Burguillos MA et al (2011) Caspase signalling controls microglia activation and neurotoxicity. Nature 472:319–324. https://doi.org/10.1038/nature09788
Cao Q, Karthikeyan A, Dheen ST, Kaur C, Ling EA (2017) Production of proinflammatory mediators in activated microglia is synergistically regulated by Notch-1, glycogen synthase kinase (GSK-3beta) and NF-kappaB/p65 signalling. 12:e0186764. https://doi.org/10.1371/journal.pone.0186764
Carrascal L, Nunez-Abades P, Ayala A, Cano M (2018) Role of melatonin in the inflammatory process and its therapeutic potential. Curr Pharm Des 24:1563–1588. https://doi.org/10.2174/1381612824666180426112832
Chaturantabut S et al (2019) Estrogen activation of G-protein-coupled estrogen receptor 1 regulates Phosphoinositide 3-kinase and mTOR signaling to promote liver growth in Zebrafish and proliferation of human hepatocytes. Gastroenterology 156:1788-1804.e1713. https://doi.org/10.1053/j.gastro.2019.01.010
Cheng J et al (2017) Autophagy regulates MAVS signaling activation in a phosphorylation-dependent manner in microglia. Cell Death Differ 24:276–287. https://doi.org/10.1038/cdd.2016.121
Chiang RP, Huang CT, Tsai YJ (2013) Melatonin reduces median nerve injury-induced mechanical hypersensitivity via inhibition of microglial p38 mitogen-activated protein kinase activation in rat cuneate nucleus. J Pineal Res 54:232–244. https://doi.org/10.1111/jpi.12029
Cianciulli A, Porro C, Calvello R, Trotta T, Lofrumento DD, Panaro MA (2020) Microglia mediated neuroinflammation: focus on PI3K modulation. Biomolecules 10:1. https://doi.org/10.3390/biom10010137
Ciechanowska A et al (2020) Changes in macrophage inflammatory protein-1 (MIP-1) family members expression induced by traumatic brain injury in mice. Immunobiology Feb 1:151911. https://doi.org/10.1016/j.imbio.2020.151911
Cosin-Roger J et al (2017) Hypoxia ameliorates intestinal inflammation through NLRP3/mTOR downregulation and autophagy activation. Nat Commun 8:98. https://doi.org/10.1038/s41467-017-00213-3
Dai J et al (2018) Inhibition of curcumin on influenza a virus infection and influenzal pneumonia via oxidative stress, TLR2/4, p38/JNK MAPK and NF-kappaB pathways. Int Immunopharmacol 54:177–187. https://doi.org/10.1016/j.intimp.2017.11.009
De Simone R, Ajmone-Cat MA, Pandolfi M, Bernardo A, De Nuccio C, Minghetti L, Visentin S (2015) The mitochondrial uncoupling protein-2 is a master regulator of both M1 and M2 microglial responses. J Neurochem 135:147–156. https://doi.org/10.1111/jnc.13244
Ding K, Wang H, Xu J, Lu X, Zhang L, Zhu L (2014) Melatonin reduced microglial activation and alleviated neuroinflammation induced neuron degeneration in experimental traumatic brain injury: possible involvement of mTOR pathway. Neurochem Int 76:23–31. https://doi.org/10.1016/j.neuint.2014.06.015
Dominguez Rubio AP et al (2017) Maternal administration of melatonin exerts short- and long-term neuroprotective effects on the offspring from lipopolysaccharide-treated mice. J Pineal Res 63:4. https://doi.org/10.1111/jpi.12439
Dong L et al (2016) The E3 ubiquitin ligase c-Cbl inhibits microglia-mediated CNS inflammation by regulating PI3K/Akt/NF-kappaB pathway. CNS neuroscience & therapeutics 22:661–669. https://doi.org/10.1111/cns.12557
Du Y et al (2017) Differential subnetwork of chemokines/cytokines in human, mouse, and rat brain cells after oxygen-glucose deprivation. J Cereb Blood Flow Metab 37:1425–1434. https://doi.org/10.1177/0271678x16656199
Han D, Yu Z (2018) Plasma hemopexin ameliorates murine spinal cord injury by switching microglia from the M1 state to the M2 state. 9:181. https://doi.org/10.1038/s41419-017-0236-8
