Preclinical Development, Research & Development, Hospira, Inc., USA.
J Toxicol Sci. 2014 Apr;39(2):251-62. doi: 10.2131/jts.39.251.
The neuroprotective effects of dexmedetomidine have been reported by many investigators; however its underlying mechanism to reduce neuronal injury during a prolonged anesthesia remains unclear. In this study, we investigated the neurotoxic effects of dexmedetomidine in fetal monkey brains. In the present study, we compare the neurotoxic effects of dexmedetomidine and ketamine, a general anesthetic with a different mechanism of action, in fetal cynomolgus monkeys. Twenty pregnant monkeys at approximate gestation day 120 were divided into 4 groups: non-treatment controls (Group 1); ketamine at 20 mg/kg intramuscularly followed by a 12-hr infusion at 20-50 mg/kg/hr (Group 2); dexmedetomidine at 3 µg/kg intravenously (i.v.) over 10 min followed by a 12-hr infusion at the human equivalent dose (HED) of 3 µg/kg/hr (Group 3); and dexmedetomidine at 30 µg/kg i.v. over 10 min followed by a 12-hr infusion at 30 µg/kg/hr, 10 times HED (Group 4). Blood samples from both dams and fetuses were measured for concentration of dexmedetomidine. Each fetus was perfusion-fixed, serial sections were cut through the frontal cortex, and stained to detect for apoptosis (activated caspase 3 and TUNEL) and neurodegeneration (silver stain). In utero treatment with ketamine resulted in marked apoptosis and degeneration primarily in layers I and II of the frontal cortex. In contrast, fetal brains from animals treated with dexmedetomidine showed none to minimal neuroapoptotic or neurodegenerative lesions at both low- and high-dose treatments. Plasma levels confirmed systemic exposure of dexmedetomidine in both dams and fetuses. In conclusion, these results demonstrate that dexmedetomidine at both low-dose (HED) and high-dose (10 times HED) does not induce apoptosis in the frontal cortex (layers I, II, and III) of developing brain of cynomolgus monkeys.
许多研究人员已经报道了右美托咪定的神经保护作用;然而，其在长时间麻醉期间减少神经元损伤的潜在机制尚不清楚。在这项研究中，我们研究了右美托咪定在胎猴大脑中的神经毒性作用。在本研究中，我们比较了右美托咪定和氯胺酮的神经毒性作用，氯胺酮是一种具有不同作用机制的全身麻醉剂。20 只妊娠 120 天左右的猕猴分为 4 组:非治疗对照组(第 1 组);肌肉注射氯胺酮 20mg/kg，然后以 20-50mg/kg/hr 的速度持续输注 12 小时(第 2 组);静脉注射右美托咪定 3μg/kg(第 3 组);静脉注射右美托咪定 30μg/kg(第 4 组)。从母体和胎儿中抽取血样，检测右美托咪定的浓度。每个胎儿均经灌注固定，连续切片穿过额皮质，并进行凋亡(活化的 caspase 3 和 TUNEL)和神经退行性变(银染色)检测。宫内给予氯胺酮治疗可导致明显的凋亡和变性，主要发生在额皮质的 I 和 II 层。相比之下，用右美托咪定治疗的胎儿大脑在低剂量和高剂量治疗下均未显示出神经凋亡或神经退行性病变。血浆水平证实了右美托咪定在母体和胎儿中的全身暴露。总之，这些结果表明，低剂量(人等效剂量)和高剂量(10 倍人等效剂量)的右美托咪定均不会引起食蟹猴发育中大脑额皮质(I、II 和 III 层)的细胞凋亡。
