Treatment of parkinsonism with L-DOPA in association with a decarboxylase inhibitor

Summary Attempts to treat Parkinson's disease with L-DOPA have led to a turning-point in the therapy of this disease, akinesia responding particularly well to this drug. The high doses of L-DOPA which are necessary to improve the clinical condition are not free from disadvantages. The combination with the decarboxylase inhibitor Ro 4-4602 allows a considerable reduction of the effective dose of L-DOPA, the results being equally satisfactory. A pilot study involving 10 treated patients was conducted to compare the effects of L-DOPA alone and of the combination with Ro-4-4602. Objective assessment was obtained with the help of psycho-physiological senso-motor tests which are briefly described.This study was supported with the aid of grants No. 4004 and No. 4801.3 of the Swiss National Foundation for Scientific Research, and also with funds from the Eric-Slack-Gyr Foundation, Zurich, and Hoffmann-La Roche, Basel.Study group on Parkinsonism, Kantonsspital, Zürich     

Effect of the NMDA antagonist MK-801 on MPTP-induced parkinsonism in the monkey

Current evidence suggests that the motor symptoms of parkinsonism are due to abnormal overactivity of the medial segment of the globus pallidus, brought about by overactivity of the subthalamic nucleus, from which it receives an excitatory amino acid-mediated projection. The possibility exits, therefore, that excitatory amino acid antagonists might have an anti-parkinson effect by normalising medial pallidal activity. The NMDA antagonist MK-801 was administered i.m. to a single cynomolgus monkey with parkinsonism induced by the neurotoxin MPTP. In fact, MK-801 exacerbated the symptoms of parkinsonism. When administered after a therapeutic dose of L-DOPA it antagonised the anti-parkinson action of L-DOPA. The results suggest that any potential anti-parkinson action of excitatory amino acid antagonists will depend upon an action at non-NMDA sites. The administration of the selective neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to produce a primate model of Parkinson's disease is well-documented (Burns, Markey, Phillips & Chiuch, 1984; Crossman, 1987; Langston, Forno, Rebert & Irwin, 1984). Intravenous injection of MPTP, titrated judiciously over a period of several weeks, can produce a stable manifestation of the motor disability seen in the idiopathic disease of man, with a remarkable correspondence of both symptoms and pathology. Additionally, primates rendered parkinsonian by MPTP respond well to L-DOPA treatment. As in human Parkinson's disease, long-term L-DOPA therapy of MPTP-induced parkinsonism tends to be complicated by the emergence of choreiform movements and dystonic postures (Boyce, Clarke, Luquin, Peggs, Robertson, Mitchell, Sambrook & Crossman, 1989; Clarke, Sambrook, Mitchell & Crossman, 1987).(ABSTRACT TRUNCATED AT 250 WORDS)     

Mexidol corrects model post-reanimation changes in cerebral lipid metabolism

The lipid spectrum of brain tissues in various stages of post-reanimation period was studied in rats upon clinical death modeled by cardiovascular fascicle ligation according to V. G. Korpachev. Reproduction of same model on the background of mexidol was characterized by (i) an increase in phosphatidylserine, (ii) normalization of the relative content of phosphatidylethanolamine and cholesterol, (iii) stabilization of the content of phosphatidylcholine, sphyngomyelin, lysophosphatidylethanolamine, and free fatty acids, and (iv) the absence of lysophosphatidylserine in late post-reanimation period (30 days) upon mexidol reperfusion. Mexidol also favored the development of protective and adaptive reactions on the level of lipid components of cerebral cell membranes in the early period upon reperfusion and prevented from the development of irreversible changes in cerebral phospholipid metabolism in the late post-reanimation period.     