Han CJ et al (2019) The oncometabolite 2-hydroxyglutarate inhibits microglial activation via the AMPK/mTOR/NF-kappaB pathway. Acta Pharmacol Sin 40:1292–1302. https://doi.org/10.1038/s41401-019-0225-9
Hassan S et al (2020) Dipsacus inermis wall. Modulates inflammation by inhibiting NF-kappaB pathway: an in vitro and in vivo study. J Ethnopharmacol 112710. https://doi.org/10.1016/j.jep.2020.112710
Hattori Y, Ihara M (2016) [SIRT1]. Nihon rinsho [Article in Japanese] 74:589–594
Hickman S, Izzy S (2018) Microglia in neurodegeneration. Nat Neurosci 21:1359–1369. https://doi.org/10.1038/s41593-018-0242-x
Hong Y, Palaksha KJ, Park K, Park S, Kim HD, Reiter RJ, Chang KT (2010) Melatonin plus exercise-based neurorehabilitative therapy for spinal cord injury. J Pineal Res 49:201–209. https://doi.org/10.1111/j.1600-079X.2010.00786.x
Hopp SC (2020) Targeting microglia L-type voltage-dependent calcium channels for the treatment of central nervous system disorders. J Neurosci Res. https://doi.org/10.1002/jnr.24585
Hou L, Sun F, Huang R, Sun W, Zhang D, Wang Q (2019) Inhibition of NADPH oxidase by apocynin prevents learning and memory deficits in a mouse. Parkinson’s disease model Redox biology 22:101134. https://doi.org/10.1016/j.redox.2019.101134
Hu X, Leak RK, Shi Y, Suenaga J, Gao Y, Zheng P, Chen J (2015) Microglial and macrophage polarization-new prospects for brain repair nature reviews. Neurology 11:56–64. https://doi.org/10.1038/nrneurol.2014.207
Hu Y et al (2017) Melatonin protects against blood-brain barrier damage by inhibiting the TLR4/ NF-kappaB signaling pathway after LPS treatment in neonatal rats. Oncotarget 8:31638–31654. https://doi.org/10.18632/oncotarget.15780
Hu L et al (2019) Melatonin decreases M1 polarization via attenuating mitochondrial oxidative damage depending on UCP2 pathway in prorenin-treated microglia. PLoS One 14:e0212138. https://doi.org/10.1371/journal.pone.0212138
Jang MH et al (2005) Melatonin attenuates amyloid beta25-35-induced apoptosis in mouse microglial BV2 cells. Neurosci Lett 380:26–31. https://doi.org/10.1016/j.neulet.2005.01.003
Kata D, Foldesi I, Feher LZ, Hackler L Jr, Puskas LG, Gulya K (2017) A novel pleiotropic effect of aspirin: beneficial regulation of pro- and anti-inflammatory mechanisms in microglial cells. Brain Res Bull 132:61–74. https://doi.org/10.1016/j.brainresbull.2017.05.009
Krauss S, Zhang CY, Lowell BB (2005) The mitochondrial uncoupling-protein homologues nature reviews. Nat Rev Mol Cell Biol 6:248–261. https://doi.org/10.1038/nrm1572
Lam JS, Anderson EM, Hao Y (2014) LPS quantitation procedures. Methods Mol Biol 1149:375–402. https://doi.org/10.1007/978-1-4939-0473-0_31
Lawrimore CJ, Crews FT (2017) Ethanol, TLR3, and TLR4 agonists have unique innate immune responses in neuron-like SH-SY5Y and microglia-like BV2. Alcohol Clin Exp Res 41:939–954. https://doi.org/10.1111/acer.13368
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. https://doi.org/10.1073/pnas.1432609100
Leibowitz B, Yu J (2010) Mitochondrial signaling in cell death via the Bcl-2 family. Cancer Biol Ther 9:417–422. https://doi.org/10.4161/cbt.9.6.11392
Lim JL, Wilhelmus MM, de Vries HE, Drukarch B, Hoozemans JJ, van Horssen J (2014) Antioxidative defense mechanisms controlled by Nrf2: state-of-the-art and clinical perspectives in neurodegenerative diseases. Arch Toxicol 88:1773–1786. https://doi.org/10.1007/s00204-014-1338-z
Lin CC, Yang AH, Lin AT (2017) Activation of the mTOR dependent signaling pathway underlies ketamine-induced uropathy. Neurourol Urodyn 36:1988–1995. https://doi.org/10.1002/nau.23234
