Abstract
There is a great concern in the literature for the development of neuroprotectant drugs to treat Parkinson's disease. Since anesthetic drugs have hyperpolarizing properties, they can possibly act as neuroprotectants. In the present study, we have investigated the neuroprotective effect of a mixture of ketamine (85 mg/kg) and xylazine (3 mg/kg) (K/X) on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 6-hydroxydopamine (6-OHDA) rat models of Parkinson's disease. The bilateral infusion of MPTP (100 µg/side) or 6-OHDA (10 µg/side) into the substantia nigra pars compacta of adult male Wistar rats under thiopental anesthesia caused a modest (~67%) or severe (~91%) loss of tyrosine hydroxylase-immunostained cells, respectively. On the other hand, an apparent neuroprotective effect was observed when the rats were anesthetized with K/X, infused 5 min before surgery. This treatment caused loss of only 33% of the nigral tyrosine hydroxylase-immunostained cells due to the MPTP infusion and 51% due to the 6-OHDA infusion. This neuroprotective effect of K/X was also suggested by a less severe reduction of striatal dopamine levels in animals treated with these neurotoxins. In the working memory version of the Morris water maze task, both MPTP- and 6-OHDA-lesioned animals spent nearly 10 s longer to find the hidden platform in the groups where the neurotoxins were infused under thiopental anesthesia, compared to control animals. This amnestic effect was not observed in rats infused with the neurotoxins under K/X anesthesia. These results suggest that drugs with a pharmacological profile similar to that of K/X may be useful to delay the progression of Parkinson's disease.
Highlights
Parkinson’s disease is among the neurodegenerative diseases for which there is no treatment proved to be clinically effective to halt or retard neurodegeneration [1]
Perinigral infusion of MPTP or 6-OHDA caused a significant reduction in the number of the tyrosine hydroxylase (TH)-immunoreactive neuron cells mainly in the substantia nigra pars compacta (SNc) (F(4,25) = 22.93, P < 0.001, one-way analysis of variance (ANOVA)), spreading more modestly to the ventral tegmental area (F(4,25) = 5.57, P < 0.001, one-way ANOVA). 6-OHDA caused a significantly greater cell loss in the SNc compared to MPTP (P < 0.05, Newman-Keuls test) when the animals were anesthetized with thiopental
6-OHDA was more effective than MPTP in reducing dopamine levels in animals anesthetized with thiopental (P < 0.05, NewmanKeuls test), but no significant difference was observed between these groups when the animals were anesthetized with K/X (P = 0.21, Newman-Keuls test)
Summary
Parkinson’s disease is among the neurodegenerative diseases for which there is no treatment proved to be clinically effective to halt or retard neurodegeneration [1]. 6-Hydroxydopamine (6-OHDA) and 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) cause large or partial loss of dopaminergic cells, respectively, in the SNc of rats. Their effects have been studied as models of the advanced or the early phase of Parkinson’s disease [4,5,6,7]. 6-OHDA induces nigral dopaminergic lesion mainly by generating reactive oxygen species as a result of its oxidation This can occur spontaneously or be induced by monoamine oxidase or iron [1,6]. MPP+ accumulates in SNc dopaminergic cells and acts mainly by inhibiting mitochondrial complex I, leading to a decrease in cellular ATP levels and cell death [8]
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