Lee Choong-Hyun, Ahn Ji Hyeon, Won Moo-Ho
Department of Pharmacy, College of Pharmacy, Dankook University, Cheonan 31116, Republic of Korea.
Department of Physical Therapy, College of Health Science, Youngsan University, Yangsan 50510, Republic of Korea.
Int J Mol Sci. 2025 May 25;26(11):5079. doi: 10.3390/ijms26115079.
Brain ischemia-reperfusion (IR) injury is a critical pathological process that leads to extensive neuronal death, with hippocampal pyramidal cells, particularly those in the cornu Ammonis 1 (CA1) subfield, being highly vulnerable. Until now, human olfactory mitral cell resistance to IR injury has not been directly studied, but olfactory dysfunction in humans is frequently reported in systemic vascular conditions such as ischemic heart failure and may serve as an early clinical marker of neurological or cardiovascular disease. Mitral cells, the principal neurons of the olfactory bulb (OB), exhibit remarkable resistance to IR injury, suggesting the presence of unique molecular adaptations that support their survival under ischemic stress. Several factors may contribute to the resilience of mitral cells. They have a lower susceptibility to excitotoxicity, mitigating the harmful effects of excessive glutamate signaling. Additionally, they maintain efficient calcium homeostasis, preventing calcium overload-a major trigger for cell death in vulnerable neurons. Mitral cells may also express high baseline levels of antioxidant enzymes and their activities, counteracting oxidative stress. Their robust mitochondrial function enhances energy production and reduces susceptibility to metabolic failure. Furthermore, neuroprotective signaling pathways, including phosphatidylinositol-3-kinase (PI3K)/Akt, mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), and nuclear factor erythroid-2-related factor 2 (Nrf2)-mediated antioxidative responses, further bolster their resistance. In addition to these intrinsic mechanisms, the unique microvascular architecture and metabolic support within the olfactory bulb provide an extra layer of protection. By comparing mitral cells to ischemia-sensitive neurons, key vulnerabilities-such as oxidative stress, excitotoxicity, calcium dysregulation, and mitochondrial dysfunction-can be identified and potentially mitigated in other brain regions. Understanding these molecular determinants of neuronal survival may offer valuable insights for developing novel neuroprotective strategies to combat IR injury in highly vulnerable areas, such as the hippocampus and cortex.
脑缺血再灌注（IR）损伤是一个关键的病理过程，会导致大量神经元死亡，海马锥体细胞，尤其是海马1区（CA1）亚区的细胞，极易受损。到目前为止，尚未直接研究人类嗅球内侧细胞对IR损伤的抗性，但在诸如缺血性心力衰竭等全身性血管疾病中，经常报告人类存在嗅觉功能障碍，这可能是神经或心血管疾病的早期临床标志物。嗅球内侧细胞是嗅球（OB）的主要神经元，对IR损伤表现出显著的抗性，这表明存在独特的分子适应性变化来支持它们在缺血应激下存活。有几个因素可能有助于嗅球内侧细胞的恢复能力。它们对兴奋性毒性的敏感性较低，可减轻过量谷氨酸信号的有害影响。此外，它们维持有效的钙稳态，防止钙超载——这是易损神经元细胞死亡的主要触发因素。嗅球内侧细胞还可能表达高水平的抗氧化酶及其活性，以对抗氧化应激。它们强大的线粒体功能增强了能量产生，并降低了对代谢衰竭的易感性。此外，神经保护信号通路，包括磷脂酰肌醇-3-激酶（PI3K）/蛋白激酶B（Akt）、丝裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/ERK）以及核因子E2相关因子2（Nrf2）介导的抗氧化反应，进一步增强了它们的抗性。除了这些内在机制外，嗅球内独特的微血管结构和代谢支持提供了额外的保护。通过将嗅球内侧细胞与对缺血敏感的神经元进行比较，可以识别关键的脆弱性因素，如氧化应激、兴奋性毒性、钙调节异常和线粒体功能障碍，并有可能在其他脑区减轻这些因素的影响。了解这些神经元存活的分子决定因素，可能为开发新的神经保护策略提供有价值的见解，以对抗海马体和皮层等高度易损区域的IR损伤。
