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

Swapan K. Ray

摘要

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.nnLiu 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.nnWang 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.nnAdibhatla 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.nnTitsworth 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).

机译：蛋白酶在中枢神经系统（CNS）损伤和疾病的发病机理中起重要作用。不同种类的蛋白酶，例如钙蛋白酶，半胱氨酸蛋白酶和组织蛋白酶，可以独立发挥作用，也可以协同作用来进行中枢神经系统细胞中关键蛋白的蛋白水解，从而导致细胞死亡和神经系统疾病[1-5]。蛋白水解活性的增加会导致中枢神经系统损伤（例如缺血性脑损伤（IBI），外伤性脑损伤（TBI），脊髓损伤（SCI））以及中枢神经系统疾病（例如阿尔茨海默氏病（AD），青光眼，帕金森氏病（PD））的神经退行性变）和多发性硬化症（MS）。此外，磷脂酶的活化可导致血脑屏障（BBB）的破坏，从而引起中枢神经系统疾病的发炎[6]。不同实验室的当代研究证实了蛋白酶和磷脂酶在这些和其他中枢神经系统疾病发病机理中的明确作用，并提出了预防蛋白酶和磷脂酶表达和活性的治疗策略[7，8]。我很荣幸地向读者提出这一卷的《中枢神经系统与神经系统疾病–药物靶标》，其中包括来自重要研究小组的9篇评论文章，描述了蛋白酶和磷脂酶在IBI，TBI，SCI，AD发病机理中的作用，PD和MS，也表明了预期的治疗策略。已经描述了促红细胞生成素（EPO）（一种糖蛋白激素和细胞因子）在治疗IBI，TBI和PD中的巨大潜力。 EPO介导的神经系统疾病改善的机制包括预防神经变性以及促进血管生成和神经发生。 EPO的治疗作用是通过在CNS细胞中表达的EPO受体介导的。 EPO的治疗功效包括减少缺血性梗塞和出血量以及神经元凋亡，并提高动物模型的存活率。令人鼓舞的是，一些在神经系统疾病中使用EPO的临床试验已显示出令人满意的结果。尽管仍需要评估新生儿和婴儿中EPO的安全性，但已证明在动物和成年人类患者中EPO的给药是安全的。迄今为止，可用数据表明EPO有望成为治疗神经系统疾病的有前途的治疗剂。已经解释了针对靶向细胞外基质蛋白水解对于预防由于使用美国食品和药物管理局（FDA）批准的唯一丝氨酸蛋白酶组织纤溶酶原激活剂（tPA）进行的缺血性卒中治疗所引起的出血并发症的重要性。尽管tPA的溶栓活性有助于实现血管再灌注和临床获益，但实际上，由于症状性颅内出血的高风险和较低的治疗时间窗（可最大程度地减少出血并发症），tPA仅在美国约2-5％的中风患者中使用。当前，正在探索组合策略以增加tPA的溶栓效力，以有益地进行再灌注，同时降低神经毒性和出血并发症。由于失调的细胞外蛋白酶会引发神经血管基质的破坏，从而破坏导致血肿和/或出血的BBB，因此针对神经血管单元内的细胞外基质蛋白水解可能为提高中风溶栓再灌注治疗的安全性和有效性提供了新的策略。 Hatcher和Hatcher警告说，丝氨酸蛋白酶tPA的溶栓活性与基质金属蛋白酶（MMPs）的抑制结合可能不是治疗缺血性中风的可行治疗策略。由于事实上可能通过激活MMPs破坏BBB，因此tPA作为中风的溶栓疗法也与出血和炎症的高风险相关。根据IBI的治疗时机，抑制MMP可能导致有益或有害作用。尽管MMP在中风的早期损伤阶段引起BBB的破坏和神经元损伤，但MMP在中风的后期修复阶段也有助于血管重构，血管生成，神经发生和轴突再生。任何针对MMP的治疗方案都必须考虑IBI早期和晚期阶段MMP的冲突作用。已经提出了分泌型磷脂酶A2（sPLA2）在中枢神经系统疾病，特别是SCI中的炎症中的作用。 sPLA2是一种脂肪分解酶，因此可以水解甘油磷脂以产生游离脂肪酸和溶血磷脂，它们是生物活性类花生酸和血小板活化因子（PAF）的前体。

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

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