The MPTP-induced mouse model is a commonly used neurotoxin-induced model. The use of neurotoxins can establish animal models that are similar to human PD and partially reflect the pathological characteristics of human PD, which can provide a good way for PD therapeutic drug screening and mechanism research. In PD induction models, commonly used neurotoxins include MPTP, 6-OHDA, Drugs such as paraquat and rotenone.
The MPTP-induced mouse model has a short modeling period (1-2 weeks), is simple to operate, can be directly injected by intraperitoneal or subcutaneous injection, and has obvious neuronal deletion and abnormal behavioral detection. It is currently the most commonly used PD animal model. one.
MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is highly lipid-soluble and easily penetrates the blood-brain barrier. After entering the brain, it can be converted by the action of glial cell monoamine oxidase For its active ingredient MPP+. After MPP+ is taken up into the mitochondria of dopaminergic neurons by dopamine transporters, it can inhibit the activity of mitochondrial complex I, resulting in degeneration and death of dopaminergic neurons.
There are species differences in the toxicity of MPTP. Mice are more sensitive, while rats have a certain tolerance, so MPTP-induced mouse models are often used.
MPTP-induced mouse models are divided into acute injury models and chronic injury models of dopamine neurons. Acute injury models show rapid and severe neuronal damage with marked behavioral abnormalities, but without α-synuclein to aggregate MPP+ [4]. However, despite the accumulation of α-synuclein in the chronic injury model, neuronal injury and behavioral abnormalities were not significant.
The potency of MPTP in a PD model was serendipitously discovered when seven individuals were intravenously administered the synthetic heroin analog meperidine. They exhibited PD-like symptoms, such as motor stiffness, and were recovered by levodopa. Further studies showed that systemic administration of MPTP to non-human primates and mice resulted in irreversible and selective degeneration of dopaminergic neurons in the substantia nigra. MPTP is a highly lipophilic molecule capable of crossing the blood-brain barrier and is converted to the hydrophilic metabolite 1-methyl-4-phenylpyridinium (MPP+) by MAO-B expressed in astrocytes. ). The production of MPP+ leads to impaired ATP production, elevated intracellular Ca levels, and production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), causing apoptotic cell death of dopaminergic neurons. In addition, MPP+ also triggers an inflammatory response that promotes the synthesis and secretion of inflammation-related molecules, including cytokines, chemokines, and prostaglandins.
The sensitivity of different species of animals to MPTP is very different, and this difference may be due to the difference in the metabolic activity of MPTP. For example, the activity of monoamine oxidase B in rat brain capillary endothelial cells is higher, which makes MPTP metabolized to the nerves. The amount of cells is relatively small, resulting in reduced sensitivity in rats. Monkeys and C57BL/6 mice are known to be the most sensitive animals to MPTP, they can better reflect the pathological characteristics of PD in neuroanatomical and chemical changes, especially the monkey model is more suitable for behavioral changes, movement and changes. Evaluation of mental disorders and in vitro dynamic imaging studies of neuroanatomy, and can simulate the long-term chronic onset process of human PD to prepare a chronic MPTP model. Rats are less sensitive to MPTP and are not ideal animals for PD preparation. Compared with rats and other kinds of mice, C57BL/6 mice have the highest sensitivity to MPTP and have good response consistency (parallelism), and are currently the most widely used model animals.
There was no significant difference in sensitivity to MPTP in C57BL/6 mice of different sexes. MPTP is relatively toxic and long-lasting in aged animals, and young animals show more obvious compensatory repair function; comparing 3-month-old and 9-12-month-old C57BL/6 male mice receiving intraperitoneal injection of MPTP (per kg body weight every 2 hours) 15mg dose, 4 times). The number of TH-positive cells in the substantia nigra decreased at different times, 33.4% and 49.6% on day 1, 45.1% and 56.1% on day 3, 47.1% and 71.7% on day 7, and 46.9% and 721% on day 14 (P<0. 0.01), the differences in the sensitivity of animals to MPTP at different ages may be due to differences in oxidative stress monoamine oxidase B (the activity of this enzyme increased from 2 months to 10 months in mice) and neuromelanin.
Medicilon has effective models for evaluating new drugs for PD, including MPTP-induced mouse subacute PD model, MPTP+ probenecid-induced mouse chronic PD model, oxytremorine-induced cholinergic symptom model, etc. Rod rod method, climbing rod method, grip test and other methods were used to evaluate the improvement effect of the test substance on PD symptoms. Immunohistochemical staining (ICH) method can be used to observe whether the test substance has protection on dopamine neurons (TH staining). By immunohistochemical staining of α-synuclein, GFAP, Iba-1, etc., the influence of the test substance on the corresponding pathology was observed. We have successfully provided Chinese and foreign customers with effective new drug evaluation services.
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