Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ASCO Annual Meeting 2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

2024 ASCO Annual Meeting

Keep up to date with all the top stories and latest evidence with our hub page, including official congress videos and expert takeaways.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2019

Open Access 01-12-2019 | Chloroquin | Research

URB597 protects against NLRP3 inflammasome activation by inhibiting autophagy dysfunction in a rat model of chronic cerebral hypoperfusion

Authors: Shao-Hua Su, Yi-Fang Wu, Qi Lin, Da-Peng Wang, Jian Hai

Published in: Journal of Neuroinflammation | Issue 1/2019

Login to get access

Abstract

Background

Previous studies reported that URB597 (URB) had therapeutic potential for treating chronic cerebral hypoperfusion (CCH)-induced neuroinflammation and autophagy dysfunction. However, the interaction mechanisms underlying the CCH-induced abnormal excessive autophagy and neuroinflammation remain unknown. In this study, we investigated the roles of impaired autophagy in nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing (NLRP) 3 inflammasome activation in the rat hippocampus and the underlying mechanisms under the condition of induced CCH as well as the effect of URB treatment.

Methods

The CCH rat model was established by bilateral common carotid artery occlusion (BCCAo), and rats were randomly divided into 11 groups as follows: (1) sham-operated, (2) BCCAo; (3) BCCAo+autophagy inhibitor 3-methyladenine (3-MA), (4) BCCAo+lysosome inhibitor chloroquine (CQ), (5) BCCAo+microglial activation inhibitor minocycline, (6) BCCAo+ROS scavenger N-acetylcysteine (NAC), (7) BCCAo+URB, (8) BCCAo+URB+3-MA, (9) BCCAo+URB+CQ, (10) BCCAo+URB+minocycline, (11) BCCAo+URB+NAC. The cell localizations of LC3, p62, LAMP1, TOM20 and NLRP3 were assessed by immunofluorescence staining. The levels of autophagy-related proteins (LC3, p62, LAMP1, BNIP3 and parkin), NLRP3 inflammasome-related proteins (NLRP3, CASP1 and IL-1β), microglial marker (OX-42) and proinflammatory cytokines (iNOS and COX-2) were evaluated by western blotting, and proinflammatory cytokines (IL-1β and TNF-a) were determined by ELISA. Reactive oxygen species (ROS) were assessed by dihydroethidium staining. The mitochondrial ultrastructural changes were examined by electron microscopy.

Results

CCH induced microglial overactivation and ROS accumulation, promoting the activation of the NLRP3 inflammasome and the release of IL-1β. Blocked autophagy and mitophagy flux enhanced the activation of the NLRP3-CASP1 inflammasome pathway. However, URB alleviated impaired autophagy and mitophagy by decreasing mitochondrial ROS and microglial overactivation as well as restoring lysosomal function, which would further inhibit the activation of the NLRP3-CASP1 inflammasome pathway.

