As a CRO specializing in neurodegenerative disease preclinical research, Creative Biolabs offers two most commonly used toxin-based rodent Parkinson's Disease (PD) models for the identification and development of new therapies: MPTP mouse model and 6-OHDA model. Particularly, we are capable of providing acute, subacute, and chronic versions of this model to better suit your research needs.
MPTP Mechanisms of Action
The potency of MPTP to be utilized in PD models was found by chance when a synthesized heroin analog meperidine, was administered intravenously by seven individuals. They showed PD-like symptoms such as akinetic rigidity and were recovered by L-dopa. Further studies showed that systemic administration of MPTP into nonhuman primates and mice caused an 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 into the hydrophilic metabolite 1-methyl-4-phenyl-pyridinium (MPP+) by MAO-B expressed in astrocytes. The generation of MPP+ leads to the impairment of ATP production, elevated intracellular Ca2+ levels, and generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), eliciting apoptotic cell death of the dopaminergic neurons. Moreover, MPP+ also triggers inflammatory reactions, facilitating synthesis and secretion of inflammation-related molecules including cytokines, chemokines, and prostaglandins.
Fig. 1 Reactive astrocytes are key players in nigrostriatal dopaminergic
neurorepair in MPTP mouse model of PD. (Bianca et al. 2013)
Model Description
A wide variety of animals have been demonstrated to have the sensitivity to MPTP and nonhuman primates exhibit the highest sensitivity. However, rodents are still the most widely used animals due to convenience. Mice are more favorably used than rats as rats are found to be resistant to this toxin. Briefly, the induction of PD in mice can be achieved by subcutaneous or intraperitoneal administration of MPTP dissolved in water, saline or dimethyl-sulfoxide. Acute, subacute, and chronic versions can be achieved using three different dosing patterns: 10–20 mg/kg given four times at 1–2 h intervals as an acute model; 30 mg/kg/day for 4–5 days as a subacute model; 25 mg/kg given 2 times with 250 mg/kg of probenecid in a week for 5 weeks as a chronic model. Among them, acute and subacute models are suitable for the screening of therapeutic substances, while chronic models reflect the process of PD progression and are suitable to analyze the molecular pathophysiology as well as to screen protective substances.
Features of MTPT Model
Fig.2 Effects of hypercholesterolemia on tyrosine hydroxylase (TH)-immunoreactivity in striatum (NCP) and
TH-positive nigral (SN) neurons in MPTP-treated mice. CS, control; HCD, high cholesterol diet. (Paul et al. 2017)
Assessments
For testing the efficacy of potential new therapeutics, Creative Biolabs offers a wide range of measurements. For example, behavioral tests of the model can be conducted, including Pole test, Open field test, and Rotarod test. Moreover, after the final MPTP dosing, mice are decapitated and brains are harvested, sectioned, processed for immunohistochemical and biochemical analysis. Typically, we provide assessments including but not limited to:
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The portfolio of rodent preclinical neurological disease models at Creative Biolabs is placed below for your review:
With years of experience in drug discovery and pharmacology, Creative Biolabs can deliver a range of contract research services that are tailored to their individual requirements in terms of science, timelines, and cost. Contact us to discuss your specific requirements.
References
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