Development of an animal model for the specific disease under investigation is very important to further the understanding of the underlying mechanism of disease, and provides the chance to test newly developed new drugs before their human application [1
]. However, the plethora of existing animal models can make the decision of the most appropriate model challenging. It is true for investigating the interactions in brain on the pharmacological and/or toxicological effects of certain agents that link to delineate neural mechanisms underlying in a specific disease [27
PD is a progressive neurodegenerative disease caused by the destruction of dopaminergic neurons in the substantia nigra [28
]. The underlying mechanisms are still not fully understood [5
]. Moreover, the current approach to the treatment of PD involves suppressing disease progression rather than achieving a cure [28
]. This approach is unsatisfactory, given the high prevalence of PD worldwide, with its concomitant morbidity and mortality; improved understanding of the underlying mechanisms and novel therapeutics are crucial [2
Neuromelanin-containing dopamine neurons in the substantia nigra projecting to the striatum in the brain are selectively degenerated in this disease [29
]. In PD animal model, several agents effective against dopaminergic neurons are available [30
]. Of these, the administration of MPTP is an established and valid method to induce PD symptoms in mice [3
]. The effect of the parkinsonism-inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine on central catecholamine neuron in C57BL/6 mice revealed that MPTP caused a severe reduction of endogenous DA in substantia nigra and striatum which was following by an increase in the 3,4-dihydroxyphenylacetic acid (DOPAC)/dopamine ratio [27
]. But, little is known about MPTP susceptibilities between different mice strains. C57BL/6, Balb-C, and ICR strains of mice, among others, have been used to develop disease models. However, there is limited information about the different responses among those mice strains after injection of MPTP, which hinders research concerning the underlying mechanisms of PD.
In this study, we evaluated behavioral changes after subcutaneous injection of MPTP using the Rota-rod test and open field behavior recording. In parallel, we evaluate the MPTP-induced mouse model of PD by determining the levels of BH4 and dopamine in brain regions of three selected mouse strains. BH4 is an essential cofactor for hydroxylation of cyclic amino acids including dopamine catalyzed in a rate limiting fashion by tyrosine hydroxylase [14
]. Recently, we reported a novel method for direct detection of BH4 and dopamine in rat brain using LC-ESI-MS [20
]. Here, the method was applied to the MPTP-induced mouse models of PD to monitor the changes of dopamine concentration and the levels of endogenous BH4. We directly quantified the endogenous levels of dopamine in ICR, C57BL/6, and Balb-C mouse strains using LC-MS/MS. The changes of neurotransmitter concentration in several brain regions are influential in the development of a variety of psychiatric and neurodegenerative diseases [25
]. Therefore, it is clearly necessary to precisely determine the level of dopamine as a means of diagnostically evaluating PD and for the screening of potential therapeutic products to modulate dopamine levels [32
Presently, repeated administration of MPTP affected exercise abilities of mice, including moving distances and rearing frequencies. However, the generally used methods for evaluation of motor-activities appeared to be too insensitive to detect the fine behavioral changes in the Parkinsonian mice models. The endogenous dopamine concentrations were significantly decreased after repeated MPTP injection, but BH4 was unchanged in mouse brain regions. In addition, the expression levels of tyrosine hydroxylase in the striatum were significantly decreased by MPTP injection. These results suggest that the decreased levels of dopamine in the striatum are mainly due to the extensive damage of dopaminergic neurons in this region. Consistent with previous reports [3
], marked differences were evident in the sensitivity of the three strains of mice to MPTP, although the reasons for the strain-related differences in response to MPTP remain unclear. The fundamental difference in the sensitivity to toxic MPTP may be one possibility.
In conclusion, we tested the effects of repeated MPTP injedctions, an animal model of Parkinson's disease, in three strains of mice on rota-rod performance, locomotor activity, as well as striatal, hippocampal, and substantia nigra levels of dopamine and tetrahydrobiopterin and striatal levels of tyrosine hydroxylase. Our results showed that the ICR strain was generally less sensitive to MPTP on rota-rod performance, locomotor suppression, and striatal tyrosine hydroxylase suppression. We found that C57BL/6 and Balb-C mice were more sensitive to the dopaminergic neuronal toxicity of MPTP than was ICR mice based on open field test, tyrosine hydroylase expression.