Clinical neuroprotection in Parkinson's disease — Still waiting for the breakthrough
Introduction
Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's and is estimated to affect 1% of individuals over the age of 65. In the most populous nations, the approximate number of PD patients over age 50 was 4.1 million in 2005 and, as worldwide life expectancy increases, is projected to reach 8.7 million in 2030 [1]. This development constitutes an enormous public health challenge for the future since affected individuals need to be identified and offered cost-effective medical treatment.
Before initiation of treatment, it is crucial to properly diagnose idiopathic PD, which is clinically characterized by the cardinal symptoms bradykinesia, rigidity, resting tremor and postural instability, and to differentiate the disease from disorders that may manifest with similar symptoms, such as multiple cerebral infarct state, drug-induced Parkinsonism or normal pressure hydrocephalus. Thus, cerebral imaging (preferably magnet resonance imaging) is recommended to exclude structural abnormalities before diagnosing PD. Furthermore, PD needs to be distinguished from Parkinson's plus syndromes such as multiple system atrophy, progressive supranuclear palsy and corticobasal degeneration. Differential diagnosis of PD has shown to be difficult, as even movement disorder specialists misdiagnose about 10% of cases [2]. Therefore, functional imaging of the post synapse can be helpful in order to differentiate PD from Parkinson-plus syndromes that usually show no response to antiparkinsonian medication and have a worse prognosis.
Data from placebo groups of randomized controlled intervention trials of 6 to 18 month duration have been able to provide information on the progression of motor dysfunction in the natural course of PD by using the Unified Parkinson's Disease Rating Scale (UPDRS) [3], [4], [5], [6], [7]. From these trials, annual decline in total UPDRS score in early PD patients without medication can be averaged to 8 to 11 points. Due to this rapid deterioration in motor function, untreated PD can be expected to result in severe disability within less than 10 years [8], [9], [10] emphasizing the need for therapies that slow the progression of the underlying neurodegenerative processes of the disease and the development of disability. In recent years, it has however become clear that there is also considerable heterogeneity in the natural course of PD [11] and that a classification based on phenotypic patterns of the disease may be useful for a better prediction of disease progression for different groups of patients [12]. For example, tremor dominant PD has been associated with slower disease progression and less cognitive impairment than PD with predominant postural instability and gait disturbance [12]. Furthermore, an increasing age at disease onset has been shown to be associated with higher Hoehn and Yahr stages, level of disability and lower perceived quality of life [13].
Section snippets
The need for neuroprotective treatment
Since the first intravenous administration of levodopa in PD patients by Birkmeyer and Hornykiewicz [14] substantial progress has taken place in the development of symptomatic dopaminergic therapies. Some studies after the introduction of levodopa and dopamine agonists demonstrated a prolonged latency from symptom onset to the development of significant disability in comparison to the pre-levodopa era and thus nourished hope that antiparkinsonian treatment could also have disease-modifying
Limitations of clinical neuroprotection trials
In the past, numerous clinical trials attempted to investigate neuroprotective properties of various substances used for the treatment of PD. It is crucial to understand the limitations of these studies in order to determine which trial methodologies are sufficient to identify substances that slow or halt the progressive loss of dopaminergic projections from the substantia nigra to the striatum. Since the number of remaining dopaminergic neurons cannot be measured directly in vivo, outcome
Results of clinical neuroprotection trials
Several randomized controlled trials have intended to examine the effect of therapeutic agents on disease progression in PD (Table 1), which will be discussed according to substance classes in alphabetical order.
Conclusions
Despite numerous ambitious efforts in the search for disease-modifying therapies in PD, clinical trials so far have failed to identify any compound with compelling proof for neuroprotective properties. The results of clinical studies have been repeatedly disappointing, but also teach us important lessons for the future evaluation of neuroprotective therapies in PD and call for a change in our approach to this topic [122].
The striking discrepancy between often promising data from preclinical
References (129)
- et al.
