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Published on: May 4, 2020
Postnatal iron overload destroys NA-DA functional interactions
1Department of Neuroscience, Psychiatry Ulleråker, University of Uppsala, Uppsala, Sweden.
Insights
Postnatal iron overload worsens MPTP-induced Parkinsonism in mice, impairing motor activity and L-Dopa response. This highlights permanent noradrenergic and dopaminergic pathway vulnerability after early iron exposure.
Area of Science:
- Neuroscience
- Neuropharmacology
- Toxicology
Background:
- Early-life iron exposure can impact neurodevelopment and long-term brain function.
- Parkinson's disease models often involve dopaminergic neurodegeneration.
- Noradrenergic pathways play a role in motor control and can be affected in neurodegenerative conditions.
Purpose of the Study:
- To investigate the long-term effects of postnatal iron administration on neurotoxicity induced by MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine).
- To examine the interaction between iron, noradrenergic denervation (DSP4), and dopaminergic pathways in a mouse model.
- To assess the impact on motor behavior and response to dopaminergic and noradrenergic therapies.
Main Methods:
- C57/BL6 mice received postnatal iron or vehicle, followed by DSP4 (noradrenergic neurotoxin) or vehicle administration later in life.
- Mice were subsequently treated with MPTP (dopaminergic neurotoxin) or vehicle.
- Behavioral testing included spontaneous activity, L-Dopa induced activity, and clonidine-L-Dopa induced activity.
Main Results:
- Postnatal iron exacerbated MPTP-induced bradykinesia and abolished spontaneous motor activity in NA-denervated, MPTP-treated mice.
- Iron reduced L-Dopa's restorative effect on motor activity and diminished the synergistic effect of clonidine and L-Dopa.
- DSP4 pretreatment eliminated L-Dopa's restorative effect, and combined DSP4 and iron treatments abolished therapeutic responses in MPTP mice.
Conclusions:
- Postnatal iron overload causes enduring vulnerability in both noradrenergic and dopaminergic pathways.
- Early iron exposure permanently impairs motor function and responsiveness to dopaminergic therapies in MPTP-treated mice.
- Noradrenergic innervation is crucial for dopaminergic functional expression and motor recovery.
Abstract:
C57/BL6 mice were administered either postnatal iron (Fe(2+) 7.5 mg/kg, on postnatal days 10-12) or vehicle, followed by administration of either DSP4 (50 mg/kg, s.c., 30 min after injection of zimeldine, 20 mg/kg, s.c.) or vehicle (saline) at 63 days of age. Three weeks later, iron/vehicle treated, DSP4/vehicle treated mice were injected with either a low dose of MPTP (2 x 20 mg/kg, with a 24-hr interval between injections) or vehicle. Behaviour testing took place a further three weeks (spontaneous behaviour and L-Dopa induced) and two weeks (clonidine-L-Dopa induced) later. Postnatal iron administration exacerbated the bradykinesia induced by MPTP and virtually abolished all spontaneous motor activity in NA-denervated mice that were MPTP-treated. Postnatal iron administration reduced markedly the restoration of motor activity by suprathreshold L-Dopa (20 mg/kg) following a 60-min habituation to the test chambers. Pretreatment with DSP4 effectively eliminated the restorative effect of L-Dopa in the MPTP mice. The synergistic effects of co-administration of clinidine (1 mg/kg) with a subthreshold dose of L-Dopa (5 mg/kg) in elevating the motor activity of MPTP mice were reduced markedly by postnatal iron administration, as well as by pretreatment with DSP4. NA-denervation by DSP4, after postnatal iron treatment, totally abolished the activity-elevating effects of the alpha-adrenoceptor agonist + DA-precursor combination in MPTP mice, and virtually eliminated these effects in saline (non-MPTP) mice. Postnatal iron administration caused enduring higher levels of total iron content in all the groups with an increased level in mice treated with DSP4 followed by MPTP. These divergent findings confirm the direct influence of NA innervation upon dopaminergic functional expression and indicate a permanent vulnerability both in the noradrenergic and dopaminergic pathways following the postnatal infliction of an iron overload.
