Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Dev Neurosci. 2010;32(5-6):480-7. doi: 10.1159/000323178. Epub 2011 Jan 12.
Traumatic brain injury (TBI) is the leading cause of mortality and morbidity in children and is characterized by reduced aerobic cerebral energy metabolism early after injury, possibly due to impaired activity of the pyruvate dehydrogenase complex. Exogenous acetyl-L-carnitine (ALCAR) is metabolized in the brain to acetyl coenzyme A and subsequently enters the tricarboxylic acid cycle. ALCAR administration is neuroprotective in animal models of cerebral ischemia and spinal cord injury, but has not been tested for TBI. This study tested the hypothesis that treatment with ALCAR during the first 24 h following TBI in immature rats improves neurologic outcome and reduces cortical lesion volume. Postnatal day 21-22 male rats were isoflurane anesthetized and used in a controlled cortical impact model of TBI to the left parietal cortex. At 1, 4, 12 and 23 h after injury, rats received ALCAR (100 mg/kg, intraperitoneally) or drug vehicle (normal saline). On days 3-7 after surgery, behavior was assessed using beam walking and novel object recognition tests. On day 7, rats were transcardially perfused and brains were harvested for histological assessment of cortical lesion volume, using stereology. Injured animals displayed a significant increase in foot slips compared to sham-operated rats (6 ± 1 SEM vs. 2 ± 0.2 on day 3 after trauma; n = 7; p < 0.05). The ALCAR-treated rats were not different from shams and had fewer foot slips compared to vehicle-treated animals (2 ± 0.4; n = 7; p< 0.05). The frequency of investigating a novel object for saline-treated TBI animals was reduced compared to shams (45 ± 5% vs. 65 ± 10%; n = 7; p < 0.05), whereas the frequency of investigation for TBI rats treated with ALCAR was not significantly different from that of shams but significantly higher than that of saline-treated TBI rats (68 ± 7; p < 0.05). The left parietal cortical lesion volume, expressed as a percentage of the volume of tissue in the right hemisphere, was significantly smaller in ALCAR-treated than in vehicle-treated TBI rats (14 ± 5% vs. 28 ± 6%; p < 0.05). We conclude that treatment with ALCAR during the first 24 h after TBI improves behavioral outcomes and reduces brain lesion volume in immature rats within the first 7 days after injury.
创伤性脑损伤（TBI）是儿童死亡和发病的主要原因，其特征是损伤后早期有氧脑能量代谢减少，可能是由于丙酮酸脱氢酶复合物活性受损所致。外源性乙酰左旋肉碱（ALCAR）在大脑中代谢为乙酰辅酶 A，随后进入三羧酸循环。ALCAR 在脑缺血和脊髓损伤的动物模型中具有神经保护作用，但尚未在 TBI 中进行测试。本研究假设在未成熟大鼠 TBI 后 24 小时内给予 ALCAR 治疗可改善神经功能结局并减少皮质病变体积。出生后第 21-22 天的雄性大鼠用异氟烷麻醉，并在左顶叶皮质进行 TBI 的控制性皮质撞击模型中使用。在损伤后 1、4、12 和 23 小时，大鼠接受 ALCAR（100mg/kg，腹腔内）或药物载体（生理盐水）。手术后第 3-7 天，使用束行走和新物体识别测试评估行为。在第 7 天，通过心脏灌注处死大鼠，并使用立体学评估皮质病变体积的组织学评估来收获大脑。与假手术大鼠相比，受伤动物的足滑明显增加（创伤后第 3 天 6 ± 1 SEM 与 2 ± 0.2；n = 7；p <0.05）。与 vehicle 处理的动物相比，ALCAR 处理的大鼠与 sham 没有区别，并且足滑的发生率较低（2 ± 0.4；n = 7；p <0.05）。与 sham 相比，TBI 动物对新物体的探索频率降低（45 ± 5%与 65 ± 10%；n = 7；p <0.05），而用 ALCAR 治疗的 TBI 大鼠的探索频率与 sham 没有显著差异，但明显高于用盐水治疗的 TBI 大鼠（68 ± 7；p <0.05）。用 ALCAR 治疗的 TBI 大鼠的左顶叶皮质病变体积，以右侧半球组织体积的百分比表示，明显小于 vehicle 治疗的 TBI 大鼠（14 ± 5%与 28 ± 6%；p <0.05）。我们得出结论，在 TBI 后 24 小时内给予 ALCAR 治疗可改善未成熟大鼠的行为结果，并在损伤后 7 天内降低其大脑病变体积。
