帕金森氏病的治疗策略_英文_

66 Neurosci Bull February 1, 2010, 26(1): 66-76. http://www.neurosci.cn DOI: 10.1007/s12264-010-0302-z ·Minireview· Corresponding author: Hong YUAN Tel: 86-10-88276190; Fax: 86-10-68211327 E-mail: blsphd2005@126.com Article ID: 1673-7067(2010)01-0066-11 Received date: 2009-03-02; Accepted date: 2009-11-02 Treatment strategies for Parkinson's disease Hong YUAN1, Zhen-Wen ZHANG1, Li-Wu LIANG1, Quan SHEN 1, Xiang-Dang WANG1, Su-Mei REN1, Hong-Jie MA1, Shu- Jun JIAO1, Ping LIU2 1Department of Integrated Traditional Chinese & Western Medicine, the General Hospital of Chinese People's Armed Police Forces , Beijing 100039, China 2Department of Immunology, Harbin Medical University, Harbin 150086, China © Shanghai Institutes for Biological Sciences, CAS and Springer-Verlag Berlin Heidelberg 2010 Abstract: Parkinson’s disease (PD) is caused by progressive degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNpc), resulting in the deficiency of DA in the striatum. Thus, symptoms are developed, such as akinesia, rigidity and tremor. The aetiology of neuronal death in PD still remains unclear. Several possible mechanisms of the degenera- tion of dopaminergic neurons are still elusive. Various mechanisms of neuronal degeneration in PD have been proposed, including formation of free radicals, oxidative stress, mitochondrial dysfunction, excitotoxicity, calcium cytotoxicity, trophic factor deficiency, inflammatory processes, genetic factors, environmental factors, toxic action of nitric oxide, and apoptosis. All these factors interact with each other, inducing a vicious cycle of toxicity causing neuronal dysfunction, atrophy and finally cell death. Considerable evidence suggests that free radicals and oxidative stress may play key roles in the pathogen- esis of PD. However, currently, drug therapy cannot completely cure the disease. DA replacement therapy with levodopa (L- Dopa), although still being a gold standard for symptomatic treatment of PD, only alleviates the clinical symptoms. Furthermore, patients usually experience severe side effects several years after the L-Dopa treatment. Until now, no therapy is available to stop or at least slow down the neurodegeneration in patients. Therefore, efforts are made not only to improve the effect of L- Dopa treatment for PD, but also to investigate new drugs with both antiparkinsonian and neuroprotective effects. Here, the advantages and limitations of current and future therapies for PD were dicussed. Current therapies include dopaminergic therapy, DA agonists, MAO-B inhibitor, COMT inhibitors, anticholinergic drugs, surgical procedures such as pallidotomy and more specifically deep brain stimulation of the globus pallidus pars interna (GPi) or subthalamic nucleus (STN), and stem cell transplantation. Keywords: Parkinson's disease; treatment strategy; pharmacological neuroprotection 1 Advantages and limitations of current therapy The diagnosis of Parkinson’s disease (PD) generally re- lies on the clinical observation of 4 cardinal motor signs: tremor, rigidity, bradykinesia, and balance impairment or pos- tural instability. These symptoms, typically the first three, can be improved by dopamine (DA) replacement therapy, and a “good” response to levodopa (L-Dopa) is mandatory for the diagnosis of the disease[1]. However, not all the par- kinsonian motor symptoms can be adequately controlled with dopaminergic medication. Furthermore, non-motor features, such as dysfunctions in autonomic, cognitive and psychiat- 67Hong YUAN, et al. Treatment strategies for Parkinson's disease ric systems, are also frequent and have become an important source of disability in patients. These non-motor features also tend to be poorly responsive to L-Dopa and may even be wors- ened by antiparkinsonian medications[2]. 1.1 Dopaminergic therapy L-Dopa is the precursor of DA, and dopaminergic therapy was first introduced by Horny- kiewicz in 1970. After 4 decades of universal usage, L-Dopa therapy remains a gold standard for the treatment of PD. Its major advantages include the relatively cheap price, and its ability to cross the blood-brain barrier after the conversion into DA. In the early stage of PD, L-Dopa is effective in ameliorating the motor symptoms, such as alleviation of aki- nesia or bradykinesia and rigidity, and partial response to tremor. This period is also known as the L-Dopa “honeymoon”. Besides, L-Dopa is the only drug that has been reported to improve life expectancy[3]. However, this therapy also has limitations in various facets. Firstly, after long-term usage, disabilities in motor symptoms such as speech, gait, posture, and balance, tend to deteriorate despite of the optimal L- Dopa therapy[4]. Non-motor features of PD are also present during the treatment, such as hallucination, cognitive impairment, and orthostatic hypotension. Besides, “wearing off” or “on-off” fluctuations and dyskinesia tend to worsen with continuing L-Dopa exposure, in approximately 50% of the patients after 5-year medication. Moreover, it has been reported that L-Dopa may accelerate the neuronal degenera- tion by way of oxidative metabolism[5], although this propo- sition is still controversial today. Finally, L-Dopa can neither halt or retard the disease progression, nor reverse the PD- associated biochemical abnormalities. 