Parkinson’s disease model

There is evidence from experimental Parkinson s disease models that excessive activation of NMDA receptors might be an important factor for induction of Parkinson s disease. However, the involvement of NMDA receptors has not been shown in all parkinsonian models. 

In a recent study, scientists directed mouse embryonic stem cells to differentiate into DA neurons by introducing the gene Nurr 1. When transplanted into the brains of a rat model of Parkinson s disease, these stem cell-derived DA neurons reinnervated the brains of the mouse Parkinson s disease model, released dopamine, and improved motor function. 

Long J, Gao H, Sun L, Liu J, Zhao-WUson X (2009) Grape extract protects mitochondria from oxidative damage and improves locomotor dysfunction and extends lifespan in a Drosophila Parkinson s disease model. Rejuvenation Res 12 321-331 Lopez-Miranda J, Delgado-lista J, Perez-Martinez P, Jimenez-G6mez Y, Puentes F, Ruano J, Matin C (2007) Ohve oil and the haemostatic system. Mol Nutr Food Res 51 1249-1259... 

Applications of the methods described here will likely include investigations of disease states like Parkinson s disease models and perhaps more. It will also be useful to determine the effect of drugs on vesicular content and therefore provide novel targets for pharmaceuticals related to vesicles and disease. 

A large number of molecules have provided experimental evidence of neuroprotection in in vitro and in vivo models of Parkinson s disease and many of these putative neuroprotective substances are now the objects of clinical trials. Recently, a team of experts has identified potential neuroprotective agents to be tested in pilot studies [4]. Twelve compounds have been considered for clinical trials caffeine, coenzyme Q 10, creatine, estrogen, GPI1485, GM-1 ganglioside, minocycline, nicotine, pramipexole, ropinirol, rasagiline, and selegiline (for individual discussion see [4]). 

Chan CS, Guzman JN, Ihij ic E, Mercer JN, Rick C, Tkatch T, Meredith GE, Sunneier DJ (2007) Rejuvenation protects neurons in mouse models of Parkinson s disease. Nature 447 1081-1086... 

Catechol-O-Methyltransferase. Figure 4 Rat model of Parkinson s disease. Comparison of entacapone, tolcapone and CGP 28014 in the rat turning model of Parkinson s disease [4]. 

Parkinson s disease (PD) 1. In a non-human primate model of PD endocannabinoid levels are elevated in the basal ganglia and may contribute to the generation of parkinsonian symptoms and/or to expression of levodopa-induced dyskinesia. The cerebrospinal fluid of untreated PD patients contains elevated levels of AEA 1. CB-) antagonists or biosynthesis inhibitors... 

The neural mechanisms underlying the placebo effect are only partially understood and most of our knowledge comes from pain, although recently Parkinson s disease, immune and endocrine responses, and depression have emerged as interesting models (Fig. 1). In each of these... 

Feany, MB and Bender, WW (2000) A Drosophila model of Parkinson s disease. Nature 404 394-398. 

Astaxanthin is a powerful bioactive antioxidant and has demonstrated efficacy in animal and human models of macular degeneration, a cause of blindness in a large population. It is also helpful in treating Alzheimer s and Parkinson s diseases and is known to offer protection against cancer. 

COMMENT I would like to know why you thought the amphetamine model of dopamine neurotoxicity might be more suitable or more revealing for the study of Parkinson s disease than the MPTP model. 

I have argued in the past that looking further at amphetamine toxicity in terms of understanding the mechanism by which those neurons die, might be more revealing. That is not to belittle the importance of MPTP as a model of Parkinson s disease. Certainly in terms of effects in the MPTP-treated monkeys, these animals are of unquestioned value. But in terms of the mechanism by which the neurons die, that was the point that I was questioning, whether the MPTP model would mimic as well as the amphetamine model. 

It has been revealed that cannabinoids exhibit neuroprotectant activities in both in vitro and in vivo models [249]. The neuroprotective effects are mainly based on regulation of transmitter release, modulation of calcium homeostasis, anti-oxidant properties and modulation of immune responses. A number of neurological disorders, including brain trauma, cerebral ischaemia, Parkinson s disease and Alzheimer s disease represent possible therapeutic areas for cannabinoids with neuroprotective properties. Cannabinoids are also suggested to have potential against glaucoma due to their neuroprotective nature and lowering of intraocular pressure [250]. 

Jiao, S., Gurevich, V., and Wolff, J. A. (1993). Long-term correction of rat model of Parkinson s disease by gene therapy. Nature 362 450- 153. 

DR Cooper, C Marrel, H Van de Waterbeemd, B Testa, P Jenner, C D Marsden. L-Dopa esters as potential prodrugs Behavioural activity in experimental models of parkinson s disease. J Pharm Pharmacol 39 627-635, 1987. 

Kim, J. H., Auerbach, J. M., Rodriguez-Gomez, J.A. Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson s disease. Nature 418 50-56,2002... 

Alzheimer s disease, Parkinson s disease, Huntington s disease and amyotrophic lateral sclerosis (ALS) are four prominent fatal neurodegenerative disorders that involve the death of specific populations of neurons (see details in respective chapters). Studies of patients and animal and culture models have provided considerable insight in the cellular and molecular mechanisms responsible for synaptic dysfunction and neuronal degeneration in each disorder [18], In Alzheimer s disease, abnormalities in proteolytic processing of the amyloid precursor protein, due to gene... 

The new work has established that a neurodegenerative pathway leading from soluble to insoluble, filamentous a-synuclein is central to Lewy body diseases and multiple system atrophy. The development of experimental models of a-synucleinopathies has opened the way to the identification of the detailed mechanisms by which the formation of inclusions causes disease. These model systems have also made it possible to identify disease modifiers that may well lead to the development of the first mechanism-based therapies for these diseases. At a conceptual level, it will be important to understand whether a-synuclein has a role to play in disorders, such as autosomal-recessive juvenile forms of parkinsonism caused by mutations in the Parkin, DJ-1 and PINK-1 genes, or whether there are entirely separate mechanisms by which the dopaminergic nerve cells of the substantia nigra degenerate in Parkinson s disease and in inherited disorders with parkinsonism. 

Greenamyre, J. T., Eller, R. V., Zhang, Z. et al. Antiparkinsonian effects of remacemide hydrochloride, a glutamate antagonist, in rodent and primate models of Parkinson s disease [Comment]. Ann. Neurol. 35 655-661,1994. 

Inhibitors of MLK (MKKK) [27], MKK4, 7 and JNK [6,28,29] have been disclosed to date. CEP-1347, a semi-synthetic analog of the natural product K252a, inhibits MLKs in the JNK pathway with K = 17 nM [30-32]. This compound has shown neuroprotective effects in cellular and animal models [33]. CEP-1347, an orally available compound that was well tolerated in the clinic, was advanced to Phase II/III trials for assessing efficacy in Parkinson s disease. However, the clinical trial was stopped due to a lack of significant efficacy [34],... 

Figure 18.11 A putative model of the three proteins linked with Parkinson s disease. (From Barzilai and Melamed, 2003. Copyright 2003, with permission from Elsevier.)...

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