Linkermann A, Green DR (2014) Necroptosis. N Engl J Med 370:455–465. https://doi.org/10.1056/NEJMra1310050
Liu CH et al (2016) Redistribution of Cav2.1 channels and calcium ions in nerve terminals following end-to-side neurorrhaphy: ionic imaging analysis by TOF-SIMS. Histochem Cell Biol 146:599–608. https://doi.org/10.1007/s00418-016-1470-3
Lu Y, Gu Y, Ding X, Wang J, Chen J (2017) Intracellular Ca2+ homeostasis and JAK1/STAT3 pathway are involved in the protective effect of propofol on BV2 microglia against hypoxia-induced inflammation and apoptosis. PLoS One 12:e0178098. https://doi.org/10.1371/journal.pone.0178098
Lu J et al (2019) Melatonin suppresses microglial necroptosis by regulating deubiquitinating enzyme A20 after intracerebral hemorrhage. Front Immunol 10:1360. https://doi.org/10.3389/fimmu.2019.01360
Min KJ, Jang JH, Kwon TK (2012) Inhibitory effects of melatonin on the lipopolysaccharide-induced CC chemokine expression in BV2 murine microglial cells are mediated by suppression of Akt-induced NF-kappaB and STAT/GAS activity. J Pineal Res 52:296–304. https://doi.org/10.1111/j.1600-079X.2011.00943.x
Mohebiany AN et al (2020) Microglial A20 protects the brain from CD8 T-cell-mediated immunopathology. Cell Rep 30:1585-1597.e1586. https://doi.org/10.1016/j.celrep.2019.12.097
Niedzielska E, Smaga I, Gawlik M, Moniczewski A, Stankowicz P, Pera J, Filip M (2016) Oxidative stress in neurodegenerative diseases. 53:4094–4125. https://doi.org/10.1007/s12035-015-9337-5
Okorji UP, Velagapudi R, El-Bakoush A, Fiebich BL, Olajide OA (2016) Antimalarial drug Artemether inhibits neuroinflammation in BV2 microglia through Nrf2-dependent mechanisms. Mol Neurobiol 53:6426–6443. https://doi.org/10.1007/s12035-015-9543-1
Orihuela R, McPherson CA, Harry GJ (2016) Microglial M1/M2 polarization and metabolic states. Br J Pharmacol 173:649–665. https://doi.org/10.1111/bph.13139
Park E, Chun HS (2017) Melatonin attenuates manganese and lipopolysaccharide-induced inflammatory activation of BV2 microglia. Neurochem Res 42:656–666. https://doi.org/10.1007/s11064-016-2122-7
Park J et al (2015) Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-kappaB pathways. Neurosci Lett 584:191–196. https://doi.org/10.1016/j.neulet.2014.10.016
Park BK, Kim YH, Kim YR, Choi JJ (2019, 2019) Antineuroinflammatory and neuroprotective effects of Gyejibokryeong-Hwan in lipopolysaccharide-stimulated BV2 microglia. Evid Based Complement Alternat Med 7585896. https://doi.org/10.1155/2019/7585896
Peruzzotti-Jametti L, Pluchino S (2018) Targeting mitochondrial metabolism in neuroinflammation: towards a therapy for progressive multiple sclerosis. Trends Mol Med 24:838–855. https://doi.org/10.1016/j.molmed.2018.07.007
Qin C et al (2017) Fingolimod protects against ischemic white matter damage by modulating microglia toward M2 polarization via STAT3 pathway. Stroke 48:3336–3346. https://doi.org/10.1161/strokeaha.117.018505
Radogna F et al (2006) Melatonin as an apoptosis antagonist. Ann NY Acad Sci 1090:226–233. https://doi.org/10.1196/annals.1378.025
Rajamohan F et al (2016) Probing the enzyme kinetics, allosteric modulation and activation of alpha1- and alpha2-subunit-containing AMP-activated protein kinase (AMPK) heterotrimeric complexes by pharmacological and physiological activators. Biochem J 473:581–592. https://doi.org/10.1042/bj20151051
Ransohoff RM (2016) A polarizing question: do M1 and M2 microglia exist? Nat Neurosci 19:987–991. https://doi.org/10.1038/nn.4338