1.2 DA agonists The pharmacological effects of DA ago- nists are achieved by direct stimulation of postsynaptic DA receptors in the striatum[6]. Different from L-Dopa, DA ago- nists such as pramipexole, ropinirole and pergolide[7], can delay the onset of motor fluctuations. Similarly, patients re- ceiving combined treatment of cabergoline and L-Dopa[8] are 50% less likely to develop motor function problems than when receiving L-Dopa monotherapy. Although active on motor symptoms, DA agonists are less efficacious than L-Dopa and are relatively more expensive, especially the newest ones. For the side effects, sleep disturbances and cognitive prob- lems such as confusion and hallucination occur more frequently, especially in the elderly and in those with pre- existing cognitive deficits. In patients whose symptoms are severe enough to disturb their social or work activities, symp- tomatic treatment with L-Dopa combined with DA agonist may be necessary. DA agonists not only reduce the need of L-Dopa in clinical benefit, but also independently exert neuroprotective effects in PD patients. 1.3 Monoamine oxidase-B (MAO-B) inhibitors Selegiline is a selective MAO-B inhibitor that prevents the breakdown of DA. If given in conjunction with L-Dopa, selegiline could reduce motor response fluctuations and decrease the dos- age requirement for L-Dopa[9]. Besides, it attenuates parkin- sonian motor symptoms and delays the need for L-Dopa treat- ment by several months[10]. However, it has no impact on L- Dopa–resistant motor or non-motor features. And there is growing concern about an increased risk of mortality in PD patients receiving combined treatment of selegiline and L- Dopa, although it has not been confirmed by other studies. Moreover, the therapeutic effects could be counteracted by its many neurotoxic metabolites. Thus, a novel MAO-B in- hibitor rasagiline, is developed. Rasagiline is a selective and irreversible inhibitor of MAO-B. Recently, it has been evaluated in phase III clinical trials as an adjunct to L-Dopa therapy or as a monotherapy for early stage of PD[11]. The results of the trial demonstrate that rasagiline is effective as a monotherapy in early stage of PD. However, further studies are required to evaluate the long-term effects of rasagiline in PD. 1.4 Catechol-O-methyl transferase (COMT) inhibitors The main metabolite of L-Dopa is 3-O-methyldopa, and COMT contributes a lot for this process. COMT inhibitors can in- crease the plasma half-life of L-Dopa, which allows a rela- tively larger amount of L-Dopa crossing the blood-brain barrier. Thus, the inhibitors would lead to a more constant level of L-Dopa in the brain and consequently increase “on” time and decrease “off” time[12]. Entacapone is the sole COMT inhibitor available worldwide, since the use of tolcapone (the first discovered COMT inhibitor) was suspended in several countries including the European Union and restricted in the United States due to its side effect of liver toxicity. However, 68 Neurosci Bull February 1, 2010, 26(1): 66-76 research still indicates that tolcapone widens the levodopa therapeutic window, even in patients who have not benefited from entacapone. Thus tolcapone is indicated before patients are referred for more invasive procedures[13]. 1.5 Anticholinergic drugs Anticholinergic drugs are among the oldest and cheapest antiparkinsonian medications. They are useful adjuvants to L-Dopa treatment and are more effec- tive in ameliorating the mild symptoms of tremor and rigidity without alterations in bradykinesia. However, anticholinergic drugs often produce many side effects, such as dry mouth, sweating inhibition, blurred vision, and urinary retention. Reactions in the central nervous system (CNS), such as confusion, dementia and psychiatric symptoms are also com- mon and can be a particular problem in old patients. There are no data available concerning the effects of anticholin- ergics drugs on motor fluctuations, disease progression, or mortality. It is normally accepted that the anticholinergics drugs can antagonize the hyperactive cholinergic transmission, via blockade of postsynaptic muscarinic receptors, thereby restoring the balance between DA and acetylcholine (ACh) systems in the striatum. However, re- cent studies suggest that the underlying mechanisms are more complex than previously thought[14]. Extrastriatal and different neurotransmitter systems may be also involved in the effects exerted by antimuscarinic drugs. The mostly used cholinergic antagonists include trihexyphenidyl, benztropine, biperiden, orphenadrin, and