Parametric approaches towards understanding the effects of the preferential D3 receptor agonist pramipexole on prepulse inhibition in rats

The preferential dopamine D3 receptor agonist pramipexole (PRA) disrupts prepulse inhibition (PPI) of acoustic startle, an operational measure of sensorimotor gating, in rats. Drug effects on PPI are sensitive to numerous experimental variables; proceeding with in-depth analyses of drug effects without a clear understanding of these variables is inefficient. The present studies characterized the impact on PRA-induced PPI deficits by a range of experimental parameters. As shown previously, PRA reduced both PPI and startle magnitude beginning 5-15 min post-injection; PRA effects on PPI were statistically significant through 35 min post-injection, while those on startle magnitude were still significant 65 min post-injection. PRA-induced PPI deficits were evident under conditions that matched startle magnitude in vehicle and PRA conditions and were independent of PRA-induced changes in prepulse-elicited motor activity. Additionally, PRA-induced PPI deficits did not differ significantly between uni- vs. cross-modal stimuli or between male vs. female rats, with no robust effect of estrous phase in females. These findings demonstrate that PRA effects on PPI are observed across several different experimental conditions and are dissociable from changes in startle magnitude or prepulse-elicited responses. Recommendations are made regarding “optimal” experimental conditions for studying the neurobiology of PRA-induced changes in PPI in rats.     

脑康泰胶囊联合普拉克索治疗早期帕金森病的临床研究

目的 探讨脑康泰胶囊联合普拉克索治疗早期帕金森病的临床效果。方法 选取2019年4月—2021年10月北京市和平里医院收治的136例早期帕金森病患者,采用随机数字表法将所有患者平均分为对照组和治疗组,每组各68例。对照组口服盐酸普拉克索片,起始剂量0.125 mg/次,3次/d,随后根据患者耐受情况逐渐增加剂量,每周加量1次,每次日剂量增加0.375 mg,有效剂量为0.50～0.75 mg/次,3次/d,最大日剂量为4.5 mg。治疗组在对照组基础上口服脑康泰胶囊,3粒/次,3次/d。两组疗程均为12周。观察两组的临床疗效,比较治疗前后两组国际运动障碍学会帕金森病综合评定量表（MDS-UPDRS）中各部分（Ⅰ、Ⅱ、Ⅲ、Ⅳ）评分及其总分、帕金森病睡眠评估量表中文版（PDSS-CV）总分、39项帕金森病生活质量问卷（PDQ-39）总分及血清白细胞介素（IL）-1β、IL-17、超氧化物歧化酶（SOD）、谷氨酸（Glu）和γ氨基丁酸（GABA）水平。并统计两组不良反应情况。结果 治疗后,治疗组有效率是94.12%,较对照组82.35%显著提高（P＜0.05）。治疗后,两组MDS-UPDRS中各部分（Ⅰ、Ⅱ、Ⅲ、Ⅳ）评分及其总分比治疗前均显著降低（P＜0.05）;且均以治疗组下降更显著（P＜0.05）。治疗后,两组PDSS-CV总分比治疗前均显著升高,PDQ-39总分比治疗前均显著降低（P＜0.05）;且均以治疗组改善更显著（P＜0.05）。治疗后,两组血清IL-1β、IL-17水平均显著低于治疗前,血清SOD、Glu和GABA水平均显著高于治疗前（P＜0.05）;且治疗后,治疗组血清IL-1β、IL-17水平比对照组均显著更低,血清SOD、Glu和GABA水平比对照组均显著更高（P＜0.05）。治疗后,治疗组患者不良反应发生率是14.71%,比对照组29.41%显著降低（P＜0.05）。结论 脑康泰胶囊联合普拉克索治疗早期帕金森病的整体疗效满意,可安全有效地改善患者睡眠状况,并能进一步抑制血清IL-1β和IL-17表达水平、增强体内SOD活性及提高血清Glu、GABA水平,从而对患者生活质量及病情的改善具有重要作用。     