Stereoselective reversal of MPTP-induced parkinsonism in the marmoset after dermal application of N-0437

The selective dopamine D-2 receptor agonist N-0437 produced a rapid and dose-dependent reversal of motor deficits lasting 90-120 min following i.p. or oral administration of the racemate to MPTP-treated common marmosets. In contrast, topical application of (+/-)-, (+)- or (-)-N-0437 to the skin of MPTP-treated animals did not alter locomotor activity in the initial 4 h although other motor disabilities were reduced. However, 24 h following application of the racemate or the (-) enantiomer both locomotor activity and the other motor deficits induced by MPTP were improved. The increase in locomotor activity returned to basal values by 48-52 h following application of the racemate to the skin and by 72-76 h following administration of (-)-N-0437; the other motor deficits induced by MPTP were reduced for up to 72-76 h by both (+/-)- and (-)-N-0437. Application to skin of the (+) enantiomer produced no behavioural improvement or stimulation of locomotor activity. Transdermal administration of the active enantiomer of N-0437 may be of value in producing a prolonged reversal of parkinsonian motor deficits in man.     

类叶升麻苷对MPTP所致帕金森病小鼠模型的神经保护作用

目的研究类叶升麻苷在MPTP诱导的C57小鼠的帕金森病(PD)模型中的神经保护作用及机制。方法通过自主活动实验和滚筒实验研究动物的行为表现,通过高效液相电化学检测方法观察脑纹状体多巴胺的变化,通过脑黑质酪氨酸羟化酶(tyroxinehydroxylase,TH)免疫组化染色观察多巴胺能神经元的损伤程度。并对黑质纹状体进行α-突触核蛋白(α-synuclein)的免疫印迹分析以探讨药物作用机制。结果①经MPTP诱导的C57小鼠,其自主活动次数、滚筒运动潜伏期均低于对照组(P<0·01);纹状体多巴胺含量明显降低(P<0·01);多巴胺能神经元数量明显减少;黑质纹状体α-synuclein蛋白水平下降。②经类叶升麻苷(10、30mg·kg-1)预处理后能明显改善MPTP诱导的C57小鼠的行为学表现,增加脑内多巴胺递质的含量,增加多巴胺能神经元的数量,增加黑质纹状体α-synuclein蛋白水平。结论类叶升麻苷具有神经保护作用,能对抗MPTP诱导的C57小鼠PD模型中的神经损伤。其机制可能与上调α-synuclein蛋白水平有关。     

Influences of an anticholinergic antiparkinsonian drug, parkinsonism, and psychotic symptoms on cardiac autonomic function in schizophrenia

The arguments against the use of anticholinergic antiparkinsonian drugs for neuroleptic-induced parkinsonism have been based, in part, on their autonomic side effects. Except for anecdotal case reports, there is little evidence that antiparkinsonian drugs are the main factor causing autonomic dysfunction in schizophrenic patients with parkinsonism. Therefore, in the current study, the separate influences of the anticholinergic antiparkinsonian drug (biperiden), parkinsonism, and psychotic symptoms on cardiac autonomic function were investigated in 48 patients with schizophrenia. Biperiden was discontinued in 33 patients with or without parkinsonism and commenced in 15 patients with parkinsonism. Their parkinsonism and psychotic symptoms were assessed using rating scales, and their cardiac autonomic functions were assessed using the mean R-R interval and 3 methods of analyzing heart rate variability both before and after the change in medication. Consequently, the cardiac autonomic function was not affected by biperiden or the change in parkinsonism. Cardiac vagal function decreased when psychotic symptoms were more pronounced, but cardiac sympathetic function did not show a significant change. Therefore, it appeared that psychotic symptoms played the predominant role in modifying the cardiac autonomic function, implying the existence of autonomic changes associated with cognitive processing and a possible relation between psychotic symptoms and autonomic symptoms in schizophrenia.     

Anticataleptic effect of taurine: interaction with antiparkinsonian agents

The influence of taurine on cataleptogenic effect of neuroleptics was investigated in male Wistar rats. It was found that taurine 900 micrograms/rat icv reduced significantly haloperidol or fluphenazine-induced catalepsy. In rats receiving taurine in a dose of 450 micrograms, not influencing catalepsy, with low doses of anticholinergic antiparkinsonian agents (trihexyphenidyl and pridinol) strong anticataleptic effect was observed. The results suggest that taurine facilitates neurotransmission in nigrostriatal dopaminergic neurons.     

