Resistance of Golden Hamster to l‐Methyl‐4‐Phenyl‐1,2,3,6 Tetrahydropyridine: Relationship with Low Levels of Regional Monoamine Oxidase B

Abstract

Effects of acute and chronic administration of 1 ‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) were investigated for dopamine (DA) and its metabolites, 3,4‐dihydroxyphenylacetic acid and 4‐hydroxy‐3‐methoxyphenylacetic acid, in nucleus caudatus putamen (NCP), limbic system, and substantia nigra (SN) of golden hamster and BALB/c and C57/BL mice to obtain a clue for the variance of MPTP toxicity between the strains and species. Regional differences in the levels of monoamine oxidase (MAO) and the in vitro effects of MAO inhibitors were also determined and correlated with MPTP neurotoxicity. Concentrations of MPTP in the brains of mice and golden hamster at 10 min were comparable. Golden hamster was found to be resistant to the administration of MPTP as indicated by a lack of any alteration from the normal content of DA in NCP, limbic system, and SN. Both strains of mice exhibited >50% and >75% depletion of DA (C57/BL and BALB/c, respectively). The metabolites‐to‐DA ratios were decreased and increased in golden hamster and mouse strains, respectively, after acute or chronic treatment. Whereas the content of total MAO in golden hamster was one‐third to one‐sixth of any nuclei or mitochondria of both strains of mice, the ratio of MAO A to B was significantly higher in the former species. A possible involvement of discrete regional MAO activity in determining the extent of susceptibility of a species to MPTP toxicity is indicated from the study because (1) susceptibility as evidenced by DA depletion of a species coincided with high levels of MAO activity in SN and NCP, and (2) a highly positive correlation existed with total MAO and MAO B activity, there was a lack of correlation with MAO A activity, and a negative correlation existed with MAO A‐to‐B ratio and DA depletion. Hence, we propose that the resistance of a species to MPTP toxicity may depend on the content as well as the ratios of the two forms of MAO in NCP and SN. In other words, a higher MAO activity and a relative dominance of MAO B in these nuclei are critical in determining the susceptibility of a species to MPTP neurotoxicity.

Inhibition of monoamine oxidase-B by the polyphenolic compound, curcumin and its metabolite tetrahydrocurcumin, in a model of Parkinson’s disease induced by MPTP neurodegeneration in mice

“…In the brain MPTP is converted to its biologically active metabolite 1-methyl-4-phenylpyridinium (MPP+) by the action of MAO-B which is toxic to neurons (Chiba et al, 1984). Animals with low levels of MAO-B in the brain are resistant to this neurotoxin (Mitra et al, 1994).…”

Apoptotic Mode of Cell Death in Substantia Nigra Following Intranigral Infusion of the Parkinsonian Neurotoxin, MPP+ in Sprague-Dawley Rats: Cellular, Molecular and Ultrastructural Evidences

“…It also caused parkinsonism in sub-human primates [4,5], cats [6], dogs [7], sheep [8] and mice [9,10]. Several species of mammals (such as rats and golden hamsters) have been shown to be resistant to the neurotoxin, which has been attributed to the inability of these animals to enzymatically convert MPTP into its active metabolite, 1-methyl-4-phenyl pyridinium ion (MPP + ) by the enzyme monoamine oxidase in the brain [11,12]. In consistent with this, MPP + has been shown to cause dopaminergic neurotoxicity when administered intracranially either in the substantia nigra pars compacta (SNpc), striatum or median forebrain bundle [13][14][15][16].…”

Antiparkinsonian Effects of Aqueous Methanolic Extract of Hyoscyamus niger Seeds Result From its Monoamine Oxidase Inhibitory and Hydroxyl Radical Scavenging Potency

“…), 16 h apart, a dose regime which has been shown to cause 50% or more striatal DA depletion in this strain of mice [15]. Balb/c strain of mice is shown to be resistant to MPTP administration by some [16,17].…”

“…The former two studies [16,17] have reported single dose effect on Balb/c mice, while others have resorted to singular or multiple higher doses. A comparative study with eight strains of mice receiving singular 20 mg/kg dose [18] or three doses (30 mg/kg, daily) [19], or two doses (30 mg/ kg) separated by several hours (16 h apart) [15] provided convincing evidences for the susceptibility of Balb/c mice to MPTP. Interestingly, we have reported higher neurotoxicity in Balb/c mice compared to C57/BL6 mice in terms of striatal dopamine depletion following 10 mg/kg for 10 days, and analyzed after 30 days [15].…”

“…Evaluation of Monoamine Oxidase B (MAO-B, EC 1.4.3.4) Activity MAO-B activity was determined in crude mitochondrial P 2 fraction according to the fluorimetric assay procedure of Morinan and Garratt [25] with modifications [15]. The effects of AM-HN (0.02 to 2 lg per ll of the reaction mixture) on MAO-B activity was determined from the amount of the fluorigenic product, 4-hydroxyquinoline formed due to oxidation of kynuramine by this enzyme.…”