Ruocco L A, Viggiano D, Viggiano A, Abignente E, Rimoli M G, Melisi D, Curcio A, Nieddu M, Boatto G, Carboni E, Gironi Carnevale U A, Sadile A G
Department of Experimental Medicine, Faculty of Medicine, II University of Naples, Naples, Italy.
Neuroscience. 2008 Mar 3;152(1):234-44. doi: 10.1016/j.neuroscience.2007.11.021.
Pathological conditions, such as Parkinson's disease and attention deficit hyperactivity disorder, have been linked to alterations of specific dopamine (DA) pathways. However, since exogenous DA does not cross the blood-brain barrier, DA levels can be modulated e.g. by DA precursors or DA reuptake blockers. Hereby histochemical, analytical and behavioral evidence shows that a galactosylated form of DA (GAL-DA) carries DA into the brain, thus modulating activity and nonselective attention in rats. To this aim adult male rats of the Naples high-excitability (NHE) and random bred controls (NRB) lines were given a single i.p. injection of GAL-DA (10 or 100 mg/kg). Three hours later the behavior was videotaped and analyzed for horizontal activity, orienting frequency and scanning duration. The dose of 100 mglkg of GAL-DA reduced by 25% the horizontal activity in NHE rats, mainly in the first part of the testing period. No effect was observed on orienting frequency or on scanning duration. However, GAL-DA 100 mg/kg was associated with longer rearing episodes in the second part of the testing period in NHE rats. In parallel experiments histochemistry with a galactose-specific lectin showed 10% increase in galactose residues into the striatum between 0.5 and 3.0 h. To quantify the level of GAL-DA, its metabolite DA-succinate and DA in the prefrontal cortex, neostriatum, and cerebellum, rats were killed 2.0 h after the injection of prodrug. Mass high performance liquid chromatography (HPLC) was used for analysis of GAL-DA and DA succinate whereas electrochemical HPLC for DA. Both HPLC techniques demonstrate that GAL-DA carries and releases DA into the brain. Specifically 100 mg/kg of GAL-DA increased DA level in the striatum in the NHE rats only. Moreover, DA in the mesencephalon (MES) was correlated positively with striatal and prefrontal cortex DA in NHE rats. In contrast DA in the MES was negatively correlated with striatal DA in NRB. GAL-DA disrupted these correlations in both rat lines. Thus, this new DA prodrug may modify DA neurotransmission and might have a potential clinical application.
帕金森病和注意力缺陷多动障碍等病理状况与特定多巴胺（DA）通路的改变有关。然而，由于外源性多巴胺无法穿过血脑屏障，多巴胺水平可通过多巴胺前体或多巴胺再摄取阻滞剂等进行调节。在此，组织化学、分析和行为学证据表明，一种半乳糖基化形式的多巴胺（GAL-DA）可将多巴胺带入大脑，从而调节大鼠的活动和非选择性注意力。为此，给那不勒斯高兴奋性（NHE）品系和随机繁殖对照（NRB）品系的成年雄性大鼠腹腔注射一次GAL-DA（10或100mg/kg）。三小时后，对行为进行录像，并分析水平活动、定向频率和扫描持续时间。100mg/kg剂量的GAL-DA使NHE大鼠的水平活动在测试期的第一部分降低了25%。未观察到对定向频率或扫描持续时间有影响。然而，100mg/kg的GAL-DA与测试期第二部分NHE大鼠较长的竖毛发作有关。在平行实验中，用半乳糖特异性凝集素进行组织化学分析显示，在0.5至3.0小时期间，纹状体中的半乳糖残基增加了10%。为了量化前额叶皮质、新纹状体和小脑中GAL-DA、其代谢产物DA-琥珀酸盐和多巴胺的水平，在注射前药2.0小时后处死大鼠。采用质谱高效液相色谱（HPLC）分析GAL-DA和DA琥珀酸盐，而采用电化学HPLC分析多巴胺。两种HPLC技术均表明GAL-DA可将多巴胺携带并释放到大脑中。具体而言，仅100mg/kg的GAL-DA使NHE大鼠纹状体中的多巴胺水平升高。此外，在NHE大鼠中，中脑（MES）中的多巴胺与纹状体和前额叶皮质中的多巴胺呈正相关。相比之下，在NRB大鼠中，MES中的多巴胺与纹状体中的多巴胺呈负相关。GAL-DA破坏了两个大鼠品系中的这些相关性。因此，这种新的多巴胺前药可能会改变多巴胺神经传递，并且可能具有潜在的临床应用价值。
