Ruthenium-based compounds in neurodegenerative diseases: Coordination chemistry, pharmacological mechanisms, and translational perspectives

Neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease arise from complex, self-reinforcing networks involving protein misfolding, metal dyshomeostasis, oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation. Disruption of metal homeostasis is increasingly recognized as an integral driver of disease progression rather than a secondary consequence, an observation that underscores the therapeutic potential of metal-based strategies. In this context, metallodrugs offer mechanistic properties inaccessible to purely organic compounds, including redox activity, variable coordination geometries, and tunable ligand-exchange reactivity. Among them, ruthenium complexes have emerged as particularly promising candidates due to their favorable toxicity profiles, rich coordination chemistry, and structural versatility. This review provides a critical and comparative analysis of ruthenium-based compounds investigated in neurodegenerative diseases, with emphasis on Alzheimer’s disease and Parkinson’s disease. We discuss how coordination environments and redox properties govern interactions with pathological targets such as amyloid-beta, tau protein, and alpha-synuclein, and how these interactions modulate oxidative stress, metal–protein dyshomeostasis, ferroptosis, and neuroinflammatory pathways. Emerging strategies, including photoactivatable, multifunctional, and theranostic ruthenium systems, are evaluated in terms of their biological relevance and translational potential. Among the scaffold types reviewed, arene Ru(II) complexes bearing terminal amine substituents at the 2- or 4-position of the coordinating heterocycle emerge as the most tractable candidates for preclinical advancement. Finally, key challenges limiting clinical progression, including blood–brain barrier permeability, metal speciation, selectivity, and long-term safety, are critically discussed.