Pharmacological effects of cabergoline against parkinsonism]

The pharmacological effects of cabergoline, a novel ergot alkaloid, against parkinsonism were assessed by comparing its effects with those of bromocriptine and pergolide. The affinities of cabergoline and pergolide for the D2 receptor were about the same, about 7 times stronger than that of bromocriptine. The affinity of each compound for the D1 receptor was markedly lower than its affinity for the D2 receptor. However, other data suggest that cabergoline and pergolide would have D1-receptor agonist activity, whereas bromocriptine would act as a D1-receptor antagonist. In MPTP-lesioned parkinsonian monkeys, cabergoline improved motor disability, and its effect lasted longer than those of bromocriptine and pergolide. Moreover, cabergoline induced no behavioral abnormalities even though at the highest dose used, in contrast to bromocriptine and pergolide, both of which induced hyperactivity. This beneficial effect of cabergoline did not attenuate on prolonged administration. Combined treatment with a low dose of L-dopa and a low dose of cabergoline improved motor disability without inducing the hyperactivity and dyskinesia seen during treatment with L-dopa alone at high doses. From these results, we suggest that cabergoline promises to be a useful anti-parkinsonian agent with a long lasting effect that survives prolonged administration and without the side effects induced by L-dopa.     

L-DOPA pharmacokinetics in the MPTP-lesioned macaque model of Parkinson's disease

ObjectiveThe 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned non-human primate is widely used to model Parkinson's disease (PD) and to evaluate the efficacy of new therapies. However, some doubts have been raised about the translatability of findings in the MPTP-lesioned monkey, because the doses of l-3,4-dihydroxyphenylalanine (l-DOPA) required to alleviate parkinsonism and elicit dyskinesia are high, on a mg/kg basis, when compared to clinical practice. Thus, in the MPTP-lesioned macaque, doses ranging from 20 to 40 mg/kg might be used, while in the clinic single l-DOPA administrations ranging from 100 to 200 mg are more typical. However, bioavailability of drugs varies between species and it is unknown how plasma l-DOPA levels providing therapeutic benefit in the non-human primate compare to those having similar actions in PD patients.MethodsWe administered acute challenges of l-DOPA 30 mg/kg orally to MPTP-lesioned macaques with established dyskinesia, and determined plasma, brain and cerebrospinal fluid (CSF) levels of l-DOPA using high-performance liquid chromatography–mass spectrometry/mass spectrometry.ResultsThe maximal plasma concentration of l-DOPA (C_max) was 18.2 ± 3.8 nmol/ml and was achieved 1.6 ± 0.3 h after administration (t_max). Half-life was 58.8 ± 22.7 min. l-DOPA levels in the caudate nucleus at peak behavioural effect were 3.3 ± 0.7 μg/g tissue protein while they were 1.5 ± 0.1 nmol/ml in the CSF.ConclusionsAlthough therapeutically-active doses of l-DOPA administered to the MPTP-lesioned macaque are higher on a mg/kg basis than those administered in clinical settings, they lead to l-DOPA C_max similar to those achieved with 200 mg l-DOPA in clinic. l-DOPA t_max and half-life are also similar to those reported in human.     

Azithromycin potentiates avian IgY effect against Pseudomonas aeruginosa in a murine pulmonary infection model

Cystic fibrosis (CF) patients are at risk of acquiring chronic Pseudomonas aeruginosa lung infections. The biofilm mode of growth of P. aeruginosa induces tolerance to antibiotics and the host response; accordingly, treatment failure occurs. Supplemental azithromycin has proven beneficial in CF owing to potential immunomodulatory mechanisms. Clinical studies have demonstrated a reduction in exacerbations in CF patients by avian IgY anti-Pseudomonas immunotherapy. We hypothesise that azithromycin pre-treatment could potentiate the observed anti-Pseudomonas effect of IgY opsonisation in vivo. Evaluation of phagocytic cell capacity was performed using in vitro exposure of azithromycin pre-treated human polymorphonuclear neutrophils to IgY opsonised P. aeruginosa PAO3. A murine lung infection model using nasal planktonic P. aeruginosa inoculation and successive evaluation 24 h post-infection was used to determine lung bacteriology and subsequent pulmonary inflammation. Combined azithromycin treatment and IgY opsonisation significantly increased bacterial killing compared with the two single-treated groups and controls. In vivo, significantly increased bacterial pulmonary elimination was revealed by combining azithromycin and IgY. A reduction in the inflammatory markers mobiliser granulocyte colony-stimulating factor (G-CSF), macrophage inflammatory protein 2 (MIP-2) and interleukin 1 beta (IL-1β) paralleled this effect. Combination of azithromycin and anti-Pseudomonas IgY potentiated the killing and pulmonary elimination of P. aeruginosa in vitro and in vivo. The augmented effect of combinatory treatment with azithromycin and IgY constitutes a potential clinical application for improving anti-Pseudomonas strategies.     

