Melatonin suppresses inflammation and blood‒brain barrier disruption in rats with vascular dementia possibly by activating the SIRT1/PGC-1α/PPARγ signaling pathway.
BBB disruption
Chronic cerebral hypoperfusion
Cognitive impairment
Inflammation
Melatonin
SIRT1 signaling pathway
Journal
Inflammopharmacology
ISSN: 1568-5608
Titre abrégé: Inflammopharmacology
Pays: Switzerland
ID NLM: 9112626
Informations de publication
Date de publication:
Jun 2023
Jun 2023
Historique:
received:
01
12
2022
accepted:
25
02
2023
medline:
1
6
2023
pubmed:
6
4
2023
entrez:
5
4
2023
Statut:
ppublish
Résumé
Chronic cerebral hypoxia (CCH) is caused by a reduction in cerebral blood flow, and cognitive impairment has been the predominant feature that occurs after CCH. Recent reports have revealed that melatonin is proficient in neurodegenerative diseases. However, the molecular mechanism by which melatonin affects CCH remains uncertain. In this study, we aimed to explore the role and underlying mechanism of melatonin in inflammation and blood‒brain barrier conditions in rats with CCH. Male Wistar rats were subjected to permanent bilateral common carotid artery occlusion (BCCAO) to establish the VAD model. Rats were randomly divided into four groups: Sham, BCCAO, BCCAO treated with melatonin (10 mg/kg), and BCCAO treated with resveratrol (20 mg/kg). All drugs were administered once daily for 4 weeks. Our results showed that melatonin attenuated cognitive impairment, as demonstrated by the Morris water maze tests. Furthermore, melatonin reduced the activation of inflammation by attenuating the phosphorylated nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor alpha (pIκBα), causing the suppression of proteins related to inflammation and inflammasome formation. Moreover, immunohistochemistry revealed that melatonin reduced glial cell activation and proliferation, which were accompanied by Western blotting results. Additionally, melatonin also promoted the expression of sirtuin-1 (SIRT1), peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α), and peroxisome proliferator-activated receptor-gamma (PPARγ), causing attenuated blood‒brain barrier (BBB) disruption by increasing tight junction proteins. Taken together, our results prove that melatonin treatment modulated inflammation and BBB disruption and improved cognitive function in VaD rats, partly by activating the SIRT1/PGC-1α/PPARγ signaling pathway.
Identifiants
pubmed: 37017851
doi: 10.1007/s10787-023-01181-5
pii: 10.1007/s10787-023-01181-5
doi:
Substances chimiques
Melatonin
JL5DK93RCL
Sirtuin 1
EC 3.5.1.-
PPAR gamma
0
Sirt1 protein, rat
EC 3.5.1.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1481-1493Subventions
Organisme : Thailand Science Research and Innovation (TSRI)
ID : 64/004
Organisme : Thailand and the Development and Promotion of Science and Technology Talents Project Royal Government of Thailand scholarship
ID : 572109
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.
Références
Amaral FGd, Cipolla-Neto J (2018) A brief review about melatonin, a pineal hormone. Arch Endocrinol Metab 62:472–479. https://doi.org/10.20945/2359-3997000000066
doi: 10.20945/2359-3997000000066
pubmed: 30304113
pmcid: 10118741
Braidy N, Guillemin GJ, Mansour H, Chan-Ling T, Poljak A, Grant R (2011) Age related changes in NAD+ metabolism oxidative stress and Sirt1 activity in wistar rats. PLoS One 6:e19194. https://doi.org/10.1371/journal.pone.0019194
doi: 10.1371/journal.pone.0019194
pubmed: 21541336
pmcid: 3082551
Cantó C, Auwerx J (2009) PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr Opin Lipidol 20:98. https://doi.org/10.1097/MOL.0b013e328328d0a4
