Dopamine depletion and subsequent treatment with L-DOPA, but not the long-lived dopamine agonist pergolide, enhances activity of the Akt pathway in the rat striatum
Dopamine depletion and subsequent treatment with L-DOPA, but not the long-lived dopamine agonist pergolide, enhances activity of the Akt pathway in the rat striatum
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DOI：
10.1111/j.1471-4159.2007.04586.x
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发表时间：
2007-08-01
影响因子：
4.7
通讯作者：
Gurevich, Eugenia V.
中科院分区：
文献类型：
--
作者：
Bychkov, Evgeny;Ahmed, M. Rafiuddin;Gurevich, Eugenia V.
信号传导通路的失调被认为有助于帕金森病病理学和左旋多巴诱导的运动并发症。长效多巴胺（DA）激动剂由于持续刺激DA受体而不太可能引起运动并发症。在这项研究中，我们比较了单侧6-羟基多巴胺损伤和随后的治疗与左旋多巴和DA受体激动剂培高利特对大鼠信号通路的影响。培高利特引起的行为致敏作用不如左旋多巴（25 mg/kg，i. p.，10天），特别是在较低剂量（0.5和0.25 mg/kg，i. p.）。培高利特，但不是左旋多巴，逆转病变诱导的前脑啡肽原的上调，并没有上调前强啡肽或DA D3受体在病变的半球。培高利特在逆转急性阿扑吗啡给药（0.05 mg/kg，s.c.）引起的损伤诱导的ERK 2磷酸化升高方面与L-多巴一样有效。慢性L-DOPA显著升高了Thr 308和Ser 473的Akt磷酸化水平和磷酸化GSK 3 α的浓度，而培高利特抑制了损伤和/或挑战诱导的超敏Akt反应。数据表明，左旋多巴，不像培高利特，加剧了Akt通路的不平衡所造成的损失DA。结果支持的假设，Akt通路参与长期行动的左旋多巴，并可能与左旋多巴诱导的运动障碍。
Dysregulation of signaling pathways is believed to contribute to Parkinson's disease pathology and L-DOPA-induced motor complications. Long-lived dopamine (DA) agonists are less likely to cause motor complications by virtue of continuous stimulation of DA receptors. In this study, we compared the effects of the unilateral 6-hydroxydopamine lesion and subsequent treatment with L-DOPA and DA agonist pergolide on signaling pathways in rats. Pergolide caused less pronounced behavioral sensitization than L-DOPA (25 mg/kg, i.p., 10 days), particularly at lower dose (0.5 and 0.25 mg/kg, i.p.). Pergolide, but not L-DOPA, reversed lesion-induced up-regulation of preproenkephalin and did not up-regulate preprodynorphine or DA D3 receptor in the lesioned hemisphere. Pergolide was as effective as L-DOPA in reversing the lesion-induced elevation of ERK2 phosphorylation in response to acute apomorphine administration (0.05 mg/kg, s.c.). Chronic L-DOPA significantly elevated the level of Akt phosphorylation at both Thr 308 and Ser 473 and concentration of phosphorylated GSK3 alpha, whereas pergolide suppressed the lesion- and/or challenge-induced supersensitive Akt responses. The data indicate that L-DOPA, unlike pergolide, exacerbates imbalances in the Akt pathway caused by the loss of DA. The results support the hypothesis that the Akt pathway is involved in longterm actions of L-DOPA and may be linked to L-DOPA-induced dyskinesia.