1 Department of Psychiatry and the Behavioral Sciences and Biomedical Engineering, University of Southern California, Los Angeles, California.
2 Department of Neurology, Biomedical Engineering, University of Southern California, Los Angeles, California.
J Neurotrauma. 2019 Jul 15;36(14):2233-2245. doi: 10.1089/neu.2018.6036. Epub 2019 Mar 28.
We examined benzyl quinolone carboxylic acid (BQCA), a novel M1 muscarinic-positive allosteric modulator, for improving memory and motor dysfunction after cerebral cortical contusion injury (CCI). Adult mice received unilateral motorsensory cortical CCI or sham injury. Benzyl quinolone carboxylic acid (BQCA; 5, 10, and 20 mg/kg, intraperitoneally [i.p.] × 2/day × 3-4 weeks) or vehicle (Veh) were administered, and weekly evaluations were undertaken using a battery of motor tests, as well as the Morris water maze. Thereafter, cerebral metabolic activation was investigated in awake animals during walking with [C]-2-deoxygIucose autoradiography, comparing CCI mice previously treated with BQCA (20 mg/kg) or vehicle. Relative changes in local cerebral glucose uptake (rCGU) were evaluated in three-dimensional-reconstructed brains using statistical parametric mapping. CCI resulted in mild hyperactivity in the open field, and modest significant motor deficits, as well as significantly decreased spatial learning at 3 weeks. BQCA in CCI mice resulted in significantly improved spatial recall during the third week, with minimal effects on motor outcomes. CCI significantly decreased rCGU in the ipsilesional basal ganglia-thalamocortical circuit and in somatosensory regions, with relative increases noted contralaterally, as well as in the cerebellum. Significant decreases in rCGU were noted in subregions of the ipsilesional hippocampal formation, with significant increases noted contralesionally. BQCA compared to vehicle-treated mice showed modest, though significantly increased, rCGU in motor regions, as well as a partial reversal of lesion-related rCGU findings in subregions of the hippocampal formation. rCGU in ipsilesional posterior CA1 demonstrated a significant inverse correlation with latency to find the submerged platform. BQCA at 20 mg/kg had no significant effect on general motor activity, body weight, or acute motor, secretory, or respiratory symptoms. Results suggest that BQCA is a candidate compound to improve learning and memory function after brain trauma and may not suffer the associated central nervous system side effects typically associated with even modest doses of other cholinergic enhancers.
我们研究了苯并喹诺酮羧酸（BQCA），一种新型的 M1 毒蕈碱型乙酰胆碱受体正向变构调节剂，以改善皮质脑挫伤（CCI）后的记忆和运动功能障碍。成年小鼠接受单侧运动感觉皮质 CCI 或假损伤。腹腔内（i.p.）给予苯并喹诺酮羧酸（BQCA；5、10 和 20mg/kg，×2/天×3-4 周）或载体（Veh），每周通过一系列运动测试以及 Morris 水迷宫进行评估。然后，使用 [C]-2-脱氧葡萄糖放射性自显影术在清醒动物行走时研究大脑代谢激活情况，比较先前用 BQCA（20mg/kg）或载体处理的 CCI 小鼠。使用统计参数映射在三维重建大脑中评估局部脑葡萄糖摄取（rCGU）的相对变化。CCI 导致旷场测试中轻度多动，运动功能轻度显著缺陷，以及 3 周时空间学习明显下降。CCI 小鼠中 BQCA 的使用导致第 3 周时空间记忆明显改善，对运动结果的影响最小。CCI 显著降低了同侧基底节-丘脑皮质回路和躯体感觉区的 rCGU，并在对侧和小脑中相对增加，同侧海马结构的亚区 rCGU 明显降低，对侧明显增加。与 Veh 处理的小鼠相比，BQCA 治疗的小鼠在运动区域的 rCGU 略有增加，但显著增加，在海马结构的亚区也部分逆转了与损伤相关的 rCGU 发现。同侧后 CA1 区 rCGU 与找到淹没平台的潜伏期呈显著负相关。20mg/kg 的 BQCA 对一般运动活动、体重或急性运动、分泌或呼吸症状无显著影响。结果表明，BQCA 是一种改善脑外伤后学习和记忆功能的候选化合物，并且可能不会遭受与其他胆碱能增强剂甚至适度剂量相关的中枢神经系统副作用。