doi: 10.1097/MOL.0b013e328328d0a4
pubmed: 19276888
pmcid: 3627054
Cekanaviciute E, Buckwalter MS (2016) Astrocytes: integrative regulators of neuroinflammation in stroke and other neurological diseases. Neurotherapeutics 13:685–701. https://doi.org/10.1007/s13311-016-0477-8
doi: 10.1007/s13311-016-0477-8
pubmed: 27677607
pmcid: 5081110
Corona JC, Duchen MR (2015) PPARγ and PGC-1α as therapeutic targets in Parkinson’s. Neurochem Res 40:308–316. https://doi.org/10.1007/s11064-014-1377-0
doi: 10.1007/s11064-014-1377-0
pubmed: 25007880
Cummins EP, Berra E, Comerford KM, Ginouves A, Fitzgerald KT, Seeballuck F, Godson C, Nielsen JE, Moynagh P, Pouyssegur J (2006) Prolyl hydroxylase-1 negatively regulates IκB kinase-β, giving insight into hypoxia-induced NFκB activity. Proc Natl Acad Sci 103:18154–18159. https://doi.org/10.1073/pnas.0602235103
doi: 10.1073/pnas.0602235103
pubmed: 17114296
pmcid: 1643842
Daulatzai MA (2017) Cerebral hypoperfusion and glucose hypometabolism: Key pathophysiological modulators promote neurodegeneration, cognitive impairment, and Alzheimer’s disease. J Neurosci Res 95:943–972. https://doi.org/10.1002/jnr.23777
doi: 10.1002/jnr.23777
pubmed: 27350397
Dehne N, Brüne B (2009) HIF-1 in the inflammatory microenvironment. Exp Cell Res 315:1791–1797. https://doi.org/10.1016/j.yexcr.2009.03.019
doi: 10.1016/j.yexcr.2009.03.019
pubmed: 19332053
Ding Y, Kang J, Liu S, Xu Y, Shao B (2020) The protective effects of peroxisome proliferator-activated receptor gamma in cerebral ischemia-reperfusion injury. Front Neurol 11:1469. https://doi.org/10.3389/fneur.2020.588516
doi: 10.3389/fneur.2020.588516
Du SQ, Wang XR, Xiao LY, Tu JF, Zhu W, He T, Liu CZ (2017) Molecular mechanisms of vascular dementia: what can be learned from animal models of chronic cerebral hypoperfusion? Mol. Neurobiol 54:3670–3682. https://doi.org/10.1007/s12035-016-9915-1
doi: 10.1007/s12035-016-9915-1
Fang Y, Gao S, Wang X, Cao Y, Lu J, Chen S, Zhang J (2020) Programmed cell deaths and potential crosstalk with blood–brain barrier dysfunction after hemorrhagic stroke. Front Cell Neurosci 14:68. https://doi.org/10.3389/fncel.2020.00068
doi: 10.3389/fncel.2020.00068
pubmed: 32317935
pmcid: 7146617
Govindarajulu M, Pinky PD, Bloemer J, Ghanei N, Suppiramaniam V, Amin R (2018) Signaling mechanisms of selective PPARγ modulators in Alzheimer’s disease. PPAR Res. https://doi.org/10.1155/2018/2010675
doi: 10.1155/2018/2010675
pubmed: 30420872
pmcid: 6215547
Huang JJ, Xia J, Huang LL, Li YC (2019) HIF-1α promotes NLRP3 inflammasome activation in bleomycin-induced acute lung injury. Mol Med Rep 20:3424–3432. https://doi.org/10.3892/mmr.2019.10575
doi: 10.3892/mmr.2019.10575
pubmed: 31432144
Hubbard BP, Gomes AP, Dai H, Li J, Case AW, Considine T, Riera TV, Lee JE, Lamming DW, Pentelute BL (2013) Evidence for a common mechanism of SIRT1 regulation by allosteric activators. Science 339:1216–1219. https://doi.org/10.1126/science.1231097
doi: 10.1126/science.1231097
pubmed: 23471411
pmcid: 3799917
Hugo J, Ganguli M (2014) Dementia and cognitive impairment: epidemiology, diagnosis, and treatment. Clin Geriatr Med 30:421–442. https://doi.org/10.1016/j.cger.2014.04.001
doi: 10.1016/j.cger.2014.04.001
pubmed: 25037289
pmcid: 4104432
Imai S-i (2011) Dissecting systemic control of metabolism and aging in the NAD World: the importance of SIRT1 and NAMPT-mediated NAD biosynthesis. FEBS Lett 585:1657–1662. https://doi.org/10.1016/j.febslet.2011.04.060
doi: 10.1016/j.febslet.2011.04.060
pubmed: 21550345
pmcid: 3104082
Kleszcz R, Paluszczak J, Baer-Dubowska W (2015) Targeting aberrant cancer metabolism–The role of sirtuins. Pharmacol Rep 67:1068–1080. https://doi.org/10.1016/j.pharep.2015.03.021
