Minocycline Protects against Permanent Cerebral Ischemia in Wild Type but Not in Matrix Metalloprotease-9-Deficient Mice

Abstract

Minocycline is protective in models of transient middle cerebral artery occlusion (MCAO). We studied whether minocycline and doxycycline, another tetracycline derivative, provide protection in permanent MCAO. Because minocycline inhibits matrix metalloprotease-9 (MMP-9), we also compared minocycline's protective effect in wild type (wt) and MMP-9 knock-out (ko) mice. Wt FVB/N, Balb/C, and two lines of MMP-9 ko and their wt C57Bl/6 control mice were subjected to 24- or 72-hour permanent MCAO. Drug administration was started either 12 hours before or 2 hours after the onset of MCAO. Infarct size was determined by triphenyltetrazolium staining or T2-weighted MRI. Zymography was used to study the expression of MMPs. In wt strains, tetracycline treatments started before MCAO reduced the infarct size by 25% to 50%, whereas the treatment started after MCAO was not protective. Minocycline inhibited ischemia-provoked pro-MMP-9 induction in wt mice, but was not protective in MMP-9 ko mice. Pro-MMP-2 was induced by MCAO in wt and MMP-9 ko mice. MCAO-induced pro-MMP-2 was downregulated by minocycline treatment in wt mice but remained in MMP-9 ko mice at the same level as in saline-treated wt mice. Tetracyclines are protective in permanent MCAO when the treatment is started before the insult. Minocycline may provide protection by interfering with MMPs.

Impaired Vascular Remodeling after Endothelial Progenitor Cell Transplantation in MMP9-Deficient Mice Suffering Cortical Cerebral Ischemia

“…7,8 Although pharmacological or immunological inhibition of MMP9 has proven to be neuroprotective, as evidenced by a decreased infarct size, discrepant results have been reported in MMP9-deficient mice. 8,9,11 These discrepancies could be attributed to the use of different experimental models of cerebral ischemia (proximal and distal MCA occlusion in the presence or absence of reperfusion) and/or to the use of different techniques to assess the lesion extension (tissue staining for 2,3,5-triphenyl-tetrazolium-chloride). The present study includes the largest sample size of WT and MMP9/KO mice used to evaluate the infarct volume (n = 16 per group), and our results support the previous findings showing that MMP9 inhibition reduces the inflammatory response, blood-brain barrier disruption, and the development of edema after cerebral ischemia.…”

“…8 Published studies on MMP9-deficient mice have demonstrated the pivotal role of this protease in infarct expansion, 9,10 although the results remain controversial. 11 Our core hypothesis is that tissue MMP9 is a key protease required for an effective and successful cell-based therapy to potentiate vascular remodeling. In this study, we investigated the effects of brain MMP9 deficiency on the cerebral ischemia after EPC-based treatment to potentiate angio-vasculogenesis.…”

Microglial Activation in Stroke: Therapeutic Targets

“…20 Minocycline protects against permanent cerebral ischemia in wild-type but not in MMP-9 -deficient mice, suggesting this as a mechanism by which minocycline exerts its neuroprotective effect. 48 Doxycycline also suppresses postischemic MMP-9 activity, 49 and both direct and indirect pathways for MMP-9 inhibition by minocycline and doxycycline have been described. 50,51 …”

Inhibitory Effects of Coptis japonica Alkaloids on the LPS-Induced Activation of BV2 Microglial Cells

“…Several researchers including us reported the essential role of MAPK pathway in the regulation of MMP-9 and iNOS expression in immunostimulated glial cells (Fiebich et al, 2004;Koistinaho et al, 2005;Shin et al, 2007). Therefore, we investigated whether C. japonica alkaloids affect ERK1/2 phosphorylation by Western blot.…”