Conclusion

These findings extended previous studies indicating the function of URB in the mitigation of chronic ischemic injury of the brain.
Literature
1.
Arsava EM, Hansen MB, Kaplan B, Peker A, Gocmen R, Arat A, Oguz KK, Topcuoglu MA, Østergaard L, Dalkara T. The effect of carotid artery stenting on capillary transit time heterogeneity in patients with carotid artery stenosis. Eur Stroke J. 2018;3:263–71.PubMedPubMedCentralCrossRef
2.
Shang J, Yamashita T, Zhai Y, Nakano Y, Morihara R, Li X, Tian F, Liu X, Huang Y, Shi X, Sato K, Takemoto M, Hishikawa N, Ohta Y, Abe K. Acceleration of NLRP3 inflammasome by chronic cerebral hypoperfusion in Alzheimer’s disease model mouse. Neurosci Res. 2019;143:61–70.PubMedCrossRef
3.
Hai J, Su SH, Lin Q, Zhang L, Wan JF, Li H, Chen YY, Lu Y. Cognitive impairment and changes of neuronal plasticity in rats of chronic cerebral hypoperfusion associated with cerebral arteriovenous malformations. Acta Neurol Belg. 2010;110:180–5.PubMed
4.
Chen L, Mao Y, Zhou LF. Local chronic hypoperfusion secondary to sinus high pressure seems to be mainly responsible for the formation of intracranial dural arteriovenous fistula. Neurosurgery. 2009;64:973–83.PubMedCrossRef
5.
Choi SA, Chong S, Kwak PA, Moon YJ, Jangra A, Phi JH, Lee JY, Park SH, Kim SK. Impaired functional recovery of endothelial colony-forming cells from moyamoya disease in a chronic cerebral hypoperfusion rat model. J Neurosurg Pediatr. 2018;23:204–13.PubMedCrossRef
6.
Hainsworth AH, Markus HS. Do in vivo experimental models reflect human cerebral small vessel disease? A systematic review. J Cereb Blood Flow Metab. 2008;28:1877–91.PubMedCrossRef
7.
Su SH, Wu YF, Lin Q, Hai J. Cannabinoid receptor agonist WIN55,212-2 and fatty acid amide hydrolase inhibitor URB597 suppress chronic cerebral hypoperfusion-induced neuronal apoptosis by inhibiting c-Jun N-terminal kinase signaling. Neuroscience. 2015;301:563–75.PubMedCrossRef
8.
Su SH, Wang YQ, Wu YF, Lin Q, Hai J. Cannabinoid receptor agonist WIN55,212-2 and fatty acid amide hydrolase inhibitor URB597 may protect against cognitive impairment in rats of chronic cerebral hypoperfusion via PI3K/AKT signaling. Behav Brain Res. 2016;313:334–44.PubMedCrossRef
9.
Su SH, Wu YF, Lin Q, Hai J. Cannabinoid receptor agonist WIN55,212-2 and fatty acid amide hydrolase inhibitor URB597 ameliorate neuroinflammatory responses in chronic cerebral hypoperfusion model by blocking NF-κB pathways. Naunyn Schmiedeberg’s Arch Pharmacol. 2017;390:1189–200.CrossRef
10.
Wang D, Lin Q, Su S, Liu K, Wu Y, Hai J. URB597 improves cognitive impairment induced by chronic cerebral hypoperfusion by inhibiting mTOR-dependent autophagy. Neuroscience. 2017;344:293–304.PubMedCrossRef
11.
Su SH, Wu YF, Wang DP, Hai J. Inhibition of excessive autophagy and mitophagy mediates neuroprotective effects of URB597 against chronic cerebral hypoperfusion. Cell Death Dis. 2018;9:733.PubMedPubMedCentralCrossRef
12.
Bond WS, Rex TS. Evidence that erythropoietin modulates neuroinflammation through differential action on neurons, astrocytes, and microglia. Front Immunol. 2014;5:523.PubMedPubMedCentralCrossRef
13.
Hovens IB, van Leeuwen BL, Nyakas C, Heineman E, van der Zee EA, Schoemaker RG. Postoperative cognitive dysfunction and microglial activation in associated brain regions in old rats. Neurobiol Learn Mem. 2015;118:74–9.PubMedCrossRef
14.
Lozano D, Gonzales-Portillo GS, Acosta S, de la Pena I, Tajiri N, Kaneko Y, Borlongan CV. Neuroinflammatory responses to traumatic brain injury: etiology, clinical consequences, and therapeutic opportunities. Neuropsychiatr Dis Treat. 2015;11:97–106.PubMedPubMedCentral
15.
Kanneganti TD, Lamkanfi M, Núñez G. Intracellular NOD-like receptors in host defense and disease. Immunity. 2007;27:549–59.PubMedCrossRef
16.
17.
18.
Pan Y, Chen XY, Zhang QY, Kong LD. Microglial NLRP3 inflammasome activation mediates IL-1β-related inflammation in prefrontalcortex of depressive rats. Brain Behav Immun. 2014;41:90–100.PubMedCrossRef
19.
Hong P, Gu RN, Li FX, Xiong XX, Liang WB, You ZJ, Zhang HF. NLRP3 inflammasome as a potential treatment in ischemic stroke concomitant with diabetes. J Neuroinflammation. 2019;16:121.PubMedPubMedCentralCrossRef
