Potential Antiparkinsonian Agents Research Articles

Dopaminergic regulation of inflammation and immunity in Parkinson's disease: friend or foe?

Parkinson's disease (PD) is a neurodegenerative disease affecting 7-10 million people worldwide. Currently, there is no treatment available to prevent or delay PD progression, partially due to the limited understanding of the pathological events which lead to the death of dopaminergic neurons in the substantia nigra in the brain, which is known to be the cause of PD symptoms. The current available treatments aim at compensating dopamine (DA) deficiency in the brain using its precursor levodopa, dopaminergic agonists and some indirect dopaminergic agents. The immune system is emerging as a critical player in PD. Therefore, immune-based approaches have recently been proposed to be used as potential antiparkinsonian agents. It has been well-known that dopaminergic pathways play a significant role in regulating immune responses in the brain. Although dopaminergic agents are the primary antiparkinsonian treatments, their immune regulatory effect has yet to be fully understood. The present review summarises the current available evidence of the immune regulatory effects of DA and its mimics and discusses dopaminergic agents as antiparkinsonian drugs. Based on the current understanding of their involvement in the regulation of neuroinflammation in PD, we propose that targeting immune pathways involved in PD pathology could offer a better treatment outcome for PD patients.

Pyrimido[1,2-b]indazole derivatives: Selective inhibitors of human monoamine oxidase B with neuroprotective activity.

Structurally diverse heterotricyclic compounds are recognized as monoamine oxidase (MAO) inhibitors and thus represent an appealing scaffold in development and optimization of novel MAO inhibitors. Herein we explored the chemical space of pyrimido[1,2-b]indazoles as MAO inhibitors by preparing a small library of (hetero)aryl derivatives. An efficient synthetic strategy was developed starting from commercially available 1H-indazol-3-amines, which were converted to various 3-bromoheterotricyclic derivatives and further functionalized via Suzuki-Miyaura coupling reaction. Derivatives 4a-t selectively inhibited human MAO-B isoform in a reversible and competitive manner as confirmed by kinetic experiments and docking studies. Selected derivatives were not cytotoxic to neuroblastoma SH-SY5Y cells. Moreover, analogue 4i protected human neuroblastoma SH-SY5Y cells against 6-hydroxydopamine-induced cell death, which confirms the applicability of the pyrimido[1,2-b]indazoles as potential antiparkinsonian agents.

Further structure-activity relationships study of substituted dithiolethiones as glutathione-inducing neuroprotective agents.

BackgroundParkinson’s disease is a neurodegenerative disorder associated with oxidative stress and glutathione depletion. The induction of cellular glutathione levels by exogenous molecules is a promising neuroprotective approach to limit the oxidative damage that characterizes Parkinson’s disease pathophysiology. Dithiolethiones, a class of sulfur-containing heterocyclic molecules, are known to increase cellular levels of glutathione; however, limited information is available regarding the influence of dithiolethione structure on activity. Herein, we report the design, synthesis, and pharmacological evaluation of a further series of dithiolethiones in the SH-SY5Y neuroblastoma cell line.ResultsOur structure–activity relationships data show that dithiolethione electronic properties, given as Hammett σp constants, influence glutathione induction activity and compound toxicity. The most active glutathione inducer identified, 6a, dose-dependently protected cells from 6-hydroxydopamine toxicity. Furthermore, the protective effects of 6a were abrogated by the inhibitor of glutathione synthesis, buthionine sulfoximine, confirming the importance of glutathione in the protective activities of 6a.ConclusionsThe results of this study further delineate the relationship between dithiolethione chemical structure and glutathione induction. The neuroprotective properties of analog 6a suggest a role for dithiolethiones as potential antiparkinsonian agents.

Medicinal Plants and Natural Products as Potential Sources for Antiparkinson Drugs.

Parkinson's disease is a progressive neurodegenerative dysfunction characterized by the loss of pigmented dopaminergic neurons of the nigrostriatal system with a consequent dopamine decrease. The reduction of dopamine levels produces neuronal damage, depigmentation of the substantia nigra, and the presence of intracellular inclusions in dopaminergic neurons. Treatments for Parkinson's disease aim for improving these motor symptoms by increasing the dopaminergic signal in the striatum with levodopa in combination with enzyme inhibitors or anticholinergic drugs. Nevertheless, natural products can act as neuroprotective agents by reducing the progression of the disease and the inflammatory process.In the present review, we have compiled data on the principal medicinal plants and natural products as potential antiparkinsonian agents. They act by different mechanisms, such as the inhibition of α-synuclein condensation, reduction of oxidative stress and neuro-inflammation, increase of dopaminergic neurons survival, or the blockade of the A2 A receptor.

