Sharma Hari S, Feng Lianyuan, Lafuente José V, Muresanu Dafin F, Tian Zhenrong R, Patnaik Ranjana, Sharma Aruna
Laboratory of Cerebrovascular Research, Dept. of Surgical Sciences, Anesthesiology & Intensive Care medicine, University Hospital, Uppsala University, Frodingsgatan 12:28, SE-75185 Uppsala, Sweden.
CNS Neurol Disord Drug Targets. 2015;14(3):386-99. doi: 10.2174/1871527314666150318114335.
We have shown previously that heat stroke produced by whole body hyperthermia (WBH) for 4 h at 38°C in diabetic rats exacerbates blood-brain barrier breakdown, brain edema formation and neuronal cell injury as compared to healthy animals after identical heat exposure. In this combination of diabetes and WBH, normal therapeutic measures do not induce sufficient neuroprotection. Thus, we investigated whether nanowired mesenchymal cells (MSCs) when delivered systemically may have better therapeutic effects on brain damage in diabetic rats after WBH. Diabetes induced by streptozotocin administration (75 mg/kg, i.p, daily for 3 days) in rats resulted in clinical symptoms of the disease within 4 to 6 weeks (blood glucose level 20 to 30 mmoles/l as compared to saline control groups (4 to 6 mmoles/l). When subjected to WBH, these diabetic rats showed a 4-to 6-fold exacerbation of blood-brain barrier breakdown to Evans blue and radioiodine, along with brain edema formation and neuronal cell injury. Intravenous administration of rat MSCs (1x10(6)) to diabetic rats one week before WBH slightly reduced brain pathology, whereas TiO2 nanowired MSCs administered in an identical manner resulted in almost complete neuroprotection. On the other hand, MSCs alone significantly reduced brain pathology in saline-treated rats after WBH. These observations indicate that nanowired delivery of stem cells has superior therapeutic potential in heat stroke with diabetes, pointing to novel clinical perspectives in the future.
我们之前已经表明，与相同热暴露后的健康动物相比，糖尿病大鼠在38°C下全身热疗（WBH）4小时所产生的中暑会加剧血脑屏障破坏、脑水肿形成和神经元细胞损伤。在糖尿病与WBH的这种组合情况下，常规治疗措施无法诱导出足够的神经保护作用。因此，我们研究了全身递送纳米owired间充质细胞（MSCs）是否可能对WBH后的糖尿病大鼠脑损伤具有更好的治疗效果。给大鼠腹腔注射链脲佐菌素（75 mg/kg，每日一次，共3天）诱导的糖尿病在4至6周内导致了疾病的临床症状（血糖水平为20至30毫摩尔/升，而生理盐水对照组为4至6毫摩尔/升）。当接受WBH时，这些糖尿病大鼠对伊文思蓝和放射性碘的血脑屏障破坏加剧了4至6倍，同时伴有脑水肿形成和神经元细胞损伤。在WBH前一周给糖尿病大鼠静脉注射大鼠MSCs（1x10(6)）可略微减轻脑病理学变化，而以相同方式给药的TiO2纳米owired MSCs则几乎产生了完全的神经保护作用。另一方面，单独的MSCs可显著减轻WBH后生理盐水处理大鼠的脑病理学变化。这些观察结果表明，纳米owired递送干细胞在糖尿病性中暑中具有卓越的治疗潜力，为未来提供了新的临床前景。
