Parkinsons Disease as a Common Progressive Neurodegenerative Disorder - Research Paper Example

Evidence for and against the claim that dopamine agonists and monoamine oxidase inhibitors are neuroprotective in patients with Parkinson’s disease Table of contents No. Title Page No. Glossary 3 1. Introduction 4 2. Dopamine agonist: Brief History 5 2.1 Dopmaine receptor agonists in PD: Neurotoxic or Neuroprotective? 6 3. Monoamine Oxidase Inhibitors 11 3.1 Monoamine Oxidase Inhibitors: The Neuurtoxic Effects 4. Conclusions 14 5. References 15 List of Tables and Figures Title Page no. Figure:1 Figure: The diagrammatic representation of DAnergic therapy for Parkinson`s disease. The site of action of different therapeutic agents are shown in the boxes. 5 Figure: 2 Relative Potentcies of DA in early Parkinson`s disease 6 Figure: 3 Dopamine agonist in PD 6 Figure 4. Cumulative probability of reaching the first dopaminergic complication (A) and the individual complications wearing off (B), dyskinesias (C), and freezing (D) by treatment assignment. First dopaminergic complication is defined as the first occurrence of wearing off, dyskinesias, or on-off fluctuations 7 Figure:5 Development of dyskinesia comparing initial treatmnet with (A) Pramipexole; and (B) ropinirole compared with levadopa . 9 Table: 1 The result characteristic of Meta-analysis of MAO-B inhibitor. 11 Glossary Parkinson`s Disease PD Striatal dopamine DA Dopaminergic DAergic precursor levodopa LD Bromocriptine BR Dopamine Agonist DA Monoamine oxidase inhibitors MAO Monoamine oxidase inhibitors-Type A MAO-A Monoamine oxidase inhibitors-Type B MAO-B Subthalamic Nucleus STN 6-hyroxydopamine,1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine MPTP (±)2-(N-phenethyl-N-propyl)amino-5-hydroxytetralin PPHT Phenyl ethyl amine PE Keywords: Parkinson`s Disease, Dopamine Agonist, Monoamine oxidase inhibitor, Neurodegerative, Levodopa. 1. Introduction Parkinson`s disease (PD) is a common progressive neurodegenerative disorder that is characterized by the loss of striatal dopamine (DA) as a result of degeneration of dopaminergic (DAergic) neurons in sunstantia nigra, thus, produces progressive disability. The clinical manifestation of this disease includes resting tumor, rigidity, bradykinesia and disturbance of posture and pace (1). The main features of PD are trembling (tremor), increased muscle tone (rigidity), slowness of movement (bradykinesia) and disturbance of posture and balance. These manifestations are encountered because of a depletion of the neurotransmitter dopamine due to the progressive loss of nigral neurons in the brain (2-4). There is a general approach followed to the treatment of patients with PD, that is the administration of drugs to assuage the symptoms. One common approach is the restoration of dopamine by administering its precursor levodopa (LD). LD provides immediate and satisfactory control of most symptoms. But, after two to five years of stable response to LD treatment, approximately half of these patients develop motor complications some of which are thought to be highly correlated with prolonged LD exposure (5,6). It is because of the above mentioned setbacks of the PD therapy using LD new therapeutic approaches have been explored. 2. Dopamine agonist: Brief History In 1974 bromocriptine (BR), a dopamine agonist, was first introduced as an adjunct to conventional LD therapy in PD patients with motor complications (7). Figure:1 The diagrammatic representation of DAnergic therapy for Parkinson`s disease. The site of action of different therapeutic agents are shown in the boxes. (8) Dopamine agonists bypass the degenerating nigral neurons and stimulate the dopamine receptors directly (9, 10). BR monotherapy or a combination of LD and BR as a first line treatment in early PD is one of the possibiltyin treating PD. These treatment strategies would allow either a later start (BR monotherapy) or a lower dose of LD (BR/LD combination therapy), thus potentially preventing or delaying the onset of the late complications of LD therapy.(11,12) 2.1 Dopmaine receptor agonists in PD: Neurotoxic or Neuroprotective? DAergic replacement therapy with the precursor levodopa or agonists,that stimulate the dopamine receptor is effective in ameliorating various signs and symptoms of the early onset of PD. Although, progressive degeneration finally leads to severe motor,mental, and functional disability. There is an increasing evidence that suggests that levodopa and dopamine receptor agonist do not only have symptomatic effects, but also accelerate or slow down the dopaminergic degeneration of PD. There is enough evidence in the recent researches pertaining to the effects of levodopa having both toxic and protective effect of dopaminergic neurons (13,14). The studies also demonstrated that dopamine receptor agonist exerts direct antioxidant and receptor-mediated antiapoptotic effects. Moreover, the dopamine receptor agonists protect cultured dopaminergic neurons from levodopa toxicity. (15-17). Figure: 2 Relative Potentcies of DA in early Parkinson`s disease (18). Figure: 3 Dopamine agonist in PD (18). Dopamine agonists (DA) have long been established