Reiter RJ, Rosales-Corral S, Tan DX, Jou MJ, Galano A, Xu B (2017) Melatonin as a mitochondria-targeted antioxidant: one of evolution’s best ideas. Cell Mol Life Sci 74:3863–3881. https://doi.org/10.1007/s00018-017-2609-7
Sarra GM et al (2005) Effect of steroidal and non-steroidal drugs on the microglia activation pattern and the course of degeneration in the retinal degeneration slow mouse. Ophthalmic Res 37:72–82. https://doi.org/10.1159/000084248
Shah SA, Khan M, Jo MH, Jo MG, Amin FU, Kim MO (2017) Melatonin stimulates the SIRT1/Nrf2 signaling pathway counteracting lipopolysaccharide (LPS)-induced oxidative stress to rescue postnatal rat brain. CNS Neurosci Ther 23:33–44. https://doi.org/10.1111/cns.12588
Shalini S, Dorstyn L, Dawar S, Kumar S (2015) Old, new and emerging functions of caspases. Cell Death Differ 22:526–539. https://doi.org/10.1038/cdd.2014.216
Singh J, Kaur G (2006) HSP70 induction and oxidative stress protection mediated by a subtoxic dose of NMDA in the retinoic acid-differentiated C6 glioma cell line. Brain Res Bull 69:37–47. https://doi.org/10.1016/j.brainresbull.2005.10.011
Sinha B et al (2018) Protection of melatonin in experimental models of newborn hypoxic-ischemic brain injury through MT1 receptor. J Pineal Res 64. https://doi.org/10.1111/jpi.12443
Slusarczyk J, Trojan E, Glombik K, Piotrowska A, Budziszewska B, Kubera M, Popiolek-Barczyk K (2018) Targeting the NLRP3 inflammasome-related pathways via tianeptine treatment-suppressed microglia polarization to the M1 phenotype in lipopolysaccharide-stimulated cultures. Int J Mol Sci 19. https://doi.org/10.3390/ijms19071965
Soni D, Wang DM, Regmi SC, Mittal M, Vogel SM, Schluter D, Tiruppathi C (2018) Deubiquitinase function of A20 maintains and repairs endothelial barrier after lung vascular injury. Cell Death Discov 4:60. https://doi.org/10.1038/s41420-018-0056-3
Tocharus J, Khonthun C, Chongthammakun S, Govitrapong P (2010) Melatonin attenuates methamphetamine-induced overexpression of pro-inflammatory cytokines in microglial cell lines. J Pineal Res 48:347–352. https://doi.org/10.1111/j.1600-079X.2010.00761.x
Tonelli C, Chio IIC, Tuveson DA (2018) Transcriptional regulation by Nrf2. Antioxid Redox Signal 29:1727–1745. https://doi.org/10.1089/ars.2017.7342
Tvrdik P, Kalani MYS (2017) In vivo imaging of microglial calcium signaling in brain inflammation and injury. Int J Mol Sci 18. https://doi.org/10.3390/ijms18112366
Van Opdenbosch N, Lamkanfi M (2019) Caspases in cell death, inflammation, and disease. Immunity 50:1352–1364. https://doi.org/10.1016/j.immuni.2019.05.020
Venero JL, Burguillos MA, Brundin P, Joseph B (2011) The executioners sing a new song: killer caspases activate microglia. Cell Death Differ 18:1679–1691. https://doi.org/10.1038/cdd.2011.107
Walton NM et al (2006) Microglia instruct subventricular zone neurogenesis. Glia 54:815–825. https://doi.org/10.1002/glia.20419
Wang Z et al (2013) Melatonin improves short and long-term neurobehavioral deficits and attenuates hippocampal impairments after hypoxia in neonatal mice. Pharmacol Res 76:84–97. https://doi.org/10.1016/j.phrs.2013.07.008
Wang C et al (2018) Salidroside attenuates neuroinflammation and improves functional recovery after spinal cord injury through microglia polarization regulation. J Cell Mol Med 22:–1148, 1166. https://doi.org/10.1111/jcmm.13368
Wang J et al (2019) Melatonin receptor activation provides cerebral protection after traumatic brain injury by mitigating oxidative stress and inflammation via the Nrf2 signaling pathway. Free Radic Biol Med 131:345–355. https://doi.org/10.1016/j.freeradbiomed.2018.12.014
