Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Neurophysiology Laboratory, Neurosurgical Service, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Neurol Res. 2022 Oct;44(10):870-878. doi: 10.1080/01616412.2022.2056817. Epub 2022 Mar 29.
Lithium has numerous neuroplastic and neuroprotective effects in patients with stroke. Here, we evaluated whether delayed and short-term lithium treatment reduces brain infarction volume and improves electrophysiological and neurobehavioral outcomes following long-term recovery after cerebral ischemia and the possible contributions of lithium-mediated mechanisms of neuroplasticity.
Male Sprague Dawley rats were subjected to right middle cerebral artery occlusion for 90 min, followed by 28 days of recovery. Lithium chloride (1 mEq/kg) or vehicle was administered via intraperitoneal infusion once per day at 24 h after reperfusion onset. Neurobehavioral outcomes and somatosensory evoked potentials (SSEPs) were examined before and 28 days after ischemia-reperfusion. Brain infarction was assessed using Nissl staining. Primary cortical neuron cultures were exposed to oxygen-glucose deprivation (OGD) and treated with 2 or 20 μM lithium for 24 or 48 h; subsequent brain-derived neurotrophic factor (BDNF), growth-associated protein-43 (GAP-43), postsynaptic density-95 (PSD-95), and synaptosomal-associated protein-25 (SNAP-25) levels were analyzed using western blotting.
Compared to controls, lithium significantly reduced infarction volume in the ischemic brain and improved electrophysiological and neurobehavioral outcomes at 28 days post-insult. In cultured cortical neurons, BDNF, GAP-43, and PSD-95 expression were enhanced by 24- and 48-h treatment with lithium after OGD.
Lithium upregulates BDNF, GAP-43, and PSD-95, which partly accounts for its improvement of neuroplasticity and provision of long-term neuroprotection in the ischemic brain. BDNF: brain-derived neurotrophic factor; ECM: extracellular matrix; EDTA: ethylenediaminetetraacetic acid; GAP-43: growth-associated protein-43; GSK-3β: glycogen synthase kinase-3β; HBSS: Hank's balanced salt solution; LCBF: local cortical blood perfusion; LDF: laser-Doppler flowmetry; MCAO: middle cerebral artery occlusion; MMP: matrix metalloproteinase; NMDA: N-methyl-D-aspartate; NMDAR: N-methyl-D-aspartate receptor; OCT: optimal cutting temperature compound; OGD: oxygen-glucose deprivation; PSD-95: postsynaptic density-95; SDS: sodium dodecyl sulfate; SNAP-25: synaptosomal-associated protein-25; SSEP: somatosensory evoked potential.
锂对中风患者具有多种神经可塑性和神经保护作用。在这里，我们评估了延迟和短期锂治疗是否可以减少脑梗死体积，并改善脑缺血后长期恢复期间的电生理和神经行为结果，以及锂介导的神经可塑性机制的可能贡献。
雄性 Sprague Dawley 大鼠接受右侧大脑中动脉闭塞 90 分钟，然后进行 28 天的恢复。再灌注开始后 24 小时，通过腹腔内输注每天一次给予氯化锂（1 mEq/kg）或载体。在缺血再灌注前和 28 天后检查神经行为结果和体感诱发电位（SSEP）。使用尼氏染色评估脑梗死。将原代皮质神经元培养物暴露于氧葡萄糖剥夺（OGD）中，并分别用 2 或 20 μM 锂处理 24 或 48 小时；随后使用 Western blot 分析脑源性神经营养因子（BDNF）、生长相关蛋白-43（GAP-43）、突触后密度蛋白-95（PSD-95）和突触小体相关蛋白-25（SNAP-25）水平。
与对照组相比，锂显著减少了缺血大脑中的梗死体积，并改善了损伤后 28 天的电生理和神经行为结果。在培养的皮质神经元中，OGD 后 24 和 48 小时用锂处理可增强 BDNF、GAP-43 和 PSD-95 的表达。
锂上调 BDNF、GAP-43 和 PSD-95，这部分解释了它对缺血大脑中神经可塑性的改善和提供长期神经保护的作用。BDNF：脑源性神经营养因子；ECM：细胞外基质；EDTA：乙二胺四乙酸；GAP-43：生长相关蛋白-43；GSK-3β：糖原合酶激酶-3β；HBSS：Hank's 平衡盐溶液；LCBF：局部皮质血流灌注；LDF：激光多普勒流量测定；MCAO：大脑中动脉闭塞；MMP：基质金属蛋白酶；NMDA：N-甲基-D-天冬氨酸；NMDAR：N-甲基-D-天冬氨酸受体；OCT：最佳切割温度化合物；OGD：氧葡萄糖剥夺；PSD-95：突触后密度蛋白-95；SDS：十二烷基硫酸钠；SNAP-25：突触小体相关蛋白-25；SSEP：体感诱发电位。
