Department of Anesthesiology, University of Florida, Gainesville, FL, 32610-0254, USA.
Amino Acids. 2011 Apr;40(4):1151-8. doi: 10.1007/s00726-010-0739-4. Epub 2010 Sep 14.
The effects of the halogenated aromatic amino acid 3,5-dibromo-D: -tyrosine (3,5-DBr-D: -Tyr) were studied in rat models of stroke and epileptic seizures caused by middle cerebral artery occlusion (MCAo) through respective intracerebral injection of endothelin-1 (ET-1) and intraperitoneal (i.p.) injection of pentylenetetrazole (PTZ). 3,5-DBr-D: -Tyr was administered as three bolus injections (30 or 90 mg/kg, i.p.) starting at 30, 90, and 180 min after ET-1 administration or as a single bolus (30 mg/kg, i.p.) 15 min prior to PTZ administration. Neurological deficits and infarct volume were estimated 3 days after ET-1 administration and seizure score was assessed during the first 20 min after PTZ administration. The safety of 3,5-DBr-D: -Tyr was evaluated in control animals using telemetry to measure cardiovascular parameters and immunostaining to assess the level of activated caspase-3. 3,5-DBr-D: -Tyr significantly improved neurological function and reduced infarct volume in the brain even when the treatment was initiated 3 h after the onset of MCAo. 3,5-DBr-D: -Tyr significantly depressed PTZ-induced seizures. 3,5-DBr-D: -Tyr did not cause significant changes in arterial blood pressure, heart rate and spontaneous locomotor activity, nor did it increase the number of activated caspase-3 positive cells in the brain. We conclude that 3,5-DBr-D: -Tyr, by alleviating the deleterious effects of MCAo and PTZ in rats with no obvious intrinsic effects on cardiovascular parameters and neurodegeneration, exhibits promising potential as a novel therapeutic direction for stroke and seizures.
3,5-二溴-D：-酪氨酸（3,5-DBr-D：-Tyr）对大脑中动脉闭塞（MCAo）引起的中风和癫痫发作大鼠模型的影响，通过脑内注射内皮素-1（ET-1）和腹腔内（i.p.）注射戊四氮（PTZ）进行研究。3,5-DBr-D：-Tyr 以三次推注（30 或 90 mg/kg，i.p.）给药，分别在 ET-1 给药后 30、90 和 180 min 开始，或在 PTZ 给药前 15 min 给予单次推注（30 mg/kg，i.p.）。在 ET-1 给药后 3 天评估神经功能缺损和梗死体积，在 PTZ 给药后前 20 min 评估癫痫发作评分。通过遥测测量心血管参数和免疫染色评估激活的 caspase-3 水平，在对照动物中评估 3,5-DBr-D：-Tyr 的安全性。3,5-DBr-D：-Tyr 显著改善了中风后大脑的神经功能并减少了梗死体积，即使在 MCAo 发作后 3 小时开始治疗也是如此。3,5-DBr-D：-Tyr 显著抑制了 PTZ 诱导的癫痫发作。3,5-DBr-D：-Tyr 未引起动脉血压、心率和自发运动活动的显著变化，也未增加大脑中激活的 caspase-3 阳性细胞的数量。我们得出结论，3,5-DBr-D：-Tyr 通过减轻 MCAo 和 PTZ 在大鼠中的有害影响，并且对心血管参数和神经退行性变没有明显的内在影响，作为中风和癫痫发作的新的治疗方向具有广阔的应用前景。
