Sagi Yotam, Driguès Noam, Youdim Moussa B H
Eve Topf and U.S.A. National Parkinson Foundation, Centers of Excellence for Neurodegenerative Diseases Research and Department of Pharmacology, Technion-Rappaport Faculty of Medicine, Haifa, Israel.
Br J Pharmacol. 2005 Oct;146(4):553-60. doi: 10.1038/sj.bjp.0706355.
The novel drugs, ladostigil (TV3326) and TV3279, are R and S isomers, respectively, derived from a combination of the carbamate cholinesterase (ChE) inhibitor, rivastigmine, and the pharmacophore of the monoamine oxidase (MAO) B inhibitor, rasagiline. They were developed for the treatment of comorbidity of dementia with Parkinsonism. In the present study, we determined the effects of these drugs on both aminergic neurotransmitter levels and motor behavioral activity in naïve and in L-dopa- or L-tryptophan-induced rats. Chronic treatment of rats with ladostigil (52 mg kg(-1) for 21 days) inhibited hippocampal and striatal MAO A and B activities by >90%, increased striatal levels of dopamine and serotonin, and inhibited striatal ChE activity by approximately 50%. Chronic TV3279 (26 mg kg(-1) for 21 days) similarly inhibited approximately 50% of striatal ChE activity, but did not affect MAO activity or amine levels. In sharp contrast to the inductive effect of the MAO A/B inhibitor, tranylcypromine (TCP), on stereotyped hyperactivity in response to L-dopa (50 mg kg(-1)) or L-tryptophan (100 mg kg(-1)), ladostigil completely inhibited these behavioral hyperactivity syndromes. Accordingly, acute rivastigmine (2 mg kg(-1)) and chronic TV3279 abolished the ability of TCP to initiate L-dopa-induced hyperactivity, while scopolamine (0.5 mg kg(-1)) reversed the inhibitory effect of chronic ladostigil on L-dopa-induced hyperactivity, suggesting that ladostigil may attenuate successive locomotion by activating central cholinergic muscarinic receptors.Finally, while chronic ladostigil administration to naïve rats resulted in preserved spontaneous motor behavior, acute treatment with ladostigil decreased motor performance, compared to control animals. In contrast, chronic as well as acute treatments with TV3279 reduced spontaneous motor activity. Thus, the aminergic potentiation by ladostigil may counteract its cholinergic inhibitory effect on spontaneous motor behavior. Our results suggest that potentiation of both aminergic and cholinergic transmission systems by ladostigil contributes equally to motor behavior performance, which is substantially impaired in comorbidity of dementia with Parkinsonism including dementia with Lewy bodies (DLB).
新型药物拉多司替吉尔（TV3326）和TV3279分别是R和S异构体，它们是由氨基甲酸酯胆碱酯酶（ChE）抑制剂卡巴拉汀与单胺氧化酶（MAO）B抑制剂雷沙吉兰的药效基团组合而成。它们被开发用于治疗痴呆与帕金森病的合并症。在本研究中，我们测定了这些药物对未用药以及左旋多巴或L-色氨酸诱导的大鼠的胺能神经递质水平和运动行为活性的影响。用拉多司替吉尔（52 mg·kg⁻¹，持续21天）对大鼠进行慢性治疗，可使海马体和纹状体的MAO A和B活性抑制>90%，增加纹状体中多巴胺和5-羟色胺水平，并使纹状体ChE活性抑制约50%。慢性给予TV3279（26 mg·kg⁻¹，持续21天）同样可使纹状体ChE活性抑制约50%，但不影响MAO活性或胺水平。与MAO A/B抑制剂反苯环丙胺（TCP）对左旋多巴（50 mg·kg⁻¹）或L-色氨酸（100 mg·kg⁻¹）诱导的刻板多动的诱导作用形成鲜明对比的是，拉多司替吉尔完全抑制了这些行为多动综合征。因此，急性给予卡巴拉汀（2 mg·kg⁻¹）和慢性给予TV3279消除了TCP引发左旋多巴诱导的多动的能力，而东莨菪碱（0.5 mg·kg⁻¹）逆转了慢性拉多司替吉尔对左旋多巴诱导的多动的抑制作用，这表明拉多司替吉尔可能通过激活中枢胆碱能毒蕈碱受体来减弱连续运动。最后，虽然对未用药大鼠长期给予拉多司替吉尔可保持自发运动行为，但与对照动物相比，急性给予拉多司替吉尔会降低运动表现。相反，慢性和急性给予TV3279均可降低自发运动活性。因此，拉多司替吉尔对胺能的增强作用可能抵消其对自发运动行为的胆碱能抑制作用。我们的结果表明，拉多司替吉尔对胺能和胆碱能传递系统的增强作用对运动行为表现的贡献相同，而在痴呆与帕金森病的合并症（包括路易体痴呆，DLB）中，运动行为表现会严重受损。