doi: 10.1016/j.pharep.2015.03.021
pubmed: 26481524
Lee CH, Park JH, Ahn JH, Won MH (2016) Effects of melatonin on cognitive impairment and hippocampal neuronal damage in a rat model of chronic cerebral hypoperfusion. Exp Ther Med 11:2240–2246. https://doi.org/10.3892/etm.2016.3216
doi: 10.3892/etm.2016.3216
pubmed: 27284307
pmcid: 4887947
Li X (2013) SIRT1 and energy metabolism. Acta Biochim Biophys Sin 45:51–60. https://doi.org/10.1093/abbs/gms108
doi: 10.1093/abbs/gms108
pubmed: 23257294
pmcid: 3527007
Li Y, Wang P, Yang X, Wang W, Zhang J, He Y, Zhang W, Jing T, Wang B, Lin R (2016) SIRT1 inhibits inflammatory response partly through regulation of NLRP3 inflammasome in vascular endothelial cells. Mol Immunol 77:148–156. https://doi.org/10.1016/j.molimm.2016.07.018
doi: 10.1016/j.molimm.2016.07.018
pubmed: 27505710
Li J, Zheng M, Shimoni O, Banks WA, Bush AI, Gamble JR, Shi B (2021) Development of novel therapeutics targeting the blood-brain barrier: from barrier to carrier. Adv Sci. https://doi.org/10.1002/advs.202101090
doi: 10.1002/advs.202101090
Liang H, Ward WF (2006) PGC-1α: a key regulator of energy metabolism. Adv Physiol Educ. https://doi.org/10.1152/advan.00052.2006
doi: 10.1152/advan.00052.2006
pubmed: 17108241
Lim J-H, Lee Y-M, Chun Y-S, Chen J, Kim J-E, Park J-W (2010) Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1α. Mol Cell 38:864–878. https://doi.org/10.1016/j.molcel.2010.05.023
doi: 10.1016/j.molcel.2010.05.023
pubmed: 20620956
Ma J, Yang H, Liu L, Wan Y, Wang F (2021) Melatonin alleviated oxidative stress induced by energy restriction on sheep Leydig cells through Sirt1/Sod2 pathway. Theriogenology 173:83–92. https://doi.org/10.1016/j.theriogenology.2021.07.011
doi: 10.1016/j.theriogenology.2021.07.011
pubmed: 34352672
Mojsilovic-Petrovic J, Callaghan D, Cui H, Dean C, Stanimirovic DB, Zhang W (2007) Hypoxia-inducible factor-1 (HIF-1) is involved in the regulation of hypoxia-stimulated expression of monocyte chemoattractant protein-1 (MCP-1/CCL2) and MCP-5 (Ccl12) in astrocytes. J Neuroinflammation 4:1–15. https://doi.org/10.1186/1742-2094-4-12
doi: 10.1186/1742-2094-4-12
Permpoonputtana K, Tangweerasing P, Mukda S, Boontem P, Nopparat C, Govitrapong P (2018) Long-term administration of melatonin attenuates neuroinflammation in the aged mouse brain. EXCLI J 17:634. https://doi.org/10.17179/excli2017-654
doi: 10.17179/excli2017-654
pubmed: 30108467
pmcid: 6088215
Price NL, Gomes AP, Ling AJ, Duarte FV, Martin-Montalvo A, North BJ, Agarwal B, Ye L, Ramadori G, Teodoro JS (2012) SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab 15:675–690. https://doi.org/10.1016/j.cmet.2012.04.003
doi: 10.1016/j.cmet.2012.04.003
pubmed: 22560220
pmcid: 3545644
Ren Z, He H, Zuo Z, Xu Z, Wei Z, Deng J (2019) The role of different SIRT1-mediated signaling pathways in toxic injury. Cell Mol Biol Lett 24:1–10. https://doi.org/10.1186/s11658-019-0158-9
doi: 10.1186/s11658-019-0158-9
Sanderson TH, Wider JM (2013) 2-vessel occlusion/hypotension: a rat model of global brain ischemia. J vis Exp. https://doi.org/10.3791/50173
doi: 10.3791/50173
pubmed: 23851591
pmcid: 3728756
Scirpo R, Fiorotto R, Villani A, Amenduni M, Spirli C, Strazzabosco M (2015) Stimulation of nuclear receptor PPAR-γ limits NF-kB-dependent inflammation in mouse cystic fibrosis biliary epithelium. Hepatology 62:1551. https://doi.org/10.1002/hep.28000
doi: 10.1002/hep.28000
pubmed: 26199136
Shen D, Tian X, Sang W, Song R (2016) Effect of melatonin and resveratrol against memory impairment and hippocampal damage in a rat model of vascular dementia. NeuroImmunoModulation 23:318–331. https://doi.org/10.1159/000454681
