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Tumor necrosis factor-alpha receptor ablation in a chronic MPTP mouse model of Parkinson's disease
Andreas Leng1, Anna Mura, Joram Feldon
1Behavioural Neurobiology Laboratory, Swiss Federal Institute of Technology Zurich, CH-8603 Schwerzenbach, Switzerland.
Abstract:
Recently, we demonstrated that mice deficient of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) were partly protected against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity. Here we extended the study and investigated TNF-alpha receptor 1 (-/-) (TNFR1) and TNF-alpha receptor 2 (-/-) (TNFR2) mice using a chronic MPTP dosing regimen (15 mg/kg MPTP on 8 consecutive days). One week after the last MPTP treatment, HPLC determination of striatal dopamine (DA) and immunostaining for the dopamine transporter (DAT) in the substantia nigra pars compacta (SNpc) was performed. MPTP treatment reduced striatal DA levels significantly; nigral DAT immunoreactivity was reduced to a lower extent. However, there was no difference in DA levels and the number of DAT positive neurons between TNFR1 (-/-), TNFR2 (-/-) and wild type mice after MPTP treatment. In contrast to TNF-alpha deficiency neither TNFR1 nor TNFR2 gene ablation showed protection against MPTP neurotoxicity, which argues for a protective mechanism of TNF-alpha not mediated by TNFR1 and TNFR2 signaling.
Insights
Tumor necrosis factor-alpha (TNF-alpha) deficiency partly protected mice against MPTP neurotoxicity. However, mice lacking TNF-alpha receptors 1 or 2 showed no protection, suggesting TNF-alpha acts independently of these receptors.
Area of Science:
- Neuroscience
- Immunology
- Toxicology
Background:
- Pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) plays a role in neuroinflammation.
- Previous studies indicated partial protection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in TNF-alpha deficient mice.
Purpose of the Study:
- To investigate the role of TNF-alpha receptors (TNFR1 and TNFR2) in MPTP-induced neurotoxicity.
- To determine if TNF-alpha's protective effects against MPTP are mediated through TNFR1 or TNFR2 signaling.
Main Methods:
- Utilized a chronic MPTP neurotoxicity mouse model (15 mg/kg/day for 8 days).
- Assessed striatal dopamine (DA) levels via HPLC and dopamine transporter (DAT) expression in the substantia nigra pars compacta (SNpc) using immunostaining.
- Compared wild-type mice with mice deficient in TNF-alpha receptor 1 (TNFR1-/-) and TNF-alpha receptor 2 (TNFR2-/-).
Main Results:
- MPTP treatment significantly reduced striatal DA levels and, to a lesser extent, nigral DAT immunoreactivity.
- No significant differences in DA levels or DAT positive neurons were observed between MPTP-treated TNFR1 (-/-), TNFR2 (-/-), and wild-type mice.
- Neither TNFR1 nor TNFR2 gene ablation conferred protection against MPTP neurotoxicity.
Conclusions:
- The findings indicate that TNF-alpha's protective mechanism against MPTP neurotoxicity is not mediated by TNFR1 or TNFR2 signaling.
- This suggests an alternative pathway for TNF-alpha's neuroprotective role in the context of MPTP-induced dopaminergic neuron damage.
