Dental School of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil.
Paris Brain Institute, Inserm U 1127, CNRS UMR 7225, Sorbonne Université, Paris, France.
Br J Pharmacol. 2021 Jul;178(13):2595-2616. doi: 10.1111/bph.15439. Epub 2021 Apr 21.
l-DOPA-induced dyskinesia is a debilitating effect of treating Parkinson's disease with this drug. New therapeutic approaches that prevent or attenuate this side effect are needed.
Wistar adult male rats submitted to 6-hydroxydopamine-induced unilateral medial forebrain bundle lesion were treated with l-DOPA (p.o. 20 mg·kg or s.c. 10 mg·kg ) once a day for 14 days. After this period, we tested if doxycycline (40 mg·kg , i.p.) and COL-3 (50 and 100 nmol, i.c.v.) could reverse l-DOPA-induced dyskinesia. In an additional experiment, doxycycline was administered together with l-DOPA to verify if it would prevent l-DOPA-induced dyskinesia development.
A single injection of doxycycline or COL-3 attenuated l-DOPA-induced dyskinesia. Co-treatment with doxycycline from the first day of l-DOPA suppressed the onset of dyskinesia. The improved motor response after l-DOPA was not affected by doxycycline or COL-3. Doxycycline treatment was associated with decreased immunoreactivity of FosB, COX-2, the astroglial protein GFAP and the microglial protein OX-42, which were elevated in the basal ganglia of rats exhibiting dyskinesia. Doxycycline decreased metalloproteinase-2/-9 activity, metalloproteinase-3 expression and ROS production. Metalloproteinase-2/-9 activity and production of ROS in the basal ganglia of dyskinetic rats showed a significant correlation with the intensity of dyskinesia.
The present study demonstrates the anti-dyskinetic potential of doxycycline and its analogue compound COL-3 in hemiparkinsonian rats. Given the long-established and safe clinical use of doxycycline, this study suggests that these drugs might be tested to reduce or prevent l-DOPA-induced dyskinesia in Parkinson's patients.
左旋多巴诱导的运动障碍是用这种药物治疗帕金森病的一种使人虚弱的副作用。需要新的治疗方法来预防或减轻这种副作用。
将 Wistar 成年雄性大鼠进行 6-羟多巴胺诱导的单侧中脑束损伤后，每天一次用左旋多巴（口服 20mg·kg 或皮下 10mg·kg）治疗 14 天。在这段时间之后，我们测试了多西环素（40mg·kg，腹腔内注射）和 COL-3（50 和 100nmol，脑室内注射）是否可以逆转左旋多巴诱导的运动障碍。在另一个实验中，给予多西环素与左旋多巴一起给药，以验证它是否会预防左旋多巴诱导的运动障碍的发展。
单次注射多西环素或 COL-3 可减轻左旋多巴诱导的运动障碍。从左旋多巴的第一天开始共同给予多西环素可抑制运动障碍的发作。左旋多巴后的运动反应改善不受多西环素或 COL-3 的影响。多西环素治疗与纹状体中 FosB、COX-2、星形胶质蛋白 GFAP 和小胶质蛋白 OX-42 的免疫反应性降低有关，这些蛋白在表现出运动障碍的大鼠的纹状体中升高。多西环素降低了基质金属蛋白酶-2/-9 的活性、基质金属蛋白酶-3 的表达和 ROS 的产生。运动障碍大鼠基底神经节中的基质金属蛋白酶-2/-9 活性和 ROS 产生与运动障碍的强度有显著相关性。
本研究表明多西环素及其类似物 COL-3 在半帕金森大鼠中具有抗运动障碍的潜力。鉴于多西环素长期确立的安全临床应用，本研究表明这些药物可能被测试用于减少或预防帕金森病患者的左旋多巴诱导的运动障碍。