20.
Choi AM, Ryter SW, Levine B. Autophagy in human health and disease. N Engl J Med. 2013;368:651–62.PubMedCrossRef
21.
Su P, Zhang J, Wang D, Zhao F, Cao Z, Aschner M, Luo W. The role of autophagy in modulation of neuroinflammation in microglia. Neuroscience. 2016;319:155–67.PubMedCrossRef
22.
Farkas E, Luiten PG, Bari F. Permanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases. Brain Res Rev. 2017;4:162–80.
23.
Ashraf T, Jiang W, Hoque MT, Henderson J, Wu C, Bendayan R. Role of anti-inflammatory compounds in human immunodeficiency virus-1 glycoprotein120-mediated brain inflammation. J Neuroinflammation. 2014;11:91.PubMedPubMedCentralCrossRef
24.
Yew WP, Djukic ND, Jayaseelan JSP, Walker FR, Roos KAA, Chataway TK, Muyderman H, Sims NR. Early treatment with minocycline following stroke in rats improves functional recovery and differentially modifies responses of peri-infarct microglia and astrocytes. J Neuroinflammation. 2019;16:6.PubMedPubMedCentralCrossRef
25.
Di-Pietro PB, Dias ML, Scaini G, Burigo M, Constantino L, Machado RA, Dal-Pizzol F, Streck EL. Inhibition of brain creatine kinase activity after renal ischemia is attenuated by N-acetylcysteine and deferoxamine administration. Neurosci Lett. 2008;434:139–43.PubMedCrossRef
26.
Paxinos G, Franklin K. The mouse brain in stereotaxic coordinates. 2nd ed. San Diego: Academic; 2001.
27.
Lu J, Wu DM, Zheng YL, Hu B, Zhang ZF. Purple sweet potato color alleviates D-galactose-induced brain aging in old mice by promoting survival of neurons via PI3K pathway and inhibiting cytochrome C-mediated apoptosis. Brain Pathol. 2010;20:598–612.PubMedCrossRef
28.
Poulet R, Gentile MT, Vecchione C, Distaso M, Aretini A, Fratta L, Russo G, Echart C, Maffei A, De Simoni MG, Lembo G. Acute hypertension induces oxidative stress in brain tissues. J Cereb Blood Flow Metab. 2005;26:253–62.CrossRef
29.
Han X, Sun S, Sun Y, Song Q, Zhu J, Song N, Chen M, Sun T, Xia M, Ding J, Lu M, Yao H, Hu G. Small molecule-driven NLRP3 inflammation inhibition via interplay between ubiquitination and autophagy: implications for Parkinson disease. Autophagy. 2019:1–22.
30.
Shi CS, Shenderov K, Huang NN, Kabat J, Abu-Asab M, Fitzgerald KA, Sher A, Kehrl JH. Activation of autophagy by inflammatory signals limits IL-1β production by targeting ubiquitinated inflammasomes for destruction. Nat Immunol. 2012;13:255–63.PubMedPubMedCentralCrossRef
31.
Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng TC, Gelpi E, Halle A, Korte M, Latz E, Golenbock DT. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature. 2013;493:674–8.PubMedCrossRef
32.
33.
Lee JH, Rao MV, Yang DS, Stavrides P, Im E, Pensalfini A, Huo C, Sarkar P, Yoshimori T, Nixon RA. Transgenic expression of a ratiometric autophagy probe specifically in neurons enables the interrogation of brain autophagy in vivo. Autophagy. 2019;15:543–57.PubMedCrossRef
34.
Wang D, Zhang J, Jiang W, Cao Z, Zhao F, Cai T, Aschner M, Luo W. The role of NLRP3-CASP1 in inflammasome mediated neuroinflammation and autophagy dysfunction in manganese-induced, hippocampal dependent impairment of learning and memory ability. Autophagy. 2017;13:914–27.PubMedPubMedCentralCrossRef
35.
36.
He W, Long T, Pan Q, Zhang S, Zhang Y, Zhang D, Qin G, Chen L, Zhou J. Microglial NLRP3 inflammasome activation mediates IL-1β release and contributes to centralsensitization in a recurrent nitroglycerin-induced migraine model. J Neuroinflammation. 2019;16:78.PubMedPubMedCentralCrossRef
37.
Arroyo DS, Gaviglio EA, Peralta Ramos JM, Bussi C, Rodriguez-Galan MC, Iribarren P. Autophagy in inflammation, infection, neurodegeneration and cancer. Int Immunopharmacol. 2014;18:55–65.PubMedCrossRef
38.
Wang Y, Liu N, Lu B. Mechanisms and roles of mitophagy in neurodegenerative diseases. CNS Neurosci Ther. 2019;25:859–75.PubMedPubMedCentral
39.
Iyer SS, He Q, Janczy JR, Elliott EI, Zhong Z, Olivier AK, Sadler JJ, Knepper-Adrian V, Han R, Qiao L, Eisenbarth SC, Nauseef WM, Cassel SL, Sutterwala FS. Mitochondrial cardiolipin is required for Nlrp3 inflammasome activation. Immunity. 2013;39:311–23.PubMedPubMedCentralCrossRef
40.
41.
