Synergistic Anti-Ferroptosis with a Minimalistic, Peroxide-Triggered Carbon Monoxide Donor for Parkinson’s Disease

Parkinson’s disease (PD) is a debilitating neurodegenerative
disease, with current treatments primarily focusing on improving dopaminergic
activity, providing symptomatic relief but failing to halt disease
progression. Ferroptosis drives PD pathogenesis and is a potential
therapeutic target. Herein, we introduce a novel peroxide-activated
carbon monoxide (CO) donor, PCOD, featuring a streamlined
structure designed to potentially enhance blood-brain barrier (BBB)
penetration and optimize therapeutic outcomes. PCOD releases
CO upon activation by nucleophilic peroxides, e.g., ONOO– and H2O2. This mechanism provides a potent
strategy against ferroptosis: first, scavenging peroxides that generate
oxidative radicals involved in ferroptosis, and second, CO is proposed
to inhibit Fenton chemistry through coordination to Fe2+. In MPTP-treated mice, PCOD prevents dopaminergic neuron
loss in the substantia nigra and alleviates PD symptoms. This peroxide-triggered
CO release offers a promising and innovative strategy to combat ferroptosis
and neurodegeneration in PD.

帕金森病（Parkinson’s disease, PD）是一种致残性神经退行性疾病，当前治疗手段主要聚焦于改善多巴胺能活性，仅能缓解临床症状，却无法阻断疾病进展。铁死亡（Ferroptosis）参与驱动帕金森病的发病机制，是潜在的治疗靶点。本研究中，我们报道一种新型过氧化物激活型一氧化碳（CO）供体PCOD，其结构经过精简设计，有望增强血脑屏障（BBB）穿透能力并优化治疗效果。PCOD可在亲核性过氧化物（如过氧亚硝基阴离子ONOO–与过氧化氢H2O2）的激活下释放一氧化碳。该机制为对抗铁死亡提供了双重强效策略：其一，可清除参与铁死亡过程、产生活性氧化自由基的过氧化物；其二，一氧化碳可通过与Fe²+配位抑制芬顿反应。在MPTP诱导的帕金森病小鼠模型中，PCOD可阻止黑质多巴胺能神经元丢失，并缓解帕金森病相关症状。这种过氧化物触发的一氧化碳释放策略，为对抗帕金森病中的铁死亡与神经退行性病变提供了极具前景的创新方案。