title: Sequential Therapy with Minocycline and Candesartan Improves Long-Term Recovery After Experimental Stroke.
abstract: Minocycline and candesartan have both shown promise as candidate therapeutics in ischemic stroke, with multiple, and somewhat contrasting, molecular mechanisms. Minocycline is an anti-inflammatory, antioxidant, and anti-apoptotic agent and a known inhibitor of matrix metalloproteinases (MMPs). Yet, minocycline exerts antiangiogenic effects both in vivo and in vitro. Candesartan promotes angiogenesis and activates MMPs. Aligning these therapies with the dynamic processes of injury and repair after ischemia is likely to improve success of treatment. In this study, we hypothesize that opposing actions of minocycline and candesartan on angiogenesis, when administered simultaneously, will reduce the benefit of candesartan treatment. Therefore, we propose a sequential combination treatment regimen to yield a better outcome and preserve the proangiogenic potential of candesartan. In vitro angiogenesis was assessed using human brain endothelial cells. In vivo, Wistar rats subjected to 90-min middle cerebral artery occlusion (MCAO) were randomized into four groups: saline, candesartan, minocycline, and sequential combination of minocycline and candesartan. Neurobehavioral tests were performed 1, 3, 7, and 14 days after stroke. Brain tissue was collected on day 14 for assessment of infarct size and vascular density. Minocycline, when added simultaneously, decreased the proangiogenic effect of candesartan treatment in vitro. Sequential treatment, however, preserved the proangiogenic potential of candesartan both in vivo and in vitro, improved neurobehavioral outcome, and reduced infarct size. Sequential combination therapy with minocycline and candesartan improves long-term recovery and maintains candesartan's proangiogenic potential.
authors.affiliation: Charlie Norwood VA Medical Center, Augusta, GA, USA.
authors.forename: Sahar
authors.initials: S
authors.lastname: Soliman
authors.forename: Tauheed
authors.initials: T
authors.lastname: Ishrat
authors.forename: Abdelrahman Y
authors.initials: AY
authors.lastname: Fouda
authors.forename: Ami
authors.initials: A
authors.lastname: Patel
authors.forename: Bindu
authors.initials: B
authors.lastname: Pillai
authors.forename: Susan C
authors.initials: SC
authors.lastname: Fagan
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D020520:Brain Infarction / Q000209:etiology / Q000517:prevention & control; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D020214:Cerebrovascular Trauma; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology; D004847:Epithelial Cells / Q000187:drug effects; D006801:Humans; D006836:Hydro-Lyases / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008911:Minocycline / Q000494:pharmacology / Q000627:therapeutic use*; D009043:Motor Activity / Q000502:physiology; D053580:Muscle Strength; D011597:Psychomotor Performance / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; D042461:Vascular Endothelial Growth Factor A; D020782:Matrix Metalloproteinases; D006836:Hydro-Lyases; C045581:lactate dehydratase; D008911:Minocycline; C081643:candesartan