The α2 adrenoceptor antagonist idazoxan alleviates l-DOPA-induced dyskinesia by reduction of striatal dopamine levels: an in vivo microdialysis study in 6-hydroxydopamine-lesioned rats
The α2 adrenoceptor antagonist idazoxan alleviates l-DOPA-induced dyskinesia by reduction of striatal dopamine levels: an in vivo microdialysis study in 6-hydroxydopamine-lesioned rats
复制标题
DOI：
10.1111/j.1471-4159.2009.06482.x
复制
发表时间：
2010-01-01
影响因子：
4.7
通讯作者：
Ferger, Boris
中科院分区：
文献类型：
--
作者：
Buck, Kerstin;Voehringer, Patrizia;Ferger, Boris
左旋多巴诱导的运动障碍的特征在于使人衰弱的不自主运动，这限制了患有帕金森病的患者的生活质量。在这里，我们调查的影响，α（2）肾上腺素受体拮抗剂咪唑克生左旋多巴诱导的运动障碍，以及在运动障碍大鼠纹状体细胞外左旋多巴和多巴胺（DA）水平的变化。雄性Wistar大鼠单侧损伤6-羟基多巴胺，随后用左旋多巴/苄丝肼治疗，以诱导稳定的运动障碍运动。给予咪唑克生[（9 mg/kg，腹膜内（i. p.）]显著减轻l-DOPA诱导的运动障碍，而咪唑克生（3 mg/kg，i. p.）并不影响运动障碍行为。双侧体内微透析显示，咪唑克生9 mg/kg降低了受损和完整纹状体中的细胞外峰值L-DOPA水平以及受损纹状体中的DA水平。同时，监测纹状体中咪唑克生的暴露。此外，在血浆、脑组织和CSF中未发现咪唑克生和l-DOPA药物相互作用。总之，损伤纹状体中L-DOPA衍生的细胞外DA水平的降低显著有助于咪唑克生的抗运动障碍作用。
l-DOPA-induced dyskinesia is characterised by debilitating involuntary movement, which limits quality of life in patients suffering from Parkinson's disease. Here, we investigate effects of the alpha(2) adrenoceptor antagonist idazoxan on l-DOPA-induced dyskinesia as well as on alterations of extracellular l-DOPA and dopamine (DA) levels in the striatum in dyskinetic rats. Male Wistar rats were unilaterally lesioned with 6-hydroxydopamine and subsequently treated with l-DOPA/benserazide to induce stable dyskinetic movements. Administration of idazoxan [(9 mg/kg, intraperitoneal (i.p.)] significantly alleviated l-DOPA-induced dyskinesia, whereas idazoxan (3 mg/kg, i.p.) did not affect dyskinetic behaviour. Bilateral in vivo microdialysis revealed that idazoxan 9 mg/kg reduces extracellular peak l-DOPA levels in the lesioned and intact striatum as well as DA levels in the lesioned striatum. In parallel, the exposure to idazoxan in the striatum was monitored. Furthermore, no idazoxan and l-DOPA drug-drug interaction was found in plasma, brain tissue and CSF. In conclusion, the decrease of l-DOPA-derived extracellular DA levels in the lesioned striatum significantly contributes to the anti-dyskinetic effect of idazoxan.