Abstract
Parkinson’s disease (PD) represents one of the neurodegenerative disorders which are caused by degeneration of dopaminergic neurons in the nigrostriatal pathway. Different toxins, e.g., 6-hydroxydopamine (6-OHDA), are used to model PD in animals. 6-OHDA is a neurotoxin which damages catecholaminergic neurons via production of oxygen radicals. Tetrahydroisoquinolines (TIQs) are endogenous amines which are present in the mammalian brain. Some of them, like TIQ and 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ), demonstrate neuroprotective properties. These compounds act as reversible MAO inhibitors and this way block free radical formation. To continue our previous experiments, we evaluated the effect of acute and chronic treatment with TIQ and 1MeTIQ on locomotor/exploratory activity and the release of dopamine as well as its metabolite 3-methoxytyramine (3-MT) in the striatum of unilaterally 6-OHDA-lesioned and sham-operated rats using in vivo microdialysis methodology. Additionally, the changes in the concentration of tyrosine hydroxylase in the substantia nigra were measured. A unilateral 6-OHDA lesion in the substantia nigra produces a strong reduction in the release of dopamine (approx. 70%) and 3-MT (approx. 50%) in the rat striatum. This effect was completely inhibited by multiple administration of TIQ and 1MeTIQ. The results obtained from the in vivo microdialysis study suggest that multiple treatment with both endogenous amines, TIQ and 1MeTIQ, protects dopaminergic neurons against a 6-OHDA-induced deficit of dopamine release. Furthermore, these amines were able to maintain physiological functions of striatal dopamine neurons damaged by a unilateral 6-OHDA lesion.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disorder which affects approximately 6 million people in the world
The Effect of a Unilateral 6-OHDA Lesion The mean control basal extracellular concentration of dopamine in dialysates obtained from the striatum was approximately 7.9 ± 2.1
A statistical analysis demonstrated a significant reduction in the extracellular dopamine concentration in the basal samples 14 days after a unilateral 6OHDA lesion in comparison with the control group (Figs. 2a and 3a)
Summary
Parkinson’s disease (PD) is a neurodegenerative disorder which affects approximately 6 million people in the world. As it was demonstrated by our team, both TIQ and 1MeTIQ strongly influence dopamine metabolism without changing the rate of total dopamine catabolism but by strongly inhibiting the MAO-dependent catabolic pathway and markedly activating the catechol-O-methyltransferase (COMT)-dependent O-methylation (Antkiewicz-Michaluk et al 2001; Patsenka et al 2004). Such molecular mechanism of action leads to inhibition of free radicals production which takes place during dopamine MAO-dependent oxidation. Some data indicated that the concentration of 1MeTIQ was significantly reduced in the brains of patients suffering from Parkinson’s disease and in the brains of rodents exposed to agents evoking experimental parkinsonism (Tasaki et al 1991)
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