TCH346 prevents motor symptoms and loss of striatal FDOPA uptake in bilaterally MPTP-treated primates
Neurobiol Dis
(2003) - et al.
TCH346 as a neuroprotective drug in Parkinson's disease: a double-blind, randomised, controlled trial
Lancet Neurol
(2006) - et al.
Discovery of CEP-1347/KT-7515, an inhibitor of the JNK/SAPK pathway for the treatment of neurodegenerative diseases
Prog Med Chem
(2002) - et al.
Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1, 2, 5, 6-tetrahydropyridine
Life Sci
(1985) - et al.
Deficiencies in complex I subunits of the respiratory chain in Parkinson's disease
Biochem Biophys Res Commun
(1989) - et al.
Biochemical, physiological and medical aspects of ubiquinone function
Biochim Biophys Acta
(1995) - et al.
Coenzyme Q10 attenuates the 1-methyl-4-phenyl-1, 2, 3, tetrahydropyridine (MPTP) induced loss of striatal dopamine and dopaminergic axons in aged mice
Brain Res
(1998) - et al.
Pilot trial of high dosages of coenzyme Q10 in patients with Parkinson's disease
Exp Neurol
(2004) - et al.
Creatine and cyclocreatine attenuate MPTP neurotoxicity
Exp Neurol
(1999) - et al.
Creatine increase survival and delays motor symptoms in a transgenic animal model of Huntington's disease
Neurobiol Dis
(2001)
Vitamin E therapy in Parkinson's disease
Toxicology
Dopamine D2 receptor-mediated antioxidant and neuroprotective effects of ropinirole, a dopamine agonist
Brain Res
Rationale for and use of NMDA receptor antagonists in Parkinson's disease
Pharmacol Ther
Riluzole prevents MPTP-induced parkinsonism in the rhesus monkey: a pilot study
Eur J Pharmacol
Neuroprotective effects of riluzole on a model of Parkinson's disease in the rat
Neuroscience
A double-blind, placebo-controlled and longitudinal study of riluzole in early Parkinson's disease
Parkinsonism Relat Disord
Differential neurotoxicity induced by L-DOPA and dopamine in cultured striatal neurons
Brain Res
Effects of bromocriptine and/or L-DOPA on neurons in substantia nigra of MPTP-treated C57BL/6 mice
Brain Res
Comparison of neurotoxicity following repeated administration of L-dopa, D-dopa, and dopamine to embryonic mesencephalic dopamine neurons in cultures derived from Fisher 344 and Sprague–Dawley donors
Cell Transplant
Disease-related and drug-induced changes in dopamine transporter expression might undermine the reliability of imaging studies of disease progression in Parkinson's disease
Parkinsonism Relat Disord
Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030
Neurology
Accuracy of clinical diagnosis of Lewy body Parkinson's disease
Neurology
Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease
N Engl J Med
Effect of lazabemide on the progression of disability in early Parkinson's disease
Ann Neurol
Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline
Arch Neurol
Levodopa and the progression of Parkinson's disease
N Engl J Med
A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease
Arch Neurol
The need for neuroprotective therapies in Parkinson's disease
Neurology
Disability and progression in Parkinson's disease
Acta Neurol Scand
Parkinsonism: onset, progression and mortality
Neurology
The natural history of Parkinson's disease
J Neurol
The heterogeneity of idiopathic Parkinson's disease
J Neurol
Clinical heterogeneity in newly diagnosed Parkinson's disease
J Neurol
L-3, 4-dioxyphenylalanin (=DOPA) Effekt bei der Parkinson-
Wien Klin Wochenschr
The Sydney multicentre study of Parkinson's disease: progression and mortality at 10 years
J Neurol Neurosurg Psychiatry
Levodopa in the treatment of Parkinson's disease
J Neural Transm Suppl
A five-year study of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or levodopa
N Engl J Med
Dyskinesias and motor fluctuations in Parkinson's disease. A community-based study
Brain
Low-dose L-dopa therapy in Parkinson's disease: a 6-year follow-up study
Neurology
End-of-dose deterioration in non ergolinic dopamine agonist monotherapy of Parkinson's disease
J Neurol
Safety and efficacy of pramipexole in early Parkinson disease. A randomized dose-ranging study
JAMA
DATATOP: a decade of neuroprotective inquiry. Deprenyl and tocopherol antioxidative therapy of parkinsonism
Ann Neurol
A “cure” for Parkinson's disease: can neuroprotection be proven with current trial designs?
