Rho-Kinase Inhibition in Neurodegenerative Diseases

Rho‐associated coiled‐coil‐containing protein kinases (ROCK1 and ROCK2) act downstream of Rho GTPases to regulate cytoskeletal dynamics, cell survival and inflammatory signalling. In neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis, aberrant activation of Rho–ROCK pathways contributes to microglial overactivity, synaptic dysfunction, axonal collapse and tau hyperphosphorylation. Pharmacological inhibition of ROCK using small-molecule drugs such as fasudil, Y27632 or RKI1447 has emerged as a promising strategy to restore homeostatic cytoskeletal remodelling, attenuate neuroinflammation and enhance autophagy-mediated clearance of protein aggregates. In preclinical models, ROCK blockade preserves blood–brain barrier integrity, promotes mitochondrial function and counteracts excitotoxicity by modulating downstream effectors including cofilin, myosin light-chain phosphatase and NF-κB. These combined actions support neuronal survival, improve synaptic connectivity and reverse pathogenic transcriptional signatures. Despite clear translational potential, challenges remain in optimising isoform specificity, minimising off-target effects and achieving sustained central nervous system exposure. The accumulated evidence positions Rho-kinase inhibition as a multifaceted therapeutic approach capable of targeting common mechanisms across diverse neurodegenerative syndromes.

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Technical terms

Rho GTPase: Small signalling proteins that cycle between GTP-bound (active) and GDP-bound (inactive) states to control cytoskeletal organisation.

ROCK (Rho-associated coiled-coil-containing protein kinase): Serine/threonine kinases downstream of Rho GTPases that modulate cell contractility, motility and survival.

Neuroinflammation: Immune response in the central nervous system marked by glial activation and release of inflammatory mediators.

Fasudil: A pan-ROCK inhibitor originally developed as a vasodilator, repurposed for neuroprotective and anti-inflammatory applications.

Tauopathy: Neurodegenerative disorders characterised by abnormal phosphorylation and aggregation of the microtubule-associated protein tau.

References

1. The RhoA-ROCK1/ROCK2 Pathway Exacerbates Inflammatory Signaling in Immortalized and Primary Microglia. Cells (2023).
2. Neurodegenerative Disease Associated Pathways in the Brains of Triple Transgenic Alzheimer’s Model Mice Are Reversed Following Two Weeks of Peripheral Administration of Fasudil. International Journal of Molecular Sciences (2023).
3. Effect of the ROCK inhibitor fasudil on the brain proteomic profile in the tau transgenic mouse model of Alzheimer's disease. Frontiers in Aging Neuroscience (2024).