to be effective drugs for the symptomatic treatment of the motor features of PD patients when used as monotherapy or as an adjunct to L-dopa (19). The side effects that these agonists possess are similar to L-dopa, but they are associated with greater frequency of sleep disturbances and cognitive problems. The problems include confusion and hallucinations, especially in the very elderly or in those with pre-existing cognitive deficits.1 But there is an important advantage of using dopamine receptor agonist over L-Dopa that it reduces the risk of inducing development of motor complications particularly dyskinesias. There is a reduced risk of motor complications observed in bromocriptine in openlabel trials (20-22) and with ropinirole, pramipexole, and cabergoline in compared to L-Dopa in prospective, double-blind controlled trials. (23–25). Figure 4. Cumulative probability of reaching the first dopaminergic complication (A) and the individual complications wearing off (B), dyskinesias (C), and freezing (D) by treatment assignment. First dopaminergic complication is defined as the first occurrence of wearing off, dyskinesias, or on-off fluctuations. (26) There is enough clinical evidence that suggest the neuroprotective nature of DA in PD. In tissue culture, DA have the capacity to enhance growth of cultured dopamine neurons and protects them form variety of toxins (27-32). There is a substantial evidence that shows that the agonist are capable of protecting nigrostriatal dopamine neurons from the toxic effects of 6-hyroxydopamine,1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP),34–36 excytotoxicity,37 ischemia, and methamphetamine 33. Dietary supplementation with low-dose pergolide reduces the age-related loss of dopamine fluorescence and accumulation of liprofuschin in the nigrostriatal system of Fischer rats. Very recently, it was shown that the administration of dopamine agonist pramipexole protect substantia nigra pars compacta (SNc) dopaminergic neurons in MPTP-lesioned marmosets (14,34,47). Two Cochrane reviews of bromocriptine therapy (11,12) and the Movement Orders Society Task Force (Movement Disorders Society Task Force.Management of Parkinson’s disease: an evidence based review, 2002) discuss the symptomatic effects of agonists in early PD. The latter concluded that romocriptine, pergolide, pramipexole, and ropinirole were clinically useful in early PD, whereas lisuride was possibly useful, and cabergoline was investigational. Cabergoline, pramipexole, and ropinirole were thought efficacious in delaying motor complications. Similarly, bromocriptine was likely efficacious and in case of lisuride and pergolide there was insufficient evidences obtained to comment. Similarly, regarding the symptomatic control of parkinsonism, pergolide, pramipexole, and ropinirole were rated as efficacious compared with bromocriptine and lisuride, which were likely efficacious, and with cabergoline, for which there was insufficient evidence. Although, the review mentioned that there are adverse effects of dopaminergic drugs with all agonists, but they all can be rated as acceptable without specialised monitoring. (35) Figure: 5 Development of dyskinesia comparing initial treatmnet with (A) Pramipexole; and (B) ropinirole compared with levadopa. (36) The mechanisms whereby DA might provide Neuroprotective Effects in PD is summarized by Schapira and Olanow., 2003 and they are as follows: a. L-Dopa Sharing; b. Antioxidant effects; c. Antireceptor effects; d. Anti-apoptotic effect;s e. Amelioration of Subthalamic Nucleus (STN)-Mediated Excitotoxicity. (6) Nowadays, DA receptor agonists are often regarded as first choice in de novo and young parkinson`s patients to delay the onset of levodopa therapy.While, in the advanced stages of the disease, they are also used as adjunct therapy together with levodopa to retard the development of motor complications. Apart from their clinical role in treating PD patients, lab studies have also suggested antioxidative and neuron-rescuing effects of DA receptor agonists either in vivo or in vitro. This involves reduced DA turnover following autoreceptor stimulation and direct free radical scavenging activity.(37) 3. Monoamine Oxidase Inhibitors Monoamine oxidase inhibitors (MAO) are categorized both as Type A (MAO-A) and Type B(MAO-B). In humans, the type A is found in intestinal tract (it provides protection form exogenous amines). The MAO-B is found in brain (38) and it regulates both releasable stores and free intraneuronal concentration of dopamine. The primary antiparkinsoniam mechanism of action of these (MAO-B) inhibitors lies in its ability to prevent dopamine degradation in the brain. (39,40). Seligniline, a MAO-B inhibitor is approved as a adjunctive therpy to levodopa and is been avialbale as an oral tablet in US for almost 10 years now. Another siganlling moecules of Seligniline is Zydis Selingiline, which is placed on the the tongue and thus absorbed through the buccal mucosa.Rasagniline, a second generation of serigniline is recently approved in US and can be used as adjuct with levodopa. (41). The effect of administration of MAO-B inhibitors on rat striatal neurone responses to dopamine was studied by (-)-Deprenyl is selective inhibitor of MAO-B and is also known for treatmnet in PD. It has also been reported to sho a potentiation of rat striatal neuron responses to two DA apomorphine and ( ± )2-(N-phenethyl-N-propyl)amino-5-hydroxytetralin (PPHT). 