Van Eldik Linda J, Thompson Wendy L, Ralay Ranaivo Hantamalala, Behanna Heather A, Martin Watterson D
Center for Drug Discovery and Chemical Biology, Northwestern University Chicago, Illinois 60611, USA.
Int Rev Neurobiol. 2007;82:277-96. doi: 10.1016/S0074-7742(07)82015-0.
Inflammation is the body's defense mechanism against threats such as bacterial infection, undesirable substances, injury, or illness. The process is complex and involves a variety of specialized cells that mobilize to neutralize and dispose of the injurious material so that the body can heal. In the brain, a similar inflammation process occurs when glia, especially astrocytes and microglia, undergo activation in response to stimuli such as injury, illness, or infection. Like peripheral immune cells, glia in the central nervous system also increase production of inflammatory cytokines and neutralize the threat to the brain. This brain inflammation, or neuroinflammation, is generally beneficial and allows the brain to respond to changes in its environment and dispose of damaged tissue or undesirable substances. Unfortunately, this beneficial process sometimes gets out of balance and the neuroinflammatory process persists, even when the inflammation-provoking stimulus is eliminated. Uncontrolled chronic neuroinflammation is now known to play a key role in the progression of damage in a number of neurodegenerative diseases. Thus, overproduction of proinflammatory cytokines offers a pathophysiology progression mechanism that can be targeted in new therapeutic development for multiple neurodegenerative diseases. We summarize in this chapter the evidence supporting proinflammatory cytokine upregulation as a therapeutic target for neurodegenerative disorders, with a focus on Alzheimer's disease. In addition, we discuss the drug discovery process and two approaches, function-driven and target-based, that show promise for development of neuroinflammation-targeted, disease-modifying therapeutics for multiple neurodegenerative disorders.
炎症是人体针对细菌感染、有害物质、损伤或疾病等威胁的防御机制。这个过程很复杂，涉及多种专门的细胞，这些细胞会动员起来中和并清除有害物质，以便身体能够愈合。在大脑中，当神经胶质细胞，尤其是星形胶质细胞和小胶质细胞，对损伤、疾病或感染等刺激做出反应而被激活时，会发生类似的炎症过程。与外周免疫细胞一样，中枢神经系统中的神经胶质细胞也会增加炎症细胞因子的产生，并中和对大脑的威胁。这种脑部炎症，即神经炎症，通常是有益的，它能使大脑对其环境变化做出反应，并清除受损组织或有害物质。不幸的是，这个有益的过程有时会失衡，即使引发炎症的刺激因素被消除，神经炎症过程仍会持续。现在已知不受控制的慢性神经炎症在多种神经退行性疾病的损伤进展中起关键作用。因此，促炎细胞因子的过度产生提供了一种病理生理学进展机制，可作为多种神经退行性疾病新治疗方法开发的靶点。在本章中，我们总结了支持将促炎细胞因子上调作为神经退行性疾病治疗靶点的证据，重点是阿尔茨海默病。此外，我们还讨论了药物发现过程以及功能驱动和基于靶点这两种方法，它们有望开发出针对多种神经退行性疾病的、以神经炎症为靶点的疾病修饰疗法。