硫酸化茯苓多糖对MPTP诱导帕金森小鼠的神经保护作用研究

目的本实验通过检测硫酸化茯苓多糖(SP)对MPTP诱导的帕金森小鼠中抗氧化酶(SOD、GSH-Px、CAT)活性、抗超氧阴离子活力、MDA及过氧化氢含量,探讨SP对帕金森小鼠中脑和脑皮层神经元细胞的保护作用。方法将ICR小鼠随机分为对照组、MPTP组和SP治疗组(SP 50、100、150mg·kg~(~(-1))),腹腔注射给药,取中脑和脑皮层匀浆,利用酶标仪检测小鼠中脑和脑皮层中SOD、GSH-Px、CAT活性、抗超氧阴离子活力、MDA及过氧化氢含量。结果 SP治疗组小鼠中脑和脑皮层3种抗氧化酶活性有不同程度的增强、抗超氧阴离子活力升高、MDA及过氧化氢含量不同程度下降。结论 SP对MPTP诱导的帕金森小鼠中脑和脑皮层神经元细胞有一定的保护作用。     

Inhibitory effects of antiparkinsonian drugs and caspase inhibitors in a parkinsonian flatworm model

It has been known that rotenone and 1-methyl-4-phenylpyridinium ion (MPP(+), a metabolite of MPTP), which inhibit mitochondrial complex I, are useful tools for parkinsonian models in vertebrates such as primates and rodents. Planarian, an invertebrate flatworm, has a high potential for regeneration, and dopamine plays a key role in its behavior. In the present study, we examined a cloned planarian, the GI strain from Dugesia japonica. Planarians that were treated with rotenone or MPTP underwent autolysis and individual death in a concentration- and time-dependent manner. In addition, these effects induced by rotenone or MPTP were inhibited by several antiparkinsonian drugs and caspase inhibitors. These results suggest that the degeneration of planarian dopaminergic system induced by rotenone or MPTP may be mediated through caspase-like activation.     

Potentiation by naloxone of the anti-oxotremorine effect of L-DOPA

Pretreatment with the catecholamine precursor L-DOPA but not the narcotic antagonist naloxone suppressed the tremorigenic effect of oxotremorine in mice. However, when animals were pretreated with both L-DOPA and several different doses of naloxone, there was a dose-related potentiation of the antitremor effect of L-DOPA. Naloxone also produced dose-dependent potentiation of the antitremor activity of lower doses of L-DOPA in the presence of the peripheral decarboxylase inhibitor carbidopa. These findings suggest a possible therapeutic application for naloxone in treatment of dopamine dysfunction disorders.     

Dopamine transporter inhibitory and antiparkinsonian effect of common flowering quince extract

