Targeting Mitochondria for Neuroprotection in Parkinson Disease

JAMA neurology 03/2014; 71(5). DOI: 10.1001/jamaneurol.2014.64
Source: PubMed
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    ABSTRACT: The neurotoxin MPTP induces nigral dopaminergic cell death in primates and produces a partial model of Parkinson's disease (PD). Pramipexole is a D2/D3 dopamine receptor agonist used in the symptomatic treatment of PD, and which also protects neuronal cells against dopaminergic toxins in vitro. We now demonstrate that pramipexole partially prevents MPTP toxicity in vivo in a primate species. Common marmosets were repeatedly treated with pramipexole either before, coincidentally with, or after low-dose MPTP treatment designed to induce a partial lesion of the substantia nigra. Animals pretreated with pramipexole had a significantly greater number of surviving tyrosine hydroxylase (TH) positive neurones in the pars compacta of the substantia nigra. Pramipexole pretreatment also prevented degeneration of striatal dopamine terminals. Treatment with pramipexole concurrently with MPTP or following MPTP did not prevent TH-positive cell loss. Pramipexole pretreatment appears to induce adaptive changes that protect against dopaminergic cell loss in primates.
    Full-text · Article · Apr 2006 · Journal of Neurochemistry
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    ABSTRACT: Recent data has indicated that the traditional view of Parkinson's disease (PD) as an isolated disorder of the nigrostriatal dopaminergic system alone is an oversimplification of its complex symptomatology. Aside from classical motor deficits, various non-motor symptoms including autonomic dysfunction, sensory and cognitive impairments as well as neuropsychiatric alterations and sleep disturbances are common in PD. Some of these non-motor symptoms can even antedate the motor problems. Many of them are associated with extranigral neuropathological changes, such as extensive α-synuclein pathology and also neuroinflammatory responses in specific brain regions, i.e. microglial activation, which has been implicated in several aspects of PD pathogenesis and progression. However, microglia do not represent a uniform population, but comprise a diverse group of cells with brain region-specific phenotypes that can exert beneficial or detrimental effects, depending on the local phenotype and context. Understanding how microglia can be neuroprotective in one brain region, while promoting neurotoxicity in another, will improve our understanding of the role of microglia in neurodegeneration in general, and of their role in PD pathology in particular. Since neuroinflammatory responses are in principle modifiable, such approaches could help to identify new targets or adjunctive therapies for the full spectrum of PD-related symptoms.
    Full-text · Article · Jun 2012 · Progress in Neurobiology
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    ABSTRACT: Parkinson’s disease (PD) affects about 1% of the over 60 population and is characterized by a combination of motor symptoms (rest tremor, bradykinesia, rigidity, postural instability, stooped posture and freezing of gait [FoG]) and non-motor symptoms (including psychiatric and cognitive disorders). Given that the loss of dopamine in the striatum is the main pathochemical hallmark of PD, pharmacological treatment of the disease has focused on restoring dopaminergic neurotransmission and thus improving motor symptoms. However, the currently licensed medications have several major limitations. Firstly, dopaminergic medications modulate all the key steps in dopamine transmission other than the most powerful determinant of extracellular dopamine levels: the activity of the presynaptic dopamine transporter. Secondly, other monoaminergic neurotransmission systems (ie noradrenergic, cholinergic and glutamatergic systems are altered in PD and may be involved in a variety of motor and non-motor symptoms. Thirdly, today’s randomized clinical trials are primarily designed to assess the efficacy and safety of treatments for motor fluctuations and dyskinesia. Fourthly, there is a need for disease- modifying treatments (DMTs) that slow disease progression and reduce the occurrence of the very disabling disorders seen in late-stage PD.
    Full-text · Article · Sep 2013 · Clinical Therapeutics
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