Serine protease inhibitors: Novel therapeutic targets for stroke?

Although the thrombolytic activity of tissue-type plasminogen activator (t- PA) may be beneficial in the acute treatment of stroke, recent studies have suggested that this serine protease could also play a critical role in det ermining the extent of neuronal death after injury to the central nervous s ystem (CNS). This hypothesis is based on several experimental results: t-PA -deficient mice are resistant to excitotoxic neuronal death induced by the intrahippocampal injection of kainate; the infarct volume induced by occlus ion of the middle cerebral artery is reduced in t-PA knockout mice; and the intravenous injection of t-PA can under certain circumstances potentiate t he infarct volume in animals subjected to middle cerebral artery occlusion. In the CNS, the serine proteases have been identified to occur both in neur ons and glial cells. Their enzymatic activity regulates the balance between the accumulation and the degradation of the extracellular matrix. They are involved in many physiologic functions, ranging from synaptic outgrowth du ring perinatal development to plasticity in adults. For instance, thrombin and t-PA are known to modulate neurite outgrowth and tissue remodeling in t hp early stages nf development In the adult brain, t-PA may contribute to t he late phase of long-term potentiation and to the subsequent synaptic grow th in the hippocampal mossy fiber pathway. This balance between the degradation and accumulation of the extracellular matrix may also be integral to various pathologic processes involved in acu te brain injury. For example, compounds that modulate the activity of serin e proteases exhibit neuroprotective activity. Based on the above, numerous studies have focused on the production and modulation of the endogenously p roduced serine protease inhibitors, termed serpins, such as type 1 plasmino gen activator inhibitor, neuroser-pin, and protease nexin-1. In the present review, we will discuss the need to distinguish between the potentially neurotoxic effects of t-PA and its beneficial effect on reperfu sion. We will present data supporting the idea that the modulation of serin e protease activity may represent a novel and efficient strategy for the tr eatment of acute cerebral injury in humans.