Neuroprotection by the Metabolic Antioxidant α-Lipoic Acid

Animal models are an important aid in experimental medical science because they enable one to study the pathogenetic mechanisms and the therapeutic principles of treating the functional disturbances (symptoms) of human diseases Once the causative mechanism is understood, animal models are also helpful in the development of therapeutic approaches exploiting this understanding On the basis of experimental and clinical findings Parkinson's disease (PD) became the first neurological disease to be treated palliatively by neurotransmitter replacement therapy The pathological hallmark of PD is a specific degeneration of nigral and other pigmented brainstem nuclei, with a characteristic inclusion, the Lewy body, in remaining nerve cells There is now a lot of evidence that degeneration of the dopaminergic nigral neurones and the resulting striatal dopamine-deficiency syndrome are responsible for its classic motor symptoms akinesia and bradykinesia PD is one of many human diseases which do not appear to have spontaneously arisen in animals The characteristic features of the disease can however be more or less faithfully imitated in animals through the administration of various neurotoxic agents and drugs disturbing the dopaminergic neurotransmission The cause of chronic nigral cell death in PD and the underlying mechanisms remain elusive The partial elucidation of the processes underlie the selective action of neurotoxic substances such as 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), has however revealed possible molecular mechanisms that give rise to neuronal death Accordingly, hypotheses concerning the mechanisms of these neurotoxines have been related to the pathogenesis of nigral cell death in PD The present contribution starts out by describing some of the clinical, pathological and neurochemical phenomena of PD The currently most important animal models (eg the reserpine model, neuroleptic-induced catalepsy, tremor models, experimentally-induced degeneration of nigro-striatal dopaminergic neurons with 6-OHDA, methamphetamine, MPTP, MPP+, tetrahydroisoquinolines, β-carbolines, and iron) critically reviewed next, and are compared with the characteristic features of the disease in man

Animal models of Parkinson's disease: an empirical comparison with the phenomenology of the disease in man.

Oxidative stress is thought to contribute to dopaminergic cell death in Parkinson's disease (PD). The neurotoxin 6-hydroxydopamine (6-OHDA), which is easily oxidized to reactive oxygen species (ROS), appears to induce neuronal death by a free radical-mediated mechanism, whereas the involvement of free radicals in N-methyl-4-phenylpyridinium (MPP+) toxicity is less clear. Using free radical-sensitive fluorophores and vital dyes with post hoc identification of tyrosine hydroxylase-positive neurons, we monitored markers of apoptosis and the production of ROS in dopaminergic neurons treated with either 6-OHDA or MPP+. Annexin-V staining suggested that 6-OHDA but not MPP+-mediated cell death was apoptotic. In accordance with this assignment, the general caspase inhibitor Boc-(Asp)-fluoromethylketone only blocked 6-OHDA neurotoxicity. Both toxins exhibited an early, sustained rise in ROS, although only 6-OHDA induced a collapse in mitochondrial membrane potential temporally related to the increase in ROS. Recently, derivatives of buckminsterfullerene (C60) molecules have been shown to act as potent antioxidants in several models of oxidative stress (Dugan et al., 1997). Significant, dose-dependent levels of protection were also seen in these in vitro models of PD using the C3 carboxyfullerene derivative. Specifically, C3 was fully protective in the 6-OHDA paradigm, whereas it only partially rescued dopaminergic neurons from MPP+-induced cell death. In either model, it was more effective than glial-derived neurotrophic factor. These data suggest that cell death in response to 6-OHDA and MPP+ may progress through different mechanisms, which can be partially or entirely saved by carboxyfullerenes.

http://www.jneurosci.org/content/jneuro/19/4/1284.full.pdf

Distinct Mechanisms Underlie Neurotoxin-Mediated Cell Death in Cultured Dopaminergic Neurons

Among the most widely used models of Parkinson’s disease (PD) are those that employ toxins, especially 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Depending on the protocol used, MPTP yields large variations in nigral cell loss, striatal dopamine loss and behavioral deficits. Motor deficits do not fully replicate those seen in PD. Nonetheless, MPTP mouse models mimic many aspects of the disease and are therefore important tools for understanding PD. In this review, we will discuss the ability of MPTP mouse models to replicate the pathophysiology of PD, the mechanisms of MPTP-induced neurotoxicity, strain differences in susceptibility to MPTP, and the models’ roles in testing therapeutic approaches.

/pdf/mptp-mouse-models-of-parkinson-s-disease-an-update-303yyaud1a.pdf

MPTP mouse models of Parkinson's disease: an update.

https://www.jbc.org/content/275/49/38581.full.pdf

The parkinsonism-inducing drug 1-methyl-4-phenylpyridinium triggers intracellular dopamine oxidation. A novel mechanism of toxicity.

Increased formation of hydroxyl free radicals (·OH) reflected by ·OH adduct of salicylate in brain dialysate was demonstrated during the sustained (more than 2 hours) dopamine overflow elicited by 75 nmol of 1-methyl-4-phenyldihydropyridine (MPDP+) and 1-methyl-4-phenylpyridinium (MPP+) in the rat striatum. Owing to its weak dopamine releasing action, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) did not significantly increase the ·OH formation. This data suggests that sustained elevation of dopamine in the extracellular fluid elicited by MPTP analogues can be auto-oxidized, which in turn leads (possibly by indirect mechanisms) to the formation of cytotoxic ·OH free radicals near the nigrostriatal terminals.

In vivo trapping of hydroxyl free radicals in the striatum utilizing intracranial microdialysis perfusion of salicylate: effects of MPTP, MPDP+, and MPP+.

T. Obata

Papers

In vivo trapping of hydroxyl free radicals in the striatum utilizing intracranial microdialysis perfusion of salicylate: effects of MPTP, MPDP+, and MPP+.