1. ¹Department of Anesthesia and Perioperative Care, University of California, San Francisco, California, USA
2. ²Center for Cerebrovascular Research, University of California, San Francisco, California, USA
3. ³Department of Biopharmaceutical Sciences, University of California, San Francisco, California, USA
4. ⁴Department of Clinical Pharmacy, University of California, San Francisco, California, USA
5. ⁵Department of Neurological Surgery, University of California, San Francisco, California, USA
6. ⁶Department of Neurology, University of California, San Francisco, California, USA

Correspondence: Dr WL Young, Center for Cerebrovascular Research, University of California, 1001 Potrero Avenue, Room 3C-38, San Francisco, CA 94110, USA. E-mail: ccr@anesthesia.ucsf.edu

Received 5 August 2005; Revised 2 November 2005; Accepted 22 November 2005; Published online 4 January 2006.

Abstract

Brain arteriovenous malformations (BAVMs) are a potentially life-threatening disorder. Matrix metalloproteinase (MMP)-9 activity was greatly increased in BAVM tissue specimens. Doxycycline was shown to decrease cerebral MMP-9 activities and angiogenesis induced by vascular endothelial growth factor (VEGF). In the present study, we determined the dose–response effects of doxycycline and minocycline on cerebral MMP-9 using our mouse model with VEGF focal hyperstimulation delivered with adenoviral vector (AdVEGF) in the brain. Mice were treated with doxycycline or minocycline, respectively, at 1, 5, 10, 30, 50, or 100 mg/kg/day through drinking water for 1 week. Our results have shown that MMP-9 messenger ribonucleic acid (mRNA) expression was inhibited by doxycycline starting at 10 mg/kg/day (P<0.02). Minocycline showed more potent inhibition on MMP-9 mRNA expression, starting at 1 (P<0.005) and further at more than 30 (P<0.001) mg/kg/day. At the enzymatic activity level, doxycycline started to suppress MMP-9 activity at 5 mg/kg/day (P<0.001), while minocycline had an effect at a lower dose, 1 mg/kg/day (P<0.02). The inhibition of cerebral MMP-9 mRNA and activity were highly correlated with drug levels in the brain tissue. We also assessed the potential relevant signaling pathway in vitro to elucidate the mechanisms underlying the MMP-9 inhibition by tetracyclines. In vitro, minocycline, but not doxycycline, inhibits MMP-9, at least in part, via the extracellular signaling-related kinase 1/2 (ERK1/2)-mediated pathway. This study provided the evidence that the tetracyclines inhibit stimulated cerebral MMP-9 at multiple levels and are effective at very low doses, offering great potential for therapeutic use.