Mov Disord
Levodopa and the progression of Parkinson's Disease
N Engl J Med
A new look at levodopa based on the ELLDOPA study
J Neural Transm Suppl
A controlled trial of rasagiline in early Parkinson disease: the TEMPO Study
Arch Neurol
Observations and suggestions on antidementia drug development
Alzheimer Dis Assoc Disord
Are delayed-start design trials to show neuroprotection in Parkinson's disease fundamentally flawed?
Mov Disord
Timing of treatment initiation in Parkinson's disease: a need for reappraisal?
Ann Neurol
Does selegiline delay progression of Parkinson's disease? A critical re-evaluation of the DATATOP study
J Neurol Neurosurg Psychiatry
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Protective effects of evening primrose oil on behavioral activities, nigral microglia and histopathological changes in a rat model of rotenone-induced parkinsonism
2023, Journal of Chemical NeuroanatomyCitation Excerpt :In addition to the fact that we have not encountered specific treatment to delay or inhibit the process of neurodegeneration. All of these necessitate the crucial need of novel innovative neuroprotective selections and interventions (Löhle and Reichmann, 2010). Evening primrose oil [EPO] is acquired by cold-pressing or solvent extraction from plant seeds [Oenothera biennis].
Utilization of Chinese herbal medicine and its association with the risk of fracture in patients with Parkinson's disease in Taiwan
2018, Journal of EthnopharmacologyCitation Excerpt :PD treatment mainly involves pharmacological therapies applying levodopa, dopamine agonists, monoamine oxidase B (MAO-B) inhibitors, anticholinergic agents, amantadine, and catechol-O-methyl transferase (COMT) inhibitors (Connolly and Lang, 2014). However, none of these therapeutic agents can decelerate or halt the progression of the disease (Lohle and Reichmann, 2010). In Taiwan, traditional Chinese medicine (TCM) is among the mainstream complementary and alternative medicine (CAM) therapies.
Aligning physiology with psychology: Translational neuroscience in neuropsychiatric drug discovery
2017, Neuroscience and Biobehavioral ReviewsCitation Excerpt :For example, the identification of family-linked mutations underlying the development of disorders such as Alzheimer’s (Wahlund et al., 1999) or Parkinson’s (Kalinderi et al., 2016) disease led to the development of transgenic animals with the same mutations (Dawson et al., 2010; Laurijssens et al., 2013). Unfortunately, there has been little clinical success of compounds discovered using these genetic models (Delrieu et al., 2012; Lohle and Reichmann, 2010), leading to the questioning of the utility of animal models of these disorders. Recent results from immunotherapy of Alzheimer’s disease, for example, have indicated that while amyloid levels may be consistently reduced, degree of cognitive improvement is minimal (Spencer and Masliah, 2014; Tayeb et al., 2013).
Early alterations of mitochondrial morphology in dopaminergic neurons from Parkinson's disease-like pathology and time-dependent neuroprotection with D2 receptor activation
2016, MitochondrionCitation Excerpt :Alternatively, quinpirole may only prevent the death of a specific subtype of DA neuron, although it does not appear to affect mitochondrial morphology in only a subtype of DA neurons. While our results suggest that quinpirole may slow the progression of the disease, clinical studies find that D2R agonists fail to prevent further progression of actual PD (Harikrishna Reddy et al., 2014; Löhle and Reichmann, 2010). One possible explanation is that these therapies are prescribed too late in the disease, i.e., too much degeneration has already occurred and the cells remaining are beyond saving.