ChemInform Abstract: Synthesis and Biological Studies of Glycosyl Dopamine Derivatives as Potential Antiparkinsonian Agents.

A new approach to deliver dopamine into the central nervous system, based on the use of D-glucose as transportable agent, has been studied. Glycosyl dopamine derivatives bearing the sugar moiety linked to either the amino group or the catechol ring of dopamine through amide, ester or glycosidic bonds were synthesised as potential antiparkinsonian agents. Studies on the binding to dopamine D2 receptor, in vitro stability, and locomotive effect in mice of the synthetic glycoconjugates are reported.

The midbrain slice preparation. An in vitro model to select potential anti-parkinsonian drugs?

Most anti-parkinsonian drugs produce a dopamine-like effect on single dopaminergic neurons. Using electrophysiological recordings, this effect is observed as an inhibition of the spontaneous firing activity. The firing activity of dopaminergic cells throughout dopamine-mediated mechanisms is inhibited not only by dopamine direct agonists but also by substances that increase the release or synthesis, or block the uptake or reduce degradation of dopamine in the brain. Here we propose the electrophysiological approach on dopaminergic neurons in in vitro slice preparation as a preliminary tool for selecting new potential anti-parkinsonian agents, before they are tested in more complex animal models.

Synthesis and biological studies of glycosyl dopamine derivatives as potential antiparkinsonian agents

A new approach to deliver dopamine into the central nervous system, based on the use of d-glucose as transportable agent, has been studied. Glycosyl dopamine derivatives bearing the sugar moiety linked to either the amino group or the catechol ring of dopamine through amide, ester or glycosidic bonds were synthesised as potential antiparkinsonian agents. Studies on the binding to dopamine D 2 receptor, in vitro stability, and locomotive effect in mice of the synthetic glycoconjugates are reported.

Tremulous jaw movements induced by the acetylcholinesterase inhibitor tacrine: effects of antiparkinsonian drugs

Several experiments were conducted to study the effects of established or potential antiparkinsonian drugs on the tremulous jaw movements induced by the anticholinesterase tacrine (9-amino-1,2,3,4-tetrahydroaminoacridine hydrochloride). In the first group of four experiments, separate groups of animals that received 2.5 or 5.0 mg/kg tacrine showed a dose-dependent decrease in tremulous jaw movements following co-administration of the non-selective dopamine receptor agonist apomorphine, the full dopamine D 2 receptor agonist bromocriptine, and the full dopamine D 1 receptor agonist APB ( R(+)-6-bromo-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine). Co-administration of the partial dopamine D 1 receptor agonist SKF 38393 ( R(+)-2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1 H-benzazepine; 7.5–30.0 mg/kg) did not reduce tremulous jaw movements produced by 2.5 or 5.0 mg/kg tacrine. In animals treated with 2.5 mg/kg tacrine, co-administration of SKF 38393 resulted in a dose-related trend towards a potentiation of tremulous jaw movements. In the second group of experiments, all rats received 2.5 mg/kg tacrine. The dopamine precursor l-DOPA ( l-3,4-dihydroxyphenylalanine), the dopamine and norepinephrine releasing agent amantadine, and the muscarinic receptor antagonist benztropine all reduced tremulous jaw movements induced by 2.5 mg/kg tacrine. Across all experiments, it was noted that apomorphine, bromocriptine and benztropine were more potent than amantadine and l-DOPA. These results are broadly consistent with the therapeutic doses of these agents noted in the clinical literature. The results of these experiments indicate that tremulous jaw movements in rats may be a useful model for evaluating potential antiparkinsonian agents. © 1997 Elsevier Science B.V. All rights reserved.

