Chung Seung-Yun, Han Seol-Heui
Department of Pediatrics, Our Lady of Mercy Hospital, Catholic University Medical College, Inchon, Korea.
J Pineal Res. 2003 Mar;34(2):95-102. doi: 10.1034/j.1600-079x.2003.00010.x.
The antioxidant and anti-inflammatory effects of melatonin on kainic acid (KA)-induced neurodegeneration in the hippocampus were evaluated in vivo. It has been suggested that the pineal secretory product, melatonin, protects neurons in vitro from excitotoxicity mediated by kainate-sensitive glutamate receptors, and from oxidative stress-induced DNA damage and apoptosis. In this study, we injected 10 mg/kg kainate intraperitoneally (i.p.) into adult male Sprague-Dawley rats. This results in selective neuronal degeneration accompanied by intense microglial activation and triggers DNA damage in the hippocampus. We tested the in vivo efficacy of melatonin in preventing KA-induced neurodegeneration, oxidative stress and neuroinflammation in the hippocampus. Melatonin (2.5 mg/kg, i.p.) was given 20 min before, immediately after, and 1 and 2 hr after KA administration. Rats were killed 72 hr later and their hippocampi were examined for evidence of DNA damage (in situ dUTP end-labeling, i.e. TUNEL staining), cell viability (hematoxylin and eosin staining), and microglial (isolectin-B4 histochemistry) and astroglial responses (glial fibrillary acidic protein immunohistochemistry), as well as lipid peroxidation (4-hydroxynonenal immunohistochemistry). A cumulative dose of 10 mg/kg melatonin attenuates KA-induced neuronal death, lipid peroxidation, and microglial activation, and reduces the number of DNA breaks. A possible mechanism for melatonin-mediated neuroprotection involves its antioxidant and anti-inflammatory actions. The present data suggest that melatonin is potentially useful in the treatment of acute brain pathologies associated with oxidative stress-induced neuronal damage such as epilepsy, stroke, and traumatic brain injury.
在体内评估了褪黑素对海藻酸（KA）诱导的海马神经变性的抗氧化和抗炎作用。有人提出，松果体分泌产物褪黑素在体外可保护神经元免受由对海藻酸盐敏感的谷氨酸受体介导的兴奋毒性，以及氧化应激诱导的DNA损伤和细胞凋亡。在本研究中，我们向成年雄性Sprague-Dawley大鼠腹腔内注射10mg/kg海藻酸。这会导致选择性神经元变性，伴有强烈的小胶质细胞激活，并引发海马中的DNA损伤。我们测试了褪黑素在预防KA诱导的海马神经变性、氧化应激和神经炎症方面的体内功效。在给予KA前20分钟、给药后立即以及给药后1小时和2小时，腹腔注射褪黑素（2.5mg/kg）。72小时后处死大鼠，检查其海马中DNA损伤（原位dUTP末端标记，即TUNEL染色）、细胞活力（苏木精和伊红染色）、小胶质细胞（异凝集素-B4组织化学）和星形胶质细胞反应（胶质纤维酸性蛋白免疫组织化学）的证据，以及脂质过氧化（4-羟基壬烯醛免疫组织化学）。累积剂量为10mg/kg的褪黑素可减轻KA诱导的神经元死亡、脂质过氧化和小胶质细胞激活，并减少DNA断裂的数量。褪黑素介导神经保护的一种可能机制涉及其抗氧化和抗炎作用。目前的数据表明，褪黑素在治疗与氧化应激诱导的神经元损伤相关的急性脑疾病（如癫痫、中风和创伤性脑损伤）方面可能有用。
