Skip to main content
PMC home page
Neuroscience Bulletin logoLink to Neuroscience Bulletin
. 2010 Feb 3;26(1):28–36. doi: 10.1007/s12264-010-0818-2

Minocycline reduces astrocytic reactivation and neuroinflammation in the hippocampus of a vascular cognitive impairment rat model

美满霉素抑制血管性认知功能损伤大鼠海马星型胶质细胞激活和神经炎症

Zhi-You Cai 1, Yong Yan 2,✉, Ran Chen 1
PMCID: PMC5560381  PMID: 20101270

Abstract

Objective

To study the neuroprotective mechanism of minocycline against vascular cognitive impairment after cerebral ischemia.

Methods

The rat model with vascular cognitive impairment was established by permanent bilateral common carotid artery occlusion (BCCAO). The observing time-points were determined at 4, 8 and 16 weeks after BCCAO. Animals were randomly divided into sham-operated group (n = 6), model group (subdivided into 3 groups: 4 weeks after BCCAO, n = 6; 8 weeks after BCCAO, n = 6; and 16 weeks after BCCAO, n = 6), and minocycline group (subdivided into 3 groups: 4 weeks after BCCAO, n = 6; 8 weeks after BCCAO, n = 6; and 16 weeks after BCCAO, n = 6). Minocycline was administered by douche via stomach after BCCAO until sacrifice. Glial fibrillary acidic protein (GFAP) was examined by Western blotting and immunohistochemistry. Levels of cyclooxygenase-2 (COX-2) and nuclear factor-kappaB (NF-κB) were measured by immunohistochemistry. IL-1β and TNF-α levels were tested with ELISA method.

Results

Levels of GFAP, COX- 2, NF-κB, IL-1β and TNF-α were all up-regulated after permanent BCCAO, which could be significantly inhibited by minocycline.

Conclusion

Minocycline could ameliorate the inflammation and oxidative stress in the hippocampus of the vascular cognitive impairment rat model.