2-phenylethylamine (PE), also acts as a potent neuromodulator of DOPAnergic responses and that of MAO-B inhibitors and also may potentiate neural responses to dopamine via the indirect echanism of elevation if PE following MAO-B inhibition. (42) Table: 1 The Result Characteristic of Meta-analysis of MAO-B inhibitor (43). MAO-B was tested as potential inhibitor as meta-analysis of 17 randomized trials that involved 3525 patients. The study suggested that the early use of seglinine delays the need of levodopa and that when siginiline is given with levodopa, low doases of levodopa is neded. The study also suggested that seglinine decreases the incidence of motor fluctuations without substantial side effects or increased mortality. The result characteristics of these study is summarized in Table: 1. However, more number of trials has to be performed to study the relative benefits and rsiks of MAO-B. (43). 3.1 MAO-B: The neurotoxic effects Although MAO-B inhibitors are effective antidepressants, but its usage is limited because of unwanted side effects and the possibility of a tyramine-induced hypertensive crisis (cheese reaction). (-)-Deprenyl is a selective MAO type B inhibitor, may be safer and have fewer side effects, but its antidepressant efficacy is uncertain. A double-blind placebo-controlled study was carried out in depressed outpatients who were treated with (-)-deprenyl in an MAO type B selective dose range and at a higher nonselective dose range. (-)-Deprenyl did not have a statistically significant antidepressant effect after three weeks of treatment at doses of 10 mg/d. However, after six weeks and at higher doses, (-)-deprenyl was superior to placebo in antidepressant effect with a positive response rate of 50%. Although no hypertensive crises were seen. The researchers also concluded that (-)-deprenyl is an effective antidepressant in a dose range where it is distinguished by the absence of many of the side effects typical of nonselective MAO inhibitors (44). There are also reports of social phobia (DSM-III-R) in the patients randomized with the treatment of MAO-B inhibitor, brofarmine (45). Apart for neuroprotective effects exerted by both Seglinine and Rasagniline, there are evidences that show the neuroprotetive advantage of rasagiline over selegiline. Selegiline reduces oxygen–glucose deprivation induced cell death by 30%. In laboratory, when the cultures are treated with rasagiline at similar concentrations, cell death induced by oxygen–glucose deprivation was reduced by 45–55%. -methamphetamine, a major selegiline metabolite, but not 1-R-aminoindan, the major rasagiline metabolite, enhanced oxygen–glucose deprivation-induced cell death by 70%. Morover, both metabolites lack neurotoxicity under normal conditions. Concomitant exposure of the cultures under oxygen–glucose deprivation, to a combination of either selegiline and -methamphetamine or rasagiline and 1-R-aminoindan, indicated that -methamphetamine, but not 1-R-aminoindan, blocked the neuroprotective effect of the parental drug (46). 4. Conclusions: Since the introduction of bromocriptine in 1974, great attention has been paid to DA receptor agonists for treating PD. They are successfully used in the initial treatment of patients with de novo PD either as monotherapy or combined with low doses of levodopa. The beneficial effects of DA receptor agonists as antiparkinsonian drugs is based on their ability to produce direct and continuous stimulation of both presynaptic (autoreceptors) and postsynaptic DA receptors. More recently, DA receptor agonists have been shown to produce neuroprotective activites in experimental models either in vivo or in vitro. (1) However, there is shortage in the literature concerning the neuroprotective role of DA receptor agonists in parkinsonian patients as there is no objective method to check thoroughly for DAergic cell death. Taken together, one can conclude that there is no drug that has been unequivocally proven to be neuroprotective in the parkinsonian patient until now. On the other hand, DA receptor agonists are promising in this respect and ongoing research with more accurate neuroimaging devices should decrease the distance between the data obtained from experimental models and clinical studies. (1) As far as MAO-B s are concerned, these drugs clearly provide symptomatic benefit and probably entail no risk of increased mortality if they are used as monotherapy and in younger and otherwise healthy patients. However, as Ives et al conclude, that the use of MAO-B with comparative efficacy with other first line drugs, particularly dopamine agonists are lacking (43). It is very wisely said that the drugs used to treat Parkinson’s disease show a seesaw effect—those that are better at improving motor disability tend to have greater risks of complications and vice versa. 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