doi: 10.1159/000454681
pubmed: 28419991
Thangwong P, Jearjaroen P, Govitrapong P, Tocharus C, Tocharus J (2022) Melatonin improves cognitive impairment by suppressing endoplasmic reticulum stress and promoting synaptic plasticity during chronic cerebral hypoperfusion in rats. Biochem Pharmacol 198:114980. https://doi.org/10.1016/j.bcp.2022.114980
doi: 10.1016/j.bcp.2022.114980
pubmed: 35219702
Tsai TH, Lin CJ, Chua S, Chung SY, Yang CH, Tong MS, Hang CL (2017) Melatonin attenuated the brain damage and cognitive impairment partially through MT2 melatonin receptor in mice with chronic cerebral hypoperfusion. Oncotarget 8:74320. https://doi.org/10.18632/oncotarget.20382
doi: 10.18632/oncotarget.20382
pubmed: 29088788
pmcid: 5650343
Venkat P, Chopp M, Chen J (2015) Models and mechanisms of vascular dementia. Exp Neurol 272:97–108. https://doi.org/10.1016/j.expneurol.2015.05.006
doi: 10.1016/j.expneurol.2015.05.006
pubmed: 25987538
pmcid: 4631710
Vorhees CV, Williams MT (2006) Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 1:848–858. https://doi.org/10.1038/nprot.2006.116
doi: 10.1038/nprot.2006.116
pubmed: 17406317
pmcid: 2895266
Watts ER, Walmsley SR (2019) Inflammation and hypoxia: HIF and PHD isoform selectivity. Trends Mol Med 25:33–46. https://doi.org/10.1016/j.molmed.2018.10.006
doi: 10.1016/j.molmed.2018.10.006
pubmed: 30442494
Weiss N, Miller F, Cazaubon S, Couraud P-O (2009) The blood-brain barrier in brain homeostasis and neurological diseases. Biochim Et Biophys Acta Biomembr 1788:842–857. https://doi.org/10.1016/j.bbamem.2008.10.022
doi: 10.1016/j.bbamem.2008.10.022
Wicha P, Tocharus J, Janyou A, Jittiwat J, Chaichompoo W, Suksamrarn A, Tocharus C (2020) Hexahydrocurcumin alleviated blood–brain barrier dysfunction in cerebral ischemia/reperfusion rats. Pharmacol Rep. https://doi.org/10.1007/s43440-019-00050-9
doi: 10.1007/s43440-019-00050-9
pubmed: 32048258
Xue Y, Tuipulotu DE, Tan WH, Kay C, Man SM (2019) Emerging activators and regulators of inflammasomes and pyroptosis. Trends Immunol 40:1035–1052. https://doi.org/10.1016/j.it.2019.09.005
doi: 10.1016/j.it.2019.09.005
pubmed: 31662274
Yang CC, Wu CH, Lin TC, Cheng YN, Chang CS, Lee KT, Tsai PJ, Tsai YS (2021) Inhibitory effect of PPARγ on NLRP3 inflammasome activation. Theranostics 11:2424. https://doi.org/10.7150/thno.46873
doi: 10.7150/thno.46873
pubmed: 33500734
pmcid: 7797672
Yawoot N, Sengking J, Wicha P, Govitrapong P, Tocharus C, Tocharus J (2022) Melatonin attenuates reactive astrogliosis and glial scar formation following cerebral ischemia and reperfusion injury mediated by GSK-3β and RIP1K. J Cell Physiol 237:1818–1832. https://doi.org/10.1002/jcp.30649
doi: 10.1002/jcp.30649
pubmed: 34825376
Yeleswaram K, McLaughlin LG, Knipe JO, Schabdach D (1997) Pharmacokinetics and oral bioavailability of exogenous melatonin in preclinical animal models and clinical implications. J Pineal Res 22:45–51. https://doi.org/10.1111/j.1600-079x.1997.tb00302.x
doi: 10.1111/j.1600-079x.1997.tb00302.x
pubmed: 9062870
Zhao L, Liu H, Yue L, Zhang J, Li X, Wang B, Lin Y, Qu Y (2017) Melatonin attenuates early brain injury via the melatonin receptor/Sirt1/NF-κB signaling pathway following subarachnoid hemorrhage in mice. Mol Neurobiol 54:1612–1621. https://doi.org/10.1007/s12035-016-9776-7
doi: 10.1007/s12035-016-9776-7
pubmed: 26867656
Zhou Y, Wang S, Li Y, Yu S, Zhao Y (2018) SIRT1/PGC-1α signaling promotes mitochondrial functional recovery and reduces apoptosis after intracerebral hemorrhage in rats. Front Mol Neurosci 10:443. https://doi.org/10.3389/fnmol.2017.00443
doi: 10.3389/fnmol.2017.00443
pubmed: 29375306
pmcid: 5767311