Keywords: vascular cognitive impairment, minocycline, inflammation, astrocyte

References

  • [1].Kumaran D., Udayabanu M., Kumar M., Aneja R., Katyal A. Involvement of angiotensin converting enzyme in cerebral hypoperfusion induced anterograde memory impairment and cholinergic dysfunction in rats. Neuroscience. 2008;155(3):626–639. doi: 10.1016/j.neuroscience.2008.06.023. [DOI] [PubMed] [Google Scholar]
  • [2].Lee J.H., Park S.Y., Shin H.K., Kim C.D., Lee W.S., Hong K.W. Protective effects of cilostazol against transient focal cerebral ischemia and chronic cerebral hypoperfusion injury. CNS Neurosci Ther. 2008;14(2):143–152. doi: 10.1111/j.1527-3458.2008.00042.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [3].He Z., Huang L., Wu Y., Wang J., Wang H., Guo L. DDPH: improving cognitive deficits beyond its alpha 1-adrenoceptor antagonism in chronic cerebral hypoperfused rats. Eur J Pharmacol. 2008;588(2–3):178–188. doi: 10.1016/j.ejphar.2008.03.060. [DOI] [PubMed] [Google Scholar]
  • [4].Zadori D., Datki Z., Penke B. The role of chronic brain hypoperfusion in the pathogenesis of Alzheimer’s disease-facts and hypotheses. Ideggyogy Sz. 2007;60(11-12):428–437. [PubMed] [Google Scholar]
  • [5].Zheng P., Zhang J., Liu H., Xu X., Zhang X. Angelica injection reduces cognitive impairment during chronic cerebral hypoperfusion through brain-derived neurotrophic factor and nerve growth factor. Curr Neurovasc Res. 2008;5(1):13–20. doi: 10.2174/156720208783565636. [DOI] [PubMed] [Google Scholar]
  • [6].Yrjänheikki J., Tikka T., Keinänen R., Goldsteins G., Chan P.H., Koistinaho J. A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci U S A. 1999;96(23):13496–13500. doi: 10.1073/pnas.96.23.13496. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [7].Alvaro-Gonzalez L.C., Freijo-Guerrero M.M., Sadaba-Garay F. Inflammatory mechanisms, arteriosclerosis and ischemic stroke: clinical data and perspectives. Rev Neurol. 2002;35(5):452–462. [PubMed] [Google Scholar]
  • [8].Hamel E., Nicolakakis N., Aboulkassim T., Ongali B., Tong X.K. Oxidative stress and cerebrovascular dysfunction in mouse models of Alzheimer’s disease. Exp Physiol. 2008;93(1):116–120. doi: 10.1113/expphysiol.2007.038729. [DOI] [PubMed] [Google Scholar]
  • [9].Gackowski D., Rozalski R., Siomek A., Dziaman T., Nicpon K., Klimarczyk M., et al. Oxidative stress and oxidative DNA damage is characteristic for mixed Alzheimer disease/vascular dementia. J Neurol Sci. 2008;266(1–2):57–62. doi: 10.1016/j.jns.2007.08.041. [DOI] [PubMed] [Google Scholar]
  • [10].Price D.L., Sisodia S.S., Gandy S.E. Amyloid beta amyloidosis in Alzheimer’s disease. Curr Opin Neurol. 1995;8(4):268–274. doi: 10.1097/00019052-199508000-00004. [DOI] [PubMed] [Google Scholar]
  • [11].Juravleva E., Barbakadze T., Mikeladze D., Kekelidze T. Creatine enhances survival of glutamate-treated neuronal/glial cells, modulates Ras/NF-kappaB signaling, and increases the generation of reactive oxygen species. J Neurosci Res. 2005;79(1–2):224–230. doi: 10.1002/jnr.20291. [DOI] [PubMed] [Google Scholar]
  • [12].Rosenberger J., Petrovics G., Buzas B. Oxidative stress induces proorphanin FQ and proenkephalin gene expression in astrocytes through p38- and ERK-MAP kinases and NF-kappaB. J Neurochem. 2001;79:35–44. doi: 10.1046/j.1471-4159.2001.00520.x. [DOI] [PubMed] [Google Scholar]
  • [13].Swanson R.A., Ying W., Kauppinen T.M. Astrocyte influences on ischemic neuronal death. Curr Mol Med. 2004;4:193–205. doi: 10.2174/1566524043479185. [DOI] [PubMed] [Google Scholar]
  • [14].Gabriel C., Justicia C., Camins A., Planas A.M. Activation of nuclear factor-kappaB in the rat brain after transient focal ischemia. Brain Res Mol Brain Res. 1999;65:61–69. doi: 10.1016/S0169-328X(98)00330-1. [DOI] [PubMed] [Google Scholar]
  • [15].He X.L., Wang Y.H., Gao M., Li X.X., Zhang T.T., Du G.H. Baicalein protects rat brain mitochondria against chronic cerebral hypoperfusion-induced oxidative damage. Brain Res. 2009;1249:212–221. doi: 10.1016/j.brainres.2008.10.005. [DOI] [PubMed] [Google Scholar]