芬太尼联合应用不同化合物对大鼠的制动效应比较

[目的]通过观察芬太尼与其他化合物联合在大鼠制动中的效应,比较筛选制动效应最佳的化合物组合.[方法]雄性Wistar大鼠55只,每组5只,随机分为对照组(NS)、芬太尼组(F)、右旋美托咪啶组(D)、普拉克索组(P)、乌拉地尔组(U)、F+P组、F+D组、F+U组、F+D+P组、F+D+U组和F+P+U组,F组、D组、P组、U组分别腹腔注射一定剂量的芬太尼、右旋美托咪啶、普拉克索和乌拉地尔进行大鼠制动实验,同时将芬太尼与其他化合物联合,以翻正反射消失时间作为制动起效时间.观察动物制动过程中运动功能的变化及呼吸频率的变化,从中筛选出制动效果最佳的化合物组合.[结果]F+D组、F+D+P组、F+D+U组和F+P+U组在实验过程中出现了明显的制动效应,其中F+D+P组制动效应起效时间最短,F+D组最长,二者相比具有显著性差异(P＜0.01),其余各组均未观察到明显制动效应发生.F组、F+D组和F+P+U组呼吸频率较生理盐水对照组显著降低(P＜0.01),其余各组呼吸频率无明显变化.F+D组、F+D+P组、F+D+U组和F+P+U组动物在制动过程中的Tarlov后肢运动功能评分和Rivlin斜板实验角度变化趋势与制动时间较为一致.[结论]F+D+P组化合物制动效果较好,且未出现明显的呼吸抑制作用,是一种具有良好制动应用前景的化合物组合.     

多巴丝肼联合普拉克索治疗帕金森病的疗效观察

目的:评定多巴丝肼与普拉克索联合应用治疗帕金森病(PD)的临床疗效。方法:52例PD患者随机分为两组,单用多巴丝肼组(A组)26例和多巴丝肼加用普拉克索组(B组)26例,临床疗效采用改良Webester量表进行治疗前后评定结果:临床总有效率A组为73.08%,B组为84.62%,B组总有效率明显高于A组(P<0.05)。结论:单用多巴丝肼和多巴丝肼加用普拉克索治疗PD均有效,但多巴丝肼加用普拉克索比单用多巴丝肼治疗PD有效率更高。     

盐酸普拉克索联合美多芭治疗帕金森病的临床疗效

目的研究联合盐酸普拉克索和美多芭治疗帕金森病的临床疗效及安全性。方法收集帕金森患者110例并随机分为对照组和治疗组。对照组给予美多芭片治疗,治疗组在对照组的基础上给予盐酸普拉克索片,疗程均为12周,于治疗前后分时间点进行UPDRS评分评估治疗效果。结果治疗后对照组总有效率为60％,治疗组总有效率为83．64％：治疗组第12周UPDRS总分和第8、12周UPDRSⅢ评分均值显著低于对照组（P〈0．01）,第8周UPDRS总分和第8、12周UPDRSⅡ评分均值低于对照组且有统计学意义（P〈0．05）。结论联合盐酸普拉克索和美多芭治疗帕金森病有效且安全,副作用明显少于单用美多芭,值得临床推广。     

金刚烷胺和普拉克索引起晕厥、外周水肿和低血压一例

一患者既往有脑梗死病史和大量饮酒史,同时服用金刚烷胺和普拉克索引起了晕厥、外周水肿和低血压,本文对此不良反应进行了分析,该病例提示应用治疗帕金森药物应谨慎、戒酒,同时个体化调整剂量,尽可能避免相同不良反应的药物联用,如必须联用,应加强监测。     

普拉克索添加治疗帕金森病的疗效和安全性的系统评价

目的:系统评价普拉克索添加治疗帕金森病(PD)的疗效与安全性。方法:计算机检索PubMed、EMbase、Cochrane图书馆、中国生物医学文献数据库、中国期刊全文数据库、维普数据库和万方数据库,收集普拉克索添加治疗PD的随机对照试验(RCT),采用Rev Man 5.1统计软件对纳入研究的相关数据进行Meta分析。结果:共纳入14项RCT,合计1 852例患者。Meta分析结果显示,普拉克索联合左旋多巴与多巴脱羧酶抑制药治疗PD可以显著提高患者总有效率[OR=3.45,95%CI(2.46,4.85),P<0.01],提高患者日常生活活动能力总评分(UPDRSⅡ)[MD=-1.38,95%CI(-2.05,-0.71),P<0.01]和运动检查总评分(UPDRSⅢ)[MD=-5.71,95%CI(-9.25,-2.17),P<0.01],减少患者每日服用左旋多巴的剂量[MD=-167.42,95%CI(-207.94,-126.90),P<0.01],与对照组比较,差异均有统计学意义。此外,普拉克索不增加患者恶心、呕吐、体位性低血压、眩晕和嗜睡的发生率,但可能增加异动症[OR=2.21,95%CI(1.66,2.95),P<0.01]、幻觉[OR=3.22,95%CI(2.04,5.09),P<0.01]和失眠[OR=1.52,95%CI(1.00,2.32),P=0.05]的发生率。结论:普拉克索添加治疗PD疗效显著,但部分不良反应发生率亦会增加。由于纳入研究的质量不统一,该结论需谨慎对待,尚需高质量、大样本的RCT进一步加以验证。     

