Andreasson K I, Savonenko A, Vidensky S, Goellner J J, Zhang Y, Shaffer A, Kaufmann W E, Worley P F, Isakson P, Markowska A L
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
J Neurosci. 2001 Oct 15;21(20):8198-209. doi: 10.1523/JNEUROSCI.21-20-08198.2001.
The cyclooxygenases catalyze the rate-limiting step in the formation of prostaglandins from arachidonic acid and are the pharmacological targets of (NSAIDs). In brain, cyclooxygenase-2 (COX-2), the inducible isoform of cyclooxygenase, is selectively expressed in neurons of the cerebral cortex, hippocampus, and amygdala. As an immediate-early gene, COX-2 is dramatically and transiently induced in these neurons in response to NMDA receptor activation. In models of acute excitotoxic neuronal injury, elevated and sustained levels of COX-2 have been shown to promote neuronal apoptosis, indicating that upregulated COX-2 activity is injurious to neurons. COX-2 may also contribute to the development of Alzheimer's disease, for which early administration of NSAIDs is protective against development of the disease. To test the effect of constitutively elevated neuronal COX-2, transgenic mice were generated that overexpressed COX-2 in neurons and produced elevated levels of prostaglandins in brain. In cross-sectional behavioral studies, COX-2 transgenic mice developed an age-dependent deficit in spatial memory at 12 and 20 months but not at 7 months and a deficit in aversive behavior at 20 months of age. These behavioral changes were associated with a parallel age-dependent increase in neuronal apoptosis occurring at 14 and 22 months but not at 8 months of age and astrocytic activation at 24 months of age. These findings suggest that neuronal COX-2 may contribute to the pathophysiology of age-related diseases such as Alzheimer's disease by promoting memory dysfunction, neuronal apoptosis, and astrocytic activation in an age-dependent manner.
环氧化酶催化花生四烯酸生成前列腺素的限速步骤，是（非甾体抗炎药）的药理学靶点。在大脑中，环氧化酶-2（COX-2）作为环氧化酶的诱导型同工酶，在大脑皮层、海马体和杏仁核的神经元中选择性表达。作为一种即刻早期基因，COX-2在这些神经元中因N-甲基-D-天冬氨酸（NMDA）受体激活而显著且短暂地被诱导。在急性兴奋性毒性神经元损伤模型中，已表明COX-2水平升高并持续存在会促进神经元凋亡，这表明COX-2活性上调对神经元有害。COX-2也可能促成阿尔茨海默病的发展，早期给予非甾体抗炎药对该病的发展具有保护作用。为了测试神经元COX-2持续升高的影响，构建了在神经元中过表达COX-2并使大脑中前列腺素水平升高的转基因小鼠。在横断面行为研究中，COX-2转基因小鼠在12个月和20个月时出现年龄依赖性空间记忆缺陷，但在7个月时未出现，在20个月大时出现厌恶行为缺陷。这些行为变化与在14个月和22个月时出现但在8个月时未出现的年龄依赖性神经元凋亡平行增加以及在24个月时出现的星形细胞激活有关。这些发现表明，神经元COX-2可能通过以年龄依赖性方式促进记忆功能障碍、神经元凋亡和星形细胞激活，从而促成阿尔茨海默病等与年龄相关疾病的病理生理学过程。
