These findings identify albumin as another signaling molecule in addition to thrombin, which can activate MMP 9 in astrocytes. These results link albumin to the diverse cellular responses mediated by MMP 9, including neuronal injury, intracer ebral hemorrhage, epileptogenesis, necessary and dendritic remod eling. The implications of these data for the use of albumin in cerebral injury in clinical practice are complex. The Saline vs. Albumin Fluid Evaluation study identified a sig nificantly higher mortality rate in patients with severe TBI assigned to albumin compared with the saline group. In stroke subjects, the Albumin in Acute Stroke Trial showed a potential beneficial therapeutic effect for albumin, and the second part of the ALIAS trial has been started with more stringent exclusion criteria.

By contrast, pre clinical and clinical data indicate improved neurologic outcomes in patients with stroke who were treated with albumin. The contrasting effects of albumin in stroke and TBI re flect the complexity of the Inhibitors,Modulators,Libraries cellular responses to MMP 9. Activation Inhibitors,Modulators,Libraries of MMPs results in the degradation of the com ponents of the vascular basement membrane, leading to breakdown of the BBB. MMP 9 levels increase after acute brain injuries including status epilepticus, and are linked to increases in permeability of the BBB. In a mouse global cerebral ischemia model, neurologic injury was reduced in MMP 9 knockout mice, in part due to attenuated proteolysis of the BBB. Deletion of MMP 9, or inhibition of MMP 9 activity, improved neurologic function after TBI or stroke.

Further more, suppression of the increase in MMPs produced by closed head injury or by stroke results in a re duction of the brain edema and improved neurological re covery. However, other lines of evidence implicate MMP 9 in Inhibitors,Modulators,Libraries the mechanisms of epileptogenesis and synaptic remod eling. MMP 9 KO mice show increased resistance to pentylenetetrazole kindling induced epilepsy. Acting through an integrin B1 dependent pathway, MMP 9 pro duces changes in dendritic spine morphology. Our finding that albumin increases MMP 9 activation in astro cytes suggests another pathway linking albumin to the mechanisms of Inhibitors,Modulators,Libraries epileptogenesis mediated by the TGF B re ceptor. The link between activation of p38 MAPK, ERK and MMP 9 found in the present study is consistent with the well established role Inhibitors,Modulators,Libraries for MAPK pathways in the produc tion of MMP 9 in astrocytes in response to different stimuli.

Our data indicate a predominant requirement for activation of p38 Brefeldin A ATPase MAPK. By contrast, the activation of MMP 9 produced by exposure to thrombin acting via protease activated receptor 1, or stimulation of protein kinase C, is regulated by ERK1/2. This suggests that the specific MAPK involved in signal transduction to MMP 9 will depend on the in citing stimulus.