Kline Anthony E, Massucci Jaime L, Marion Donald W, Dixon C Edward
The Brain Trauma Research Center, Department of Neurosurgery, University of Pittsburgh, Pennsylvania 15260, USA.
J Neurotrauma. 2002 Apr;19(4):415-25. doi: 10.1089/08977150252932370.
Cognitive impairments are pervasive and persistent sequelae of human traumatic brain injury (TBI). In vivo models of TBI, such as the controlled cortical impact (CCI) and fluid percussion (FP), are utilized extensively to produce deficits reminiscent of those seen clinically with the hope that empirical study will lead to viable therapeutic interventions. Both CCI and FP produce spatial learning acquisition deficits, but only the latter has been reported to impair working memory in rats tested in the Morris water maze (MWM). We hypothesized that a CCI injury would impair working memory similarly to that produced by FP, and that delayed and chronic treatment with the D2 receptor agonist bromocriptine would attenuate both working memory and spatial learning acquisition deficits. To test these hypotheses, isoflurane-anesthetized adult male rats received either a CCI (2.7 mm deformation, 4 m/sec) or sham injury, and 24 h later were administered bromocriptine (5 mg/kg, i.p.) or vehicle, with continued daily injections until all behavioral assessments were completed. Motor function was assessed on beam balance and beam walking tasks on postoperative days 1-5 and cognitive function was evaluated in the MWM on days 11-15 for working memory (experiment 1) and on days 14-18 for spatial learning acquisition (experiment 2). Histological examination (hippocampal CA1 and CA3 cell loss/survival and cortical lesion volume) was conducted 4 weeks after surgery. All injured groups exhibited initial impairments in motor function, working memory, and spatial learning acquisition. Bromocriptine did not affect motor function, but did ameliorate working memory and significantly attenuated spatial acquisition deficits relative to the injured vehicle-treated controls. Additionally, the injured bromocriptine-treated group exhibited significantly more morphologically intact CA3 neurons than the injured vehicle-treated group (55.60 +/- 3.10% vs. 38.34 +/- 7.78% [p = 0.03]). No significant differences were observed among TBI groups in CA1 cell survival (bromocriptine, 40.26 +/- 4.74% vs. vehicle, 29.13 +/- 6.63% [p = 0.14]) or cortical lesion volume (bromocriptine, 17.78 +/- 0.62 mm3 vs. vehicle, 19.01 +/- 1.49 mm3 [p > 0.05]). These data reveal that CCI produces working memory deficits in rats that are similar to those observed following FP, and that the delayed and chronic bromocriptine treatment regimen conferred cognitive and neural protection after TBI.
认知障碍是人类创伤性脑损伤（TBI）普遍且持续存在的后遗症。TBI的体内模型，如控制性皮质撞击（CCI）和液压冲击（FP），被广泛用于产生类似于临床所见的缺陷，以期通过实证研究找到可行的治疗干预措施。CCI和FP都会导致空间学习获取缺陷，但据报道只有后者会损害在莫里斯水迷宫（MWM）中测试的大鼠的工作记忆。我们假设CCI损伤会像FP那样损害工作记忆，并且用D2受体激动剂溴隐亭进行延迟和长期治疗会减轻工作记忆和空间学习获取缺陷。为了验证这些假设，用异氟烷麻醉的成年雄性大鼠接受CCI（2.7毫米变形，4米/秒）或假手术损伤，24小时后给予溴隐亭（5毫克/千克，腹腔注射）或溶剂，持续每日注射直至所有行为评估完成。在术后第1 - 5天通过平衡木和走木杆任务评估运动功能，在第11 - 15天在MWM中评估工作记忆（实验1），在第14 - 18天评估空间学习获取（实验2）。术后4周进行组织学检查（海马CA1和CA3细胞损失/存活情况以及皮质损伤体积）。所有损伤组在运动功能、工作记忆和空间学习获取方面均表现出初始损伤。溴隐亭不影响运动功能，但相对于损伤的溶剂处理对照组，确实改善了工作记忆并显著减轻了空间获取缺陷。此外，与损伤的溶剂处理组相比，损伤的溴隐亭处理组表现出形态上完整的CA3神经元明显更多（55.60±3.10%对38.34±7.78%[p = 0.03]）。在TBI组之间，CA1细胞存活情况（溴隐亭组，40.26±4.74%对溶剂组，29.13±6.63%[p = 0.14]）或皮质损伤体积（溴隐亭组，17.78±0.62立方毫米对溶剂组，19.01±1.49立方毫米[p＞0.05]）未观察到显著差异。这些数据表明，CCI在大鼠中产生的工作记忆缺陷与FP后观察到的相似，并且延迟和长期的溴隐亭治疗方案在TBI后提供了认知和神经保护。