Animal Models of Parkinsonism

The discovery of profound dopamine depletion of basal ganglia in patients with Parkinson's disease and the development of antiparkinsonian drug therapy were largely based on animal models. The behavioural changes caused by cholinergic drugs, reserpine and related agents, and unselective neuronal lesions were the first widely used animal models for Parkinson's disease. The crucial breakthrough was the observation of the circling behaviour in rodents after unilateral intranigral injection of 6-hydroxydopamine. This Ungerstedt model still is one of the basic animal models of Parkinson's disease. It is suitable for the screening of new potential antiparkinsonian agents with the classic spectrum. The parkinsonism induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the mouse and the monkey is the latest and the best animal model for Parkinson's disease. Especially when given to the monkey, MPTP causes biochemical, behavioural and neuropathological changes which largely mimick those of Parkinson's disease in man. The MPTP-induced parkinsonism in the monkey can be used for the study of the neurobiology and new forms of drugs therapy of Parkinson's disease. However, because the MPTP monkey model is expensive and laborious, it is not particularly convenient for the screening of new drugs. Recently, a new approach in the treatment of Parkinson's disease is to develop drugs which might prevent or retard the disease progression. The prevention of behavioural changes of aged rodents is used as an animal model and promising results with selegiline have been obtained.

Pharmacological basis for N- n-propylnoramorphine induced stereotypic cage climbing and behavioral arousal in mice

Apmorphine (APO) and its N-propyl homologue (N- n-propylnorapomorphine; NPA) are approximately equipotent in inducing stereotypic cage climbing and behavioral arousal. The time courses for the two behavioral responses of both aporphines are also quite similar. These results suggested that aporphine-induced stereotypic cage-climbing and behavioral arousal, if specific for dopamine receptor stimulation, could provide useful in vivo models for predicting dose- and time-response effects of potential antiparkinsonian agents. In the present experiments, six neurotransmitter receptor blockers (alropine, phentolamine, sotalol, cyproheptadine, naloxone, and haloperidol or spiroperidol) were compared in mice for their ability to alter cage climbing and behavioral arousal induced by NPA. Results indicated that pretreatment with the dopamine blockers haloperidol and spiroperidol, significantly antagonized both responses to NPA and shifted the cage climb dose response curve to the right 15-fold. In contrast, the muscarinic cholinergic (atropine), alpha-noradrenergic (phentolamine), beta-noradrenergic (sotalol), serotonergic (cyproheptadine), and opiate (naloxone) receptor blockers uniformly did not attenuate activity due to NPA. These results suggest that cage-climbing and arousal induced by aporphines is mediated via dopamine receptor stimulation and that these responses provide useful in vivo models for accurate evaluation of certain classes of dopamine agonists with clinical utility.

L-5-Hydroxytryptophan-induced myoclonus in guinea pigs: A model for the study of central serotonin-dopamine interactions

Myoclonic responses produced in guinea pigs by systemic administration of l-5-hydroxytryptophan ( l-5-HTP), or of l-tryptophan plus a monoamine oxidase inhibitor, were recorded and analysed quantitatively. l-5-Hydroxytryptophan-induced myoclonus involves 5-hydroxytryptamine (5-HT) neurones and receptors, and appears to be an all-or-none response due to a spill-over phenomenon, rather than to impulse released 5-HT. The myoclonus was antagonized by the 5-HT receptor blockers, cyproheptadine and methergoline. Quipazine, an agent which releases 5-HT and inhibits its reuptake, produced a low rate of myoclonic jerks. Injection of the 5-HT agonist, 5-methoxy- N, N-dimethyltryptamine, resulted in intense myoclonus as well as a behavioural syndrome characterized by writhing, turning and hyperactivity. The dopamine (DA) receptor agonists, apomorphine and N- n-propyl- N- n-butyl- β-(3,4-dihydroxyphenyl)-ethylamine-HCl (PBD), antagonized the l-5-HTP induced myoclonus. The DA receptor blockers, haloperidol and pimozide, had no appreciable effect on l-5-HTP-induced myoclonus, but antagonized the suppression of myoclonus by DA agonists, indicating a modulation of the L-5-HTP-induced myoclonus by DA neurones. It is proposed that l-5-HTP-induced myoclonus in guinea pigs represents a useful model by which to study interactions between DA and 5-HT neuronal systems. Using the recording system described, the relative 5-HT and DA agonist and antagonist properties of new compounds may be determined. Furthermore, suppression of myoclonus by DA agonists may be employed as a method for screening potential anti-Parkinsonian agents.