Cevik Betul, Solmaz Volkan, Yigitturk Gurkan, Cavusoğlu Turker, Peker Gonul, Erbas Oytun
Department of Neurology, Faculty of Medicine, Gaziosmanpasa University, Tokat, Turkey.
Department of Neurology, Turhal State Hospital, Tokat, Turkey.
Adv Clin Exp Med. 2017 Jan-Feb;26(1):23-29. doi: 10.17219/acem/61044.
Although Alzheimer's disease (AD) is the most common age-related neurodegenerative disease and characterized by memory impairment, only symptomatic treatments are available.
Because recombinant human erythropoietin (rhEPO) has various neuroprotective effects and improves cognitive function in animal models of neurodegenerative disorders, we investigated the therapeutic effects of rhEPO in an intracerebroventricular (ICV)-streptozotocin (STZ) animal model of sporadic-AD.
A total of 24 Sprague-Dawley adult rats were divided into 4 groups of naive control (n = 6), sham-operated (n = 6), ICV-STZ + saline (n = 6) and ICV-STZ + rhEPO (n = 6). Twelve rats with Alzheimer's disease, induced by STZ injection (3 mg/kg) into both lateral ventricles using a stereotaxic frame (bilaterally ICV-STZ), were divided into 2 groups 5 days after the STZ injection: one treated with rhEPO 5000 (IU/kg/day, i.p.) and the other with 0.9% NaCl (1 mL/kg/day, i.p.) for 2 weeks. The sham-operated rats received bilaterally ICV-0.9% NaCl. No surgical operation or treatment was given to the naive-control animals. On day 20, a passive avoidance learning (PAL) test was used followed by sacrification and removal of the brain tissue in all animals. Brain TNF-α and ChAT levels were determined, and neurons in the hippocampal CA1 and CA3 regions were counted by Cresyl violet staining.
ICV-STZ was found to significantly shorten the latency time on the PAL, increase brain TNF-α level, and decrease brain ChAT activity and the number of neurons in the hippocampal CA1 and CA3 regions. On the other hand, rhEPO significantly attenuated all these detrimental effects induced by STZ.
RhEPO treatment significantly prevented the ICV-STZ-induced memory deficit by attenuating the hippocampal neuronal loss, neuroinflammation and cholinergic deficit in rats. This result suggests that rhEPO may be beneficial for treating AD.
尽管阿尔茨海默病（AD）是最常见的与年龄相关的神经退行性疾病，且以记忆障碍为特征，但目前仅有对症治疗方法。
由于重组人促红细胞生成素（rhEPO）具有多种神经保护作用，并能改善神经退行性疾病动物模型的认知功能，我们研究了rhEPO在散发性AD的脑室内（ICV）-链脲佐菌素（STZ）动物模型中的治疗效果。
将24只成年Sprague-Dawley大鼠分为4组：正常对照（n = 6）、假手术（n = 6）、ICV-STZ + 生理盐水（n = 6）和ICV-STZ + rhEPO（n = 6）。通过立体定位框架向双侧侧脑室注射STZ（3 mg/kg）诱导出12只阿尔茨海默病大鼠（双侧ICV-STZ），在注射STZ 5天后将其分为2组：一组用rhEPO（5000 IU/kg/天，腹腔注射）治疗，另一组用0.9%氯化钠（1 mL/kg/天，腹腔注射）治疗2周。假手术大鼠接受双侧ICV-0.9%氯化钠注射。正常对照动物不进行手术或治疗。在第20天，对所有动物进行被动回避学习（PAL）测试，随后处死并取出脑组织。测定脑肿瘤坏死因子-α（TNF-α）和胆碱乙酰转移酶（ChAT）水平，并用甲酚紫染色对海马CA1和CA3区域的神经元进行计数。
发现ICV-STZ显著缩短了PAL测试中的潜伏期，提高了脑TNF-α水平，并降低了脑ChAT活性以及海马CA1和CA3区域的神经元数量。另一方面，rhEPO显著减轻了STZ诱导的所有这些有害影响。
rhEPO治疗通过减轻大鼠海马神经元丢失、神经炎症和胆碱能缺陷，显著预防了ICV-STZ诱导的记忆缺陷。这一结果表明rhEPO可能对治疗AD有益。
