Hook Vivian Y H
Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA.
BioDrugs. 2006;20(2):105-19. doi: 10.2165/00063030-200620020-00005.
The nervous system represents a key area for development of novel therapeutic agents for the treatment of neurological and neurodegenerative diseases. Recent research has demonstrated the critical importance of neuroproteases for the production of specific peptide neurotransmitters and for the production of toxic peptides in major neurodegenerative diseases that include Alzheimer, Huntington, and Parkinson diseases. This review illustrates the successful criteria that have allowed identification of proteases responsible for converting protein precursors into active peptide neurotransmitters, consisting of dual cysteine protease and subtilisin-like protease pathways in neuroendocrine cells. These peptide neurotransmitters are critical regulators of neurologic conditions, including analgesia and cognition, and numerous behaviors. Importantly, protease pathways also represent prominent mechanisms in neurodegenerative diseases, especially Alzheimer, Huntington, and Parkinson diseases. Recent studies have identified secretory vesicle cathepsin B as a novel beta-secretase for production of the neurotoxic beta-amyloid (Abeta) peptide of Alzheimer disease. Moreover, inhibition of cathepsin B reduces Abeta peptide levels in brain. These neuroproteases potentially represent new drug targets that should be explored in future pharmaceutical research endeavors for drug discovery.
神经系统是开发用于治疗神经和神经退行性疾病的新型治疗药物的关键领域。最近的研究表明，神经蛋白酶对于特定肽类神经递质的产生以及在包括阿尔茨海默病、亨廷顿病和帕金森病在内的主要神经退行性疾病中有毒肽的产生至关重要。本综述阐述了成功鉴定负责将蛋白质前体转化为活性肽类神经递质的蛋白酶的标准，这些蛋白酶存在于神经内分泌细胞中，包括双半胱氨酸蛋白酶和枯草杆菌蛋白酶样蛋白酶途径。这些肽类神经递质是神经状态的关键调节因子，包括镇痛和认知以及多种行为。重要的是，蛋白酶途径也是神经退行性疾病，尤其是阿尔茨海默病、亨廷顿病和帕金森病中的突出机制。最近的研究已将分泌性囊泡组织蛋白酶B鉴定为产生阿尔茨海默病神经毒性β淀粉样蛋白（Aβ）肽的新型β分泌酶。此外，抑制组织蛋白酶B可降低脑中Aβ肽水平。这些神经蛋白酶可能代表新的药物靶点，应在未来的药物研发探索中加以研究。