普拉克索治疗老年帕金森病伴发抑郁的疗效观察

目的探讨普拉克索对老年帕金森病(PD)伴发抑郁患者抑郁症状的临床疗效。方法将帕金森病合并抑郁的老年患者60例随机分为2组,即应用普拉克索和美多巴为治疗组,应用吡贝地尔缓释片和美多巴为对照组。收集两组病例治疗前后的Hamilton抑郁量表(HAMD)和统一帕金森病评分量表(UPDRS)评分。结果治疗组治疗后HAMD评分明显低于治疗前(P<0.05),对照组治疗后HAMD评分与治疗前比较,差异无统计学意义(P>0.05);两组治疗后UPDRS评分明显低于治疗前(P<0.05)。结论对于老年PD患者,普拉克索不仅可以改善运动状态,还可以明显改善抑郁症状。     

Dual motor response to l-dopa and nociceptin/orphanin FQ receptor antagonists in 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) treated mice: Paradoxical inhibition is relieved by D2/D3 receptor blockade

Motor activity of mice acutely treated with the parkinsonian toxin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) was monitored for 6 days using behavioral tests which provide complementary information on motor function: the bar, reaction time, drag, stair climbing, grip, rotarod and footprinting tests. These tests consistently disclosed a prolonged motor impairment characterized by akinesia, bradykinesia, speed reduction, loss of coordination and gait patterns. This impairment was associated with ∼ 60% loss of striatal dopamine terminals, as revealed by tyrosine hydroxylase immunohistochemistry, and was attenuated by dopaminergic drugs. Indeed, the dopamine precursor, l-dopa (1–10 mg/kg), and the D₃/D₂ receptor agonist pramipexole (0.0001–0.001 mg/kg) promoted stepping activity in the drag test (a test for akinesia/bradykinesia). The novel nociceptin/orphanin FQ receptor (NOP) antagonist 1-[1-(cyclooctylmethyl)-1,2,3,6-tetrahydro-5-(hydroxymethyl)-4-pyridinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (Trap-101, 0.001–0.1 mg/kg), an analogue of 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397), also promoted stepping and synergistically or additively (depending on test) attenuated parkinsonism when combined to dopamine agonists. High doses of l-dopa (100 mg/kg), pramipexole (0.1 mg/kg), Trap-101 and J-113397 (1 mg/kg), however, failed to modulate stepping, worsening immobility time and/or rotarod performance. Low doses of amisulpride (0.1 mg/kg) reversed motor inhibition induced by l-dopa and J-113397, suggesting involvement of D₂/D₃ receptors. This study brings further evidence for a dopamine-dependent motor phenotype in MPTP-treated mice reinforcing the view that this model can be predictive of symptomatic antiparkinsonian activity provided the appropriate test is used. Moreover, it offers mechanistic interpretation to clinical reports of paradoxical worsening of parkinsonism following l-dopa. Finally, it confirms that NOP receptor antagonists may be proven effective in reversing parkinsonism when administered alone or in combination with dopamine agonists.     

Neuroprotective effects of the novel D3/D2 receptor agonist and antiparkinson agent, S32504, in vitro against 1-methyl-4-phenylpyridinium (MPP+) and in vivo against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): a comparison to ropinirole

The novel naphtoxazine derivative and preferential D(3) vs D(2) receptor agonist, S32504, restores perturbed motor function in rodent and primate models of antiparkinsonian activity with a potency superior to those of two further, preferential D(3) receptor agonists, pramipexole and ropinirole. However, potential neuroprotective properties of S32054 have not, to date, been evaluated. Herein, employing several measures of cellular integrity, we demonstrate that S32504 robustly, concentration-dependently and completely protects terminally differentiated SH-SY5Y cells against 1-methyl-4-phenylpyridinium (MPP+)-induced cell death in vitro. Further, S32504 was substantially more potent than pramipexole and ropinirole, the latter of which was neurotoxic at high concentrations. In vivo, subchronic treatment with low (0.25 mg/kg) and high (2.5 mg/kg) doses of S32504 prior to and during treatment of mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP, provided complete protection against MPTP-induced tyrosine hydroxylase immunoreactive (TH-IR) neuronal death in the substantia nigra pars compacta and ventral tegmental area. A high dose of ropinirole (2.5 mg/kg) provided some protection but statistical significance was not attained, and a low dose (0.25 mg/kg) was ineffective. Neither drug afforded protection against the MPTP-induced loss of DA fibers in the striatum, as measured by TH-IR and dopamine transporter immunoreactive fiber counts. In conclusion, the novel naphotoxazine and dopaminergic agonist, S32504, robustly protects dopaminergic neurones against the neurotoxic effects of MPP(+) and MPTP in in vitro and in vivo models, respectively. The underlying mechanisms and therapeutic pertinence of these actions will be of interest to further evaluate in view of its potent actions in behavioral models of antiparkinson activity.