Salem VA Medical Center, Salem, VA, USA.
Med Hypotheses. 2010 Jun;74(6):1036-7. doi: 10.1016/j.mehy.2009.12.033. Epub 2010 Feb 8.
Hypoxia may result from hypoperfusion, as seen in the cardio-respiratory arrest. Subsequent to the acute neuronal damage, the delayed neuronal death ensues, and further neurons die within hours or days thereafter. An effective neuroprotective therapeutic agent should counteract one or, ideally, all well-established neuronal death pathways, i.e., excitotoxicity, oxidative stress and apoptosis. All these three mechanisms propagate through distinctive and mutual exclusive signal transduction pathway and contribute to the neuronal loss following the initial hypoxic-ischemic brain injury. Thus, the ideal therapeutic intervention against the hypoxic-ischemic neuronal injury should aim to prevent all three mechanisms of the neuronal death in a concerted effort. Recent studies demonstrated that intranasally administered leptin results in supra-physiological leptin levels at various regions of the brain (including hippocampus) within 30min of administration. We consider leptin to be an ideal neuroprotective agent, having targeted excitotoxicity (directly, by inhibiting AMDA and NMDA) oxidative stress (indirectly, by HIF1 mediation) and apoptosis (directly, by activating ERK 1/2 pathway) and hypothesize that intranasally administered leptin has neuroprotective effect against the neuronal hypoxic injury. If our hypothesis is confirmed, leptin administered before and/or soon after hypoxic injury, may be effective in minimizing the devastating sequelae of such event.
缺氧可能是由低灌注引起的，如心肺骤停时所见。急性神经元损伤后，会发生迟发性神经元死亡，随后数小时或数天内会有更多神经元死亡。有效的神经保护治疗剂应能对抗一种或理想情况下所有已确立的神经元死亡途径，即兴奋性毒性、氧化应激和细胞凋亡。这三种机制都通过独特且相互排斥的信号转导途径传播，并导致初始缺氧缺血性脑损伤后神经元丢失。因此，针对缺氧缺血性神经元损伤的理想治疗干预应旨在协同努力预防所有三种神经元死亡机制。最近的研究表明，鼻内给予瘦素可在给药后 30 分钟内使大脑（包括海马体）的各个区域的瘦素水平达到超生理水平。我们认为瘦素是一种理想的神经保护剂，它针对兴奋性毒性（直接通过抑制 AMDA 和 NMDA）、氧化应激（间接通过 HIF1 介导）和细胞凋亡（直接通过激活 ERK 1/2 途径），并假设鼻内给予瘦素对神经元缺氧损伤具有神经保护作用。如果我们的假设得到证实，在缺氧损伤之前和/或之后给予瘦素，可能有效减轻此类事件的破坏性后果。