procyclidine. They are effective in the treatment of tremor and drooling, but have limitations in other signs and symp- toms of PD. Amantadine is another old and cheap antiparkinsonian drug, and has modest effects on parkinsonian motor features. Its mechanism has not been clearly delineated, but recently it has been recognized as a weak antagonist for N-methyl-D- aspartate (NMDA) receptors. It has gained great interest in the treatment of PD due to its antidyskinetic effects, prob- ably related to the NMDA receptor antagonistic properties. The side effects of amantadine include confusion, hallucination, livedo reticularis and edema. NMDA receptor antagonists could potentially provide neuroprotective effects, and some reports suggest that amantadine may slow the rate of PD progression[15]. However, no clinical trials have been properly designed or performed. 1.6 Surgical procedures Currently, there has been a resur- gence of interest in surgical procedures such as pallidotomy and more specifically deep brain stimulation of the globus pallidus pars interna (GPi) or subthalamic nucleus (STN), in treating PD patients with severe disabilities that cannot be satisfactorily controlled with available medical therapies[16]. Neurosurgical procedures are limited to the symptoms or L- Dopa-induced dyskinesias so troublesome that they cause disabilities at home or at work. Before L-Dopa treatment, ste- reotaxic lesions of the thalamus (thalamotomy) are efficient targets for the treatment of tremor. Chronic deep brain stimu- lation is an alternative way to destructive lesions, and seems to produce a functional lesion in the target area, perhaps by depolarization block. The advantages lie that the stimulation parameters can be titrated to yield an optimum response over time and that it is reversible if adverse effects occur. However, although tremor can be controlled, akinesia is not alleviated. While response fluctuations are reduced, potentially surgery- related important side effects can occur in 2%-5% of the patients, including mechanical defects and infection. Besides, deep brain stimulation can not slow the disease progression and thus does not prevent worsening of gait and balance, cogni- tive disturbances, hypophonia or dysphagia[17]. Moreover, it is expensive and requires expertise in diagnosis, imaging, stereotactic surgery, neurophysiology, microelectrode recording, and postoperative management of the stimulator system, all of which greatly limit its widespread applicability. Transplantation of fetal dopaminergic cells can provide functional and biochemical improvement in animal models of PD[18]. Similar techniques have been applied in patients. PET scans have shown significant increases in (18F) fluorodopa uptake in the area around the graft that has been maintained for at least 6 years in several patients. Long–lasting symp- tomatic improvement has been reported in a majority of the grafted patients, and in the most successful cases, it is pos- sible to withdraw L-Dopa treatment. The main limitations of transplantation are the ethical, practical and safety issues concerning the tissue from aborted human foetuses and the large amount of tissue needed to obtain therapeutic effects. 69Hong YUAN, et al. Treatment strategies for Parkinson's disease Fetal nigral transplantation has been proved to be promising by open-label studies, but 2 consecutive placebo-controlled double-blind trials fail to meet their primary end point and have shown specific transplant-related side effects, such as off-medication dyskinesia[19]. Treatment with free-radical scavengers, caspase inhibitors or neurotrophic factors dur- ing the fetal cell preparation may improve DA neuron survival. Other approaches using stem cells and gene therapies are promising but have not been established to be effective or well tolerated in patients. Currently, no evidence has sup- ported that these surgical procedures could improve L-Dopa resistant symptoms or life expectancy, or delay the disease progression. In summary, currently available treatments to manage motor symptoms and motor complications are based on the DA replacement strategy and act by stimulating DA recep- tors (Table 1), consistent with the concept that striatal DA denervation plays a key role in the pathogenesis of motor symptoms. Non-dopaminergic medical treatments, such as anticholinergics, antiglutamate agents and surgical procedures, also have some antiparkinsonian effects but generally are used in a more restricted fashion, and no therapy provides more powerful antiparkinson effects than L-Dopa. 2 Future therapy: pharmacological neuro- protection Although the rate of nigral cell death is not exactly known, neuro-imaging techniques estimate that approximately 10% of the nigral cells die each year. Although the degenerative process is progressive, compensatory changes may develop, thus the deterioration is not a linear change. There