Minocycline and Tissue-Type Plasminogen Activator for Stroke

Abstract

Background and Purpose-New treatment strategies for acute ischemic stroke must be evaluated in the context of effective reperfusion. Minocycline is a neuroprotective agent that inhibits proteolytic enzymes and therefore could potentially both inactivate the clot lysis effect and decrease the damaging effects of tissue-type plasminogen activator (t-PA). This study aimed to determine the effect of minocycline on t-PA clot lysis and t-PA-induced hemorrhage formation after ischemia. Methods-Fibrinolytic and amidolytic activities of t-PA were investigated in vitro over a range of clinically relevant minocycline concentrations. A suture occlusion model of 3-hour temporary cerebral ischemia in rats treated with t-PA and 2 different minocycline regimens was used. Blood-brain barrier basal lamina components, matrix metalloproteinases (MMPs), hemorrhage formation, infarct size, edema, and behavior outcome were assessed. Results-Minocycline did not affect t-PA fibrinolysis. However, minocycline treatment at 3 mg/kg IV decreased total protein expression of both MMP-2 (Pϭ0.0034) and MMP-9 (Pϭ0.001 for 92 kDa and Pϭ0.0084 for 87 kDa). It also decreased the incidence of hemorrhage (Pϭ0.019), improved neurologic outcome (Pϭ0.0001 for Bederson score and Pϭ0.0391 for paw grasp test), and appeared to decrease mortality. MMP inhibition was associated with decreased degradation in collagen IV and laminin-␣1 (Pϭ0.0001). Conclusions-Combination treatment with minocycline is beneficial in t-PA-treated animals and does not compromise clot lysis. These results also suggest that neurovascular protection by minocycline after stroke may involve direct protection of the blood-brain barrier during thrombolysis with t-PA. (Stroke. 2009;40:3028-3033.)

Soluble TNF Receptor 1-Secreting ex Vivo-Derived Dendritic Cells Reduce Injury After Stroke

“…For example, treatment with tissue plasminogen activator and minocycline after stroke resulted in a non-significant, 20% reduction in damage, but animals demonstrated a significant improvement in behavioral tests compared with controls. 28 Future studies should address the behavior of animals treated with anti-inflammatory exDCs to determine the extent of functional sparing.…”

Minocycline: A Novel Stroke Therapy

“…Minocycline doesn't affect the fibrinolytic and amidolytic properties of tPA [63]. Additionally, minocycline was able to extend tPA's time window to 6 hours in an embolic focal ischemia model in rats with similar infarct volumes to tPA treatment at 1 hour post-occlusion (and was also protective without tPA at 4 hours) [64].…”

“…Minocycline has been shown to decrease plasma MMP-9 levels in multiple studies [63,64]. In fact, an analysis of the Fagan et al [21] study showed that lower MMP-9 levels were found in those treated with tPA and minocycline [65].…”

Intravenous Minocycline in Acute Stroke

“…Minocycline, a semisynthetic tetracycline antibiotic, has shown promise as a neuroprotective agent in animal models with induced spinal cord injury, traumatic brain injury, and ischemic and hemorrhagic stroke. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] It is highly lipophilic, crosses the blood-brain barrier, and acts via several pathways to inhibit microglial activation, reduce migration of T-cells, attenuate neural apoptosis, suppress free radical production, decrease central nervous system expression of chemokines and their receptors, and inhibit matrix metalloproteinases, in particular matrix metalloproteinase-9. In experimental stroke studies, minocycline improved behavioral function and reduced infarction volume and hemorrhagic transformation.…”