Wardyn JD, Ponsford AH, Sanderson CM (2015) Dissecting molecular cross-talk between Nrf2 and NF-kappaB response pathways. Biochem Soc Trans 43:621–626. https://doi.org/10.1042/bst20150014
Waseem M, Sahu U, Salman M, Choudhury A, Kar S, Tabassum H, Parvez S (2017) Melatonin pre-treatment mitigates SHSY-5Y cells against oxaliplatin induced mitochondrial stress and apoptotic cell death. PLoS One 12:e0180953. https://doi.org/10.1371/journal.pone.0180953
Wilkinson BL, Landreth GE (2006) The microglial NADPH oxidase complex as a source of oxidative stress in Alzheimer’s disease. J Neuroinflammation 3:30. https://doi.org/10.1186/1742-2094-3-30
Wu UI, Mai FD, Sheu JN, Chen LY, Liu YT, Huang HC, Chang HM (2011) Melatonin inhibits microglial activation, reduces pro-inflammatory cytokine levels, and rescues hippocampal neurons of adult rats with acute Klebsiella pneumoniae meningitis. J Pineal Res 50:159–170. https://doi.org/10.1111/j.1600-079X.2010.00825.x
Xue JF, Shi ZM, Zou J, Li XL (2017) Inhibition of PI3K/AKT/mTOR signaling pathway promotes autophagy of articular chondrocytes and attenuates inflammatory response in rats with osteoarthritis. Biomed Pharmacother 89:1252–1261. https://doi.org/10.1016/j.biopha.2017.01.130
Yan L et al (2013) JNK and NADPH oxidase involved in fluoride-induced oxidative stress in BV-2 microglia cells. Mediat Inflamm 2013:895975. https://doi.org/10.1155/2013/895975
Yan A, Cai G, Xia W, Fu Y (2017) Thromboxane A2 receptor antagonist SQ29548 suppresses the LPSinduced release of inflammatory cytokines in BV2 microglia cells via suppressing MAPK and NFkappaB signaling pathways. Mol Med Rep 16:2491–2496. https://doi.org/10.3892/mmr.2017.6884
Yao K, Zu HB (2019) Microglial polarization: novel therapeutic mechanism against Alzheimer’s disease. Inflammopharmacology 28:95–110. https://doi.org/10.1007/s10787-019-00613-5
Yao L, Lu P, Ling EA (2016) Melatonin suppresses toll like receptor 4-dependent Caspase-3 signaling activation coupled with reduced production of Proinflammatory mediators in hypoxic microglia. PLoS One 11:e0166010. https://doi.org/10.1371/journal.pone.0166010
Zhang Y et al (2019) Melatonin improves functional recovery in female rats after acute spinal cord injury by modulating polarization of spinal microglial/macrophages. J Neurosci Res 97:733–743. https://doi.org/10.1002/jnr.24409
Zhou J, Zhang S, Zhao X, Wei T (2008) Melatonin impairs NADPH oxidase assembly and decreases superoxide anion production in microglia exposed to amyloid-beta1-42. J Pineal Res 45:157–165. https://doi.org/10.1111/j.1600-079X.2008.00570.x
Funding
This work was supported by the National Natural Science Foundation of China (31870335); the Health Industry Planning Project of Gansu Provincial Health and Family Planning Commission (GSWSKY 2016–17); the Science and Technology Major Special Collaboration Project of Gansu Provincial Key Laboratory of Gene Function (BA2016036); the “Cuiying Technology Innovation” Planning Project of Lanzhou University Second Hospital (CY2017-MS19); Cuiying Graduate Supervisor Applicant Training Program Of Lanzhou University Second Hospital (201802); and the Key Laboratory of Biotherapy and Regenerative Medicine, Gansu Province (zdsyskfkt-201703).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
No potential conflict of interest was reported by the authors.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Gao, J., Su, G., Liu, J. et al. Mechanisms of Inhibition of Excessive Microglial Activation by Melatonin. J Mol Neurosci 70, 1229–1236 (2020). https://doi.org/10.1007/s12031-020-01531-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-020-01531-w