Editorial [ Proteases and Phospholipases in CNS Disorders Guest Editor: Swapan K. Ray ]

Proteases play important roles in the pathogenesis of injuries and diseases of the central nervous system (CNS). Different classes of proteases such as calpains, caspases, and cathepsins may work independently or co-operatively to carry out the proteolysis of key proteins in the CNS cells leading to cell death and neurological problems [1-5]. Increased proteolytic activities contribute to neurodegeneration in CNS injuries such as ischemic brain injury (IBI), traumatic brain injury (TBI), spinal cord injury (SCI) and also in CNS diseases such as Alzheimer's disease (AD), glaucoma, Pakinson's disease (PD), and multiple sclerosis (MS). Moreover, activation of phospholipases can contribute to disruption of the blood-brain-barrier (BBB) causing inflammation in the CNS disorders [6]. Contemporary investigations in different laboratories have confirmed the unequivocal roles of proteases and phospholipases in the pathogenesis of these and other CNS disorders and suggested therapeutic strategies for prevention of expression and activity of proteases and phospholipases [7, 8]. I have the pleasure and privilege to put forward to the readers this volume of the CNS & Neurological Disorders - Drug Targets that contains nine review articles from prominent research groups delineating the roles of proteases and phospholipases in the pathogenesis of IBI, TBI, SCI, AD, PD, and MS and also indicating the prospective therapeutic strategies. Liu et al. have described the enormous potential of erythropoietin (EPO), a glycoprotein hormone and cytokine, for the treatment of IBI, TBI, and PD. The mechanism of EPO mediated amelioration of neurological disorders includes prevention of neurodegeneration and promotion of angiogenesis and neurogenesis. The therapeutic action of EPO is mediated through the EPO receptor, which is expressed in the CNS cells. Therapeutic efficacy of EPO includes decreases in ischemic infarct and hemorrhage volume, and neuronal apoptosis, and increases in survival rates in animal models. It is encouraging that some clinical trials with EPO in neurological diseases have shown desirable outcomes. Administration of EPO has proven to be safe in animals and adult human patients, although safety features of EPO in neonates and infants still need to be evaluated. So far, available data suggest that EPO is poised to be a promising therapeutic agent for the treatment of neurological disorders. Wang et al. have explained importance of targeting extracellular matrix proteolysis for prevention of hemorrhagic complications due to ischemic stroke therapy with the serine protease tissue plasminogen activator (tPA), the only stoke treatment approved by the US Food and Drug Administration (FDA). Although the thrombolytic activity of tPA helps achieving vascular reperfusion and clinical benefit, in reality tPA is administered in only about 2-5% of stroke patients in the US because of high risks of symptomatic intracranial hemorrhage and low therapeutic time window to minimize hemorrhagic complications. Currently, combination strategies are being explored to increase thrombolytic efficacy of tPA for beneficial reperfusion with simultaneous decrease in neurotoxicity and hemorrhagic complications. Because dysregulated extracellular proteases initiate the breakdown of neurovascular matrix to disrupt the BBB causing edema and/or hemorrhage, targeting the extracellular matrix proteolysis within the neurovascular unit may provide a new strategy for improving the safety and efficacy of the thrombolytic reperfusion therapy of stroke. Adibhatla and Hatcher have cautioned that combination of the thrombolytic activity of the serine protease tPA and the inhibition of the matrix metalloproteases (MMPs) may not be a viable therapeutic strategy for treatment of ischemic stroke. Use of tPA as a thrombolytic therapy for stroke is also associated with high risks of hemorrhage and inflammation due to the factual possibility of disruption of the BBB with activation of MMPs. Inhibition of MMPs may result in either beneficial or detrimental effects depending on timing of treatment of IBI. Although MMPs cause disruption of the BBB and neuronal damage during early injury phase of stroke, MMPs also contribute to vascular remodeling, angiogenesis, neurogenesis, and axonal regeneration during the later repair phase of stroke. Any treatment regimen targeted to MMPs must consider the conflicting effects of MMPs during the early and later phases of IBI. Titsworth et al. have presented the role of secretory phospholipase A2 (sPLA2) in inflammation in CNS disorders, especially in SCI. sPLA2 is a lipolytic enzyme and thus hydrolyzes the glycerophospholipids to produce free fatty acids and lysophospholipids, which are precursors of bioactive eicosanoids and platelet-activating factor (PAF).