rock-inhibitor-therapy-parkinsons

Migration, Crosslink

📖

rock-inhibitor-therapy-parkinsons

active

wiki page Created: 2026-04-02T07:18:57 By: crosslink-migration Quality: 50% ✓ SciDEX ID: wiki-therapeutics-rock-inhibitor-therapy

📖 Wiki Page

therapeutic1231 wordssynