Repeated MPTP injections into the mouse’ intraperitoneal space result in a Parkinson´s disease brain pathology shown as degeneration of dopaminergic neurons and neuroinflammation.
Upon entering the brain, methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) oxidizes into the highly neurotoxic compound 1-methyl-4-phenylpyridinium (MPP+) which is selectively taken up by dopaminergic neurons. Inside neurons, MPP+ disrupts mitochondrial function and causes oxidative stress, ultimately leading to the death of these neurons.
The effect of the repeated MPTP injections can be validated histologically by measurement of tyrosine hydroxylase (TH) levels in the caudate putamen (Fig. 1A). In parallel, Iba-1 as a marker of activated microglia and GFAP as a marker of activated astrocytes are upregulated, indicative of neuroinflammation (Fig 1B, C).
Figure 1: Effect of repeated intraperitoneal MPTP injections on the caudate putamen. Wild type mice were repeatedly injected with MPTP for 5 days and analyzed for tyrosine hydroxylase (TH, A), Iba-1 (B), and GFAP (C) immunoreactive (IR) area. Vehicle-treated wild type littermates served as control. Unpaired t-test (A, B) and Mann-Whitney U-test (C); mean + SEM; n = 8 per group; *p<0.05, ***p<0.001.
MPP+ is taken up by the dopamine transporter into the dopaminergic terminals in the caudate putamen and initially damages them, while dopaminergic cell somata in the substantia nigra remain intact. The latter is confirmed by results showing unchanged levels of TH and Iba-1 in the substantia nigra of repeatedly MPTP-treated mice (Fig 2A, B) pointing towards the absence of neuronal damage while GFAP levels are increased, indicative of an ongoing inflammatory process (Fig 2C).
Figure 2: Effect of repeated intraperitoneal MPTP injections on the substantia nigra. Wild type mice were repeatedly injected with MPTP for 5 days and the striatum analyzed for tyrosine hydroxylase (TH, A), Iba-1 (B), and GFAP (C). Vehicle-treated wild type littermates served as control. Unpaired t-test; mean + SEM; n = 8 per group; *p<0.05.
Evaluation of the brain’s pathology caused by repeated MPTP treatment can further be evaluated using biochemical methods.
Our results show that repeated intraperitoneal MPTP injections accurately model Parkinson´s disease. The observed processes and consequential pathology in the mouse brain closely resemble a typical Parkinson´s disease pathology. Thus, the presented repeated MPTP model represents a valuable tool for understanding the disease’s mechanisms and testing drug candidates.
In parallel to this in vivo model, an in vitro MPP+ model by treating primary cortical or hippocampal neurons with MPP+ is established and ready to be used to evaluate your test compounds.
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