Abais JM, Xia M, Zhang Y, Boini KM, Li PL. Redox regulation of NLRP3 inflammasomes: ROS as trigger or effector? Antioxid Redox Signal. 2015;22:1111–29.PubMedPubMedCentralCrossRef
42.
Liu C, Wang J, Yang Y, Liu X, Zhu Y, Zou J, Peng S, Le TH, Chen Y, Zhao S, He B, Mi Q, Zhang X, Du Q. Ginsenoside Rd ameliorates colitis by inducing p62-driven mitophagy-mediated NLRP3 inflammasome inactivation in mice. Biochem Pharmacol. 2018;155:366–79.PubMedCrossRef
43.
Zhong Z, Umemura A, Sanchez-Lopez E, Liang S, Shalapour S, Wong J, He F, Boassa D, Perkins G, Ali SR, McGeough MD, Ellisman MH, Seki E, Gustafsson AB, Hoffman HM, Diaz-Meco MT, Moscat J, Karin M. NF-KB restricts inflammasome activation via elimination of damaged mitochondria. Cell. 2016;164:896–910.PubMedPubMedCentralCrossRef
44.
Narendra D, Kane LA, Hauser DN, Fearnley IM, Youle RJ. p62/SQSTM1 is required for Parkin-induced mitochondrial clustering but not mitophagy; VDAC1 is dispensable for both. Autophagy. 2010;6:1090–106.PubMedPubMedCentralCrossRef
45.
Strappazzon F, Nazio F, Corrado M, Cianfanelli V, Romagnoli A, Fimia GM, Campello S, Nardacci R, Piacentini M, Campanella M, Cecconi F. AMBRA1 is able to induce mitophagy via LC3 binding, regardless of PARKIN and p62/SQSTM1. Cell Death Differ. 2015;22:419–32.PubMedCrossRef
46.
Houtman J, Freitag K, Gimber N, Schmoranzer J, Heppner FL, Jendrach M. Beclin1-driven autophagy modulates the inflammatory response of microglia via NLRP3. EMBO J. 2019;38:e99430.PubMedCrossRefPubMedCentral
47.
Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011;469:221–5.PubMedCrossRef
48.
Fleming JC, Norenberg MD, Ramsay DA, Dekaban GA, Marcillo AE, Saenz AD, Pasquale-Styles M, Dietrich WD, Weaver LC. The cellular inflammatory response in human spinal cords after injury. Brain. 2006;129:3249–69.PubMedCrossRef
49.
Du D, Hu L, Wu J, Wu Q, Cheng W, Guo Y, Guan R, Wang Y, Chen X, Yan X, Zhu D, Wang J, Zhang S, Guo Y, Xia C. Neuroinflammation contributes to autophagy flux blockage in the neurons of rostral ventrolateral medulla in stress-induced hypertension rats. J Neuroinflammation. 2017;14:169.PubMedPubMedCentralCrossRef
50.
Jassey A, Liu CH, Changou CA, Richardson CD, Hsu HY, Lin LT. Hepatitis C virus non-structural protein 5A (NS5A) disrupts mitochondrial dynamics and induces mitophagy. Cells. 2019;8:E290.PubMedCrossRef
51.
Thangaraj A, Periyasamy P, Guo ML, Chivero ET, Callen S, Buch S. Mitigation of cocaine-mediated mitochondrial damage, defective mitophagy and microglial activation by superoxide dismutase mimetics. Autophagy. 2019:1–24.
52.
Zhang F, Dong H, Lv T, Jin K, Jin Y, Zhang X, Jiang J. Moderate hypothermia inhibits microglial activation after traumatic brain injury by modulating autophagy/apoptosis and the MyD88-dependent TLR4 signaling pathway. J Neuroinflammation. 2018;15:273.PubMedPubMedCentralCrossRef
53.
Ureshino RP, Rocha KK, Lopes GS, Trindade CB, Smaili SS. Calcium signaling alterations, oxidative stress and autophagy in aging. Antioxid Redox Signal. 2014;21:123–37.PubMedCrossRef
Metadata
Title
URB597 protects against NLRP3 inflammasome activation by inhibiting autophagy dysfunction in a rat model of chronic cerebral hypoperfusion
Authors
Shao-Hua Su
Yi-Fang Wu
Qi Lin
Da-Peng Wang
Jian Hai
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2019
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-019-1668-0

Other articles of this Issue 1/2019

Journal of Neuroinflammation 1/2019 Go to the issue

Research

Highly glycosylated CD147 promotes hemorrhagic transformation after rt-PA treatment in diabetes: a novel therapeutic target?

Research

Osteopontin and its spatiotemporal relationship with glial cells in the striatum of rats treated with mitochondrial toxin 3-nitropropionic acid: possible involvement in phagocytosis

Research

The pentose phosphate pathway regulates chronic neuroinflammation and dopaminergic neurodegeneration

Research

Neuroinflammation in the NTS is associated with changes in cardiovascular reflexes during systemic inflammation

Review

Exploiting microglial and peripheral immune cell crosstalk to treat Alzheimer’s disease

Research

Leucine-rich repeat kinase-2 (LRRK2) modulates paraquat-induced inflammatory sickness and stress phenotype