  • [16].Kasparová S., Brezová V., Valko M., Horecký J., Mlynárik V., Liptaj T., et al. Study of the oxidative stress in a rat model of chronic brain hypoperfusion. Neurochem Int. 2005;46:601–611. doi: 10.1016/j.neuint.2005.02.006. [DOI] [PubMed] [Google Scholar]
  • [17].Imre S.G., Fekete I., Farkas T. Increased proportion of docosahexanoic acid and high lipid peroxidation capacity in erythrocytes of stroke patients. Stroke. 1994;25:2416–2420. doi: 10.1161/01.str.25.12.2416. [DOI] [PubMed] [Google Scholar]
  • [18].Andersson A., Lindgren A., Hultberg B. Effect of thiol oxidation and thiol export from erythrocytes on determination of redox status of homocysteine and other thiols in plasma from healthy subjects and patients with cerebral infarction. Clin Chem. 1995;41:361–366. [PubMed] [Google Scholar]
  • [19].Endoh M., Maiese K., Wagner J. Expression of the inducible form of nitric oxide synthase by reactive astrocytes after transient global ischemia. Brain Res. 1994;651:92–100. doi: 10.1016/0006-8993(94)90683-1. [DOI] [PubMed] [Google Scholar]
  • [20].Acarin L., Peluffo H., Barbeito L., Castellano B., González B. Astroglial nitration after postnatal excitotoxic damage: correlation with nitric oxide sources, cytoskeletal, apoptotic and antioxidant proteins. J Neurotrauma. 2005;22(1):189–200. doi: 10.1089/neu.2005.22.189. [DOI] [PubMed] [Google Scholar]
  • [21].Morimoto N., Shimazawa M., Yamashima T., Hara H. Minocycline inhibits oxidative stress and decreases in vitro and in vivo ischemic neuronal damage. Brain Res. 2005;1044:8–15. doi: 10.1016/j.brainres.2005.02.062. [DOI] [PubMed] [Google Scholar]
  • [22].Cai Z.Y., Yan Y., Sun S.Q., Zhang J., Huang L.G., Yan N., et al. Minocycline attenuates cognitive impairment and restrains oxidative stress in the hippocampus of rats with chronic cerebral hypoperfusion. Neurosci Bull. 2008;24(5):305–313. doi: 10.1007/s12264-008-0324-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [23].Yrjänheikki J., Tikka T., Keinänen R., Goldsteins G., Chan P.H., Koistinaho J. A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci U S A. 1999;96:13496–13500. doi: 10.1073/pnas.96.23.13496. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [24].Kántor O., Schmitz C., Feiser J., Brasnjevic I., Korr H., Busto R., et al. Moderate loss of cerebellar Purkinje cells after chronic bilateral common carotid artery occlusion in rats. Acta Neuropathol. 2007;113(5):549–558. doi: 10.1007/s00401-007-0204-y. [DOI] [PubMed] [Google Scholar]
  • [25].Stirling D.P., Khodarahmi K., Liu J., McPhail L.T., McBride C.B., Steeves J.D., et al. Minocycline treatment reduces delayed oligodendrocyte death, attenuates axonal dieback, and improves functional outcome after spinal cord injury. J Neurosci. 2004;24:2182–2190. doi: 10.1523/JNEUROSCI.5275-03.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [26].Hewlett K.A., Corbett D. Delayed minocycline treatment reduces long-term functional deficits and histological injury in a rodent model of focal ischemia. Neuroscience. 2006;141:27–33. doi: 10.1016/j.neuroscience.2006.03.071. [DOI] [PubMed] [Google Scholar]
  • [27].Guo M., Cox B., Mahale S., Davis W., Carranza A., Hayes K., et al. Pre-ischemic exercise reduces matrix metalloproteinase-9 expression and ameliorates blood-brain barrier dysfunction in stroke. Neuroscience. 2008;151:340–351. doi: 10.1016/j.neuroscience.2007.10.006. [DOI] [PubMed] [Google Scholar]
  • [28].Mendes O., Kim H.T., Stoica G. Expression of MMP2, MMP9 and MMP3 in breast cancer brain metastasis in a rat model. Clin Exp Metastasis. 2005;22:237–246. doi: 10.1007/s10585-005-8115-6. [DOI] [PubMed] [Google Scholar]
  • [29].Sandya S., Sudhakaran P.R. Effect of glycosaminoglycans on matrix metalloproteinases in type II collagen-induced experimental arthritis. Exp Biol Med (Maywood) 2007;232:629–637. [PubMed] [Google Scholar]
  • [30].Weng Y.C., Kriz J. Differential neuroprotective effects of a minocycline-based drug cocktail in transient and permanent focal cerebral ischemia. Exp Neurol. 2007;204:433–442. doi: 10.1016/j.expneurol.2006.12.003. [DOI] [PubMed] [Google Scholar]
