Defence Institute of Physiology and Allied Sciences (DIPAS), Defence Research and Development Organization (DRDO), Lucknow Road, Timarpur, Delhi, 110 054, India.
School of Life Sciences (SLS), Jawaharlal Nehru University (JNU), New Mehrauli Road, Delhi, 110067, India.
Neuropharmacology. 2019 Mar 1;146:138-148. doi: 10.1016/j.neuropharm.2018.11.026. Epub 2018 Nov 23.
High-altitude hypoxia (HH) causes a spectrum of pathophysiological effects, including headaches, gliovascular dysfunction, and cognitive slowing. Previous studies have shown arachidonic acid (AA) metabolism due to cyclooxygenase (COX) activity before clinical manifestations in many diseases. AA metabolites, including COXs and prostaglandin E2 (PGE2), are well known immunomodulators. However, the relative contribution of COX-2 and COX-1 isoforms in the downstream proinflammatory responses and cognitive deficit in HH remains unknown. In the present study, AA metabolism via the COX pathway was investigated in Sprague Dawley rats after 0, 1, 3, and 7 days of HH exposure. Furthermore, we investigated the inflammatory response and cell-type-specific induction of both COXs. Our data revealed that AA metabolites peaked on day 3 of HH exposure. Interestingly, we observed endothelial and microglial activation on day 1, accompanied by an increase in the levels of proinflammatory cytokines, followed by astrocyte activation on day 3. We showed that the increase in COX activity during HH culminated in a significant increase in hippocampal inflammation, concomitant with spatial memory impairment and neuronal injury at day 7 of HH. We showed HH induced distinct COX-1 expression in endothelial and microglial cells, whereas it induced COX-2 expression predominantly in neurons, endothelial cells, and astrocytes. Notably, our data showed that the inhibition of COX-1 using valeryl salicylate had a prominent role in containing hippocampal inflammation by reducing microglial activation. COX-2 inhibition using celecoxib, along with COX-1 inhibition, ameliorated spatial memory impairment, astrocyte activation, and neurodegeneration after HH exposure.
高原缺氧（HH）会引起一系列病理生理效应，包括头痛、脑血管功能障碍和认知迟钝。以前的研究表明，在许多疾病中，环氧化酶（COX）活性导致花生四烯酸（AA）代谢先于临床表现。AA 代谢物，包括 COX 和前列腺素 E2（PGE2），是众所周知的免疫调节剂。然而，COX-2 和 COX-1 同工型在 HH 下游促炎反应和认知缺陷中的相对贡献仍不清楚。在本研究中，研究了 Sprague Dawley 大鼠在 HH 暴露 0、1、3 和 7 天后通过 COX 途径的 AA 代谢。此外，我们还研究了两种 COX 的炎症反应和细胞类型特异性诱导。我们的数据表明，AA 代谢物在 HH 暴露的第 3 天达到峰值。有趣的是，我们观察到内皮细胞和小胶质细胞在第 1 天激活，伴随着促炎细胞因子水平的增加，然后在第 3 天观察到星形胶质细胞激活。我们表明，HH 期间 COX 活性的增加最终导致海马体炎症显著增加，同时在 HH 的第 7 天出现空间记忆损伤和神经元损伤。我们表明 HH 在内皮细胞和小胶质细胞中诱导了明显的 COX-1 表达，而在神经元、内皮细胞和星形胶质细胞中主要诱导了 COX-2 表达。值得注意的是，我们的数据表明，使用戊酰水杨酸抑制 COX-1 通过减少小胶质细胞激活在控制海马体炎症方面发挥了重要作用。使用塞来昔布抑制 COX-2 以及抑制 COX-1，可改善 HH 暴露后空间记忆损伤、星形胶质细胞激活和神经退行性变。
