1. ¹Department of Neurobiology, AI Virtanen Institute for Molecular Sciences, University of Kuopio, Kuopio, Finland
2. ²Department of Biomedical NMR, AI Virtanen Institute for Molecular Sciences, University of Kuopio, Kuopio, Finland
3. ³Rega Institute for Medical Research, University of Leuven, Leuven, Belgium
4. ⁴Department of Oncology, Kuopio University Hospital Kuopio, Kuopio, Finland

Correspondence: Dr Jari Koistinaho, AI Virtanen Institute for Molecular Sciences, University of Kuopio, PO Box 1627, FIN-70211 Kuopio, Finland. E-mail: jari.koistinaho@uku.fi

Received 29 June 2004; Revised 3 August 2004; Accepted 31 August 2004; Published online 26 January 2005.

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.