Common flowering quince (FQ) is the fruit of Chaenomeles speciosa (Sweet) Nakai. FQ-containing cocktails have been applied to the treatment of neuralgia, migraine, and depression in traditional Chinese medicine. The present study assessed whether FQ is effective in dopamine transporter (DAT) regulation and antiparkinsonism by utilizing in vitro and in vivo assays, respectively. FQ at concentrations of 1-1000 microg/ml concentration-dependently inhibited dopamine uptake by Chinese hamster ovary (CHO) cells stably expressing DAT (D8 cells) and by synaptosomes. FQ had a slight inhibitory action on norepinephrine uptake by CHO cells expressing the norepinephrine transporter and no inhibitory effect on gamma-aminobutyric acid (GABA) uptake by CHO cells expressing GABA transporter-1 or serotonin uptake by the serotonin transporter. A viability assay showed that FQ mitigated 1-methyl-4-phenylpyridinium-induced toxicity in D8 cells. Furthermore, in behavioral studies, FQ alleviated rotational behavior in 6-hydroxydopamine-treated rats and improved deficits in endurance performance in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Furthermore, immunohistochemistry revealed that FQ markedly reduced the loss of tyrosine hydroxylase-positive neurons in the substantia nigra in MPTP-treated mice. In summary, FQ is a selective, potent DAT inhibitor and has antiparkinsonian-like effects that are mediated possibly by DAT suppression. FQ has the potential to be further developed for Parkinson's disease treatment.     

中药提取物CTE对MPTP所致帕金森病小鼠模型的神经保护作用

目的:研究中药提取物CTE对1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)所致帕金森病小鼠模型是否具有神经保护作用。方法:首先建立MPTP所致帕金森病小鼠模型,连续4 d给予MPTP(30 mg.kg-1,qd,ip)。用高低剂量(50和100 mg.kg-1,qd,ig)中药提取物CTE预处理MPTP所致帕金森模型小鼠。之后进行行为学检测,包括一般行为学检测和滚筒实验。最后,用HPLC-EC法测定纹状体中多巴胺(DA)及其代谢产物二羟苯乙酸(DOPAC)和高香草酸(HVA)含量。结果:在MPTP所致的帕金森病小鼠模型,中药提取物CTE能显著改善小鼠的行为能力;且能显著提高小鼠纹状体内多巴胺含量。结论:中药提取物CTE对MPTP所致帕金森病小鼠模型有神经保护作用。     

Doxycycline potentiates antitumor effect of cyclophosphamide in mice

Cyclophosphamide (CPA) is a widely used chemotherapeutic drug in neoplasias. It is a DNA and protein alkylating agent that has a broad spectrum of activity against variety of neoplasms including breast cancer. The therapeutic effectiveness of CPA is limited by the high-dose hematopoietic, renal, and cardiac toxicity that accompanies the systemic distribution of liver-derived activated drug metabolites. The present study examines the potential of combining well-tolerated antibiotic doxycycline (DOX) with CPA and understanding the mechanism of cell killing. Interestingly, we found that DOX significantly enhances the tumor regression activity of CPA on xenograft mice model bearing MCF-7 cells. DOX also potentiates MCF-7 cell killing by CPA in vitro. In presence of DOX (3 microg/ml), the IC50 value of CPA decreased significantly from 10 to 2.5 mM. Additional analyses indicate that the tumor suppressor p53 and p53-regulated proapoptotic Bax were upregulated in vivo and in vitro following CPA treatment in combination with DOX, suggesting that upregulation of p53 may contribute to the enhancement of antitumor effect of CPA by DOX. Furthermore, downregulation of antiapoptotic Bcl-2 was observed in animals treated with CPA and CPA plus DOX when compared to untreated or DOX-treated groups. Our results raise the possibility that this combination chemotherapeutic regimen may lead to additional improvements in treatment of breast cancer.     

The effect of L-DOPA on brain catecholamines and motility in rats

Normal rats and those pretreated with reserpine or -methyltyrosine were given L-DOPA alone or with extracerebral decarboxylase inhibitor (Ro 4-4602). Motility was measured at two different time intervals and the brain levels of noradrenaline (NA) and dopamine (DA) were subsequently determined.No simple correlation between the DA or NA level and motility was observed. The L-DOPA-induced increase in motility appeared only in rats in which: 1. the DA levels were markedly increased; 2. a sufficient amount of NA was present. Increasing the dose of L-DOPA did not cause an increase in the NA levels.The present results are in agreement with other published data and suggest that under the conditions studied NA can be displaced by DA formed from L-DOPA and that both amines (DA and NA) are of importance in L-DOPA-induced increase of motility.This work was presented at the VII Congress of CINP, Prague, August 11–15, 1970.