Objective: This study aims to investigate the impact of L-3,4-dihydroxyphenylalanine (L-DOPA) on ventral midbrain (VMB) iron levels under iron deficiency (ID) and repletion (IR) conditions in male and female rats.

Background: Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons due to iron accumulation in the substantia nigra (SN) located in the VMB. Antiparkinsonian medications, L-DOPA, and a monoamine oxidase-B (MAO-B) inhibitor, selegiline are commonly used to treat PD. However, the effect of L-DOPA on VMB iron levels during ID and IR conditions remains unclear in males and females.

Method: To investigate the effects of L-DOPA and selegiline on VMB iron homeostasis, we used post-natal day 21 male and female Long-Evans rats. The rats were initially assigned to two groups based on dietary iron levels, 35mg/kg diet for iron adequate (IA) group (n=18 males and females), 3.5mg/kg for ID group (n=36) for 5 weeks. After 5 weeks, half of the rats on ID diet (n=18) were repleted with IA diet for 3 weeks and concurrently injected with treatments. Vehicle (0.1% ascorbic acid), L-DOPA (20 mg/kg), or selegiline (0.3mg/kg) was administered via subcutaneous injection in all groups. We measured the iron levels, and iron homeostasis proteins transferrin receptor (TFR1), ferroportin-1 (FPN1), and H & L ferritin in the VMB of all groups by atomic absorption spectroscopy and immunoblotting respectively.

Results: Our findings demonstrate that L-DOPA treatment induced iron accumulation in the VMB of male IR rats but does not significantly alter iron levels in ID or IA diet groups. Notably, the L-DOPA-induced iron accumulation in IR rats was sex-specific, with males exhibiting greater susceptibility than females. Iron homeostasis proteins showed significant alterations, with increased TFR1 and FPN1 expression in L-DOPA treated IR group compared to vehicle and ID in males, however in females it was not altered. Additionally, LCN2 and GFAP levels were elevated compared to the vehicle and ID groups in  L-DOPA-treated IR males versus females.

Conclusion: These findings suggest that L-DOPA administration under ID-IR conditions disrupts iron homeostasis by promoting iron uptake and reducing iron storage capacity, particularly in males. This sex-specific vulnerability to iron accumulation highlights the need for personalized PD therapies that consider both iron status and biological sex.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/l-dopa-induced-iron-accumulation-in-the-ventral-midbrain-the-roles-of-sex-and-iron-repletion/