is a gradual decline in the number of necrotic substantia nigra pars com- pacta (SNpc) and DA neurons of the basal ganglia with aging, even in the general population. In idiopathic PD, symptoms become apparent when 70%-80% striatal and approximately 60% nigral DA neurons are lost. Recent neuroimaging (PET and SPECT) and autopsy data indicate that there is a pre- clinical period of 4-5 years before the appearance of symptoms, with the disease progression relatively more rapid during the early phase than during the more advanced stage of the disease. Thus, it is possible to conduct neuroprotective intervention during the preclinical phase. The establishment of the neuroprotective strategy against PD should be based on the etiology and pathogenesis of dopaminergic cell death, as shown in Table 2[20]. 2.1 DA agonists DA agonists can not only reduce the need for L-Dopa, but also have an independent neuroprotective effect. In vitro and in vivo studies have demonstrated their capacity to protect dopaminergic and non-dopaminergic neu- rons[21], and the DA agonists have emerged as important candidates for disease modification in PD. In tissue culture, DA agonists could enhance the growth of cultured DA neu- rons and protect them from a variety of toxins. In vivo stud- ies indicate that these agonists can similarly protect nigrostriatal DA neurons from 6-OHDA and MPTP[22]. DA agonists can also protect non-dopaminergic neurons. Table 1. Current therapeutic interventions to treat motor fea- tures of PD Current therapeutic interventions Drugs Dopaminergic medications L-Dopa Dopamine agonists: apomorphine, bromocriptine, cabergoline, dihydroergocriptine, lisuride, pergolide, piribedil, pramipexole, ropinirole MAO-B inhibitor: selegiline COMT inhibitors: entacapone (tolcapone) Non-dopaminergic medications Antiglutamate: amantadine Anticholinergic: benztropine, biperiden, orphenadrin, procyclidine, trihexyphenidyl Surgery Lesion: thalamotomy, pallidotomy, subthalamotomy Deep brain stimulation: thalamus, pallidum, subthalamus nucleus Restorative Transplantation Trophic factors (GDNF) Stem cells Gene therapies Rehabilitation Physical, occupational and speech therapy 70 Neurosci Bull February 1, 2010, 26(1): 66-76 Protective effects have been observed in a variety of agonists, including bromocriptine, pergolide, pramipexole, apomorphine and ropinirole, and it remains to be determined whether this is a class effect and if any of these agents offers benefits that are more potent or more relevant to the clinical situation in PD[23]. Recent clinical studies of pramipexole and ropinirole also indirectly evaluated the rate of disease progression in patients treated with DA agonists compared with those tak- ing L-Dopa. Results show that initial treatment with pramipexole results in lower incidences of dyskinesias and wearing off compared with initial treatment with levodopa. Besides, initial treatment with levodopa results in lower inci- dences of freezing, somnolence, and edema and provided for better symptomatic control, as measured by the Unified Parkinson’s Disease Rating Scale, compared with initial treat- ment with pramipexole. Both options result in similar quality of life. Levodopa and pramipexole both appear to be reason- able options as initial dopaminergic therapy for PD, but they are associated with different efficacy and adverse-effect pro- files[24]. In vitro and in vivo data suggest that DA agonists exert neuroprotective effects via both DA receptor and non-DA receptor. Firstly, DA agonists exert a L-Dopa-sparing effect, thereby minimizing the formation of oxidative radicals de- rived from the metabolism of L-Dopa. This is the initial basis for considering that DA agonists might be neuroprotective in PD. Secondly, DA agonists might act as free radical scav- engers in both in vitro and in vivo systems, thus providing protective effects. Thirdly, DA agonists may exert antioxi- dant effects through the activation of presynaptic autoreceptors. DA agonists may inhibit DA synthesis, release, and metabolism, thus decreasing free radical production and the risk of oxidative damage. Finally, it is also possible that DA agonists exert neuroprotective effects by preventing STN- mediated excitotoxicity. Physiological and metabolic studies indicate that the STN, which uses glutamate as its neurotransmitter, is overactive in PD. Also, DA agonists may provide neuroprotection via the anti-apoptotic effect. R-Apomorphine (R-APO) is a DA D1/D2 receptor ago- nist acting both pre- and post-synaptically. Clinical trials in- Table 2. Neuroprotective strategies against PD Etiopathogenesis (multi-factorial) Neuroprotective agents Oxidative stress Antioxidants: Vit E, Tea, CoQ, red wine, N-acetyl cysteine, ascorbic acid Scavengers: salicylic acid, flavonoids Iron increase Iron chelators: apomorphine, desferoxamine DA decrease DA agonists: pramipexole, ropinirole, quinpirole, pergolide cabergoline, apomorphin