  • [31].Rosenberg G.A., Estrada E.Y., Mobashery S. Effect of synthetic matrix metalloproteinase inhibitors on lipopolysaccharide-induced blood-brain barrier opening in rodents: Differences in response based on strains and solvents. Brain Res. 2007;1133:186–192. doi: 10.1016/j.brainres.2006.11.041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [32].Xu L., Fagan S.C., Waller J.L., Edwards D., Borlongan C.V., Zheng J., et al. Low dose intravenous minocycline is neuroprotective after middle cerebral artery occlusion-reperfusion in rats. BMC Neurol. 2004;4:7. doi: 10.1186/1471-2377-4-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [33].Pattison L.R., Kotter M.R., Fraga D., Bonelli R.M. Apoptotic cascades as possible targets for inhibiting cell death in Huntington’s disease. J Neurol. 2006;253:1137–1142. doi: 10.1007/s00415-006-0198-8. [DOI] [PubMed] [Google Scholar]
  • [34].Choi Y., Kim H.S., Shin K.Y., Kim E.M., Kim M., Kim H.S., et al. Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer’s Disease models. Neurosci Res. 2007;58(S1):S81. doi: 10.1038/sj.npp.1301377. [DOI] [PubMed] [Google Scholar]
  • [35].Zhu S., Stavrovskaya I.G., Drozda M., Kim B.Y., Ona V., Li M., et al. Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature. 2002;417:74–78. doi: 10.1038/417074a. [DOI] [PubMed] [Google Scholar]
  • [36].Wang X., Zhu S., Drozda M., Zhang W., Stavrovskaya I.G., Cattaneo E., et al. Minocycline inhibits caspase-independent and -dependent mitochondrial cell death pathways in models of Huntington’s disease. Proc Natl Acad Sci U S A. 2003;100:10483–10487. doi: 10.1073/pnas.1832501100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [37].Wu D.C., Jackson-Lewis V., Vila M., Tieu K., Teismann P., Vadseth C., et al. Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J Neurosci. 2002;22:1763–1771. doi: 10.1523/JNEUROSCI.22-05-01763.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [38].Chu L.S., Fang S.H., Zhou Y., Yu G.L., Wang M.L., Zhang W.P., et al. Minocycline inhibits 5-lipoxygenase activation and brain inflammation after focal cerebral ischemia in rats. Acta Pharmacol Sin. 2007;28:763–772. doi: 10.1111/j.1745-7254.2007.00578.x. [DOI] [PubMed] [Google Scholar]
  • [39].Liu Z., Fan Y., Won S.J., Neumann M., Hu D., Zhou L., et al. Chronic treatment with minocycline preserves adult new neurons and reduces functional impairment after focal cerebral ischemia. Stroke. 2007;38:146–152. doi: 10.1161/01.STR.0000251791.64910.cd. [DOI] [PubMed] [Google Scholar]
  • [40].Yenari M.A., Xu L., Tang X.N., Qiao Y., Giffard R.G. Microglia potentiate damage to blood-brain barrier constituents: improvement by minocycline in vivo and in vitro. Stroke. 2006;37:1087–1093. doi: 10.1161/01.STR.0000206281.77178.ac. [DOI] [PubMed] [Google Scholar]
  • [41].Wang J.Y., Wen L.L., Huang Y.N., Chen Y.T., Ku M.C. Dual effects of antioxidants in neurodegeneration: direct neuroprotection against oxidative stress and indirect protection via suppression of gliamediated inflammation. Curr Pharm Des. 2006;12(27):3521–3533. doi: 10.2174/138161206778343109. [DOI] [PubMed] [Google Scholar]
  • [42].Liu X., Sullivan K.A., Madl J.E., Legare M., Tjalkens R.B. Manganese-induced neurotoxicity: the role of astroglial-derived nitric oxide in striatal interneuron degeneration. Toxicol Sci. 2006;91(2):521–531. doi: 10.1093/toxsci/kfj150. [DOI] [PubMed] [Google Scholar]
  • [43].Buskila Y., Farkash S., Hershfinkel M., Amitai Y. Rapid and reactive nitric oxide production by astrocytes in mouse neocortical slices. Glia. 2005;52(3):169–176. doi: 10.1002/glia.20217. [DOI] [PubMed] [Google Scholar]
  • [44].Jing R., Wilhelmsson U., Goodwill W., Li L., Pan Y., Pekny M., et al. Synemin is expressed in reactive astrocytes in neurotrauma and interacts differentially with vimentin and GFAP intermediate filament networks. J Cell Sci. 2007;120(Pt7):1267–1277. doi: 10.1242/jcs.03423. [DOI] [PubMed] [Google Scholar]
  • [45].Van Beek J., Chan P., Bernaudin M., Petit E., MacKenzie E.T., Fontaine M. Glial responses, clusterin, and complement in permanent focal cerebral ischemia in the mouse. Glia. 2000;31(1):39–50. doi: 10.1002/(SICI)1098-1136(200007)31:1<39::AID-GLIA40>3.0.CO;2-1. [DOI] [PubMed] [Google Scholar]

Articles from Neuroscience Bulletin are provided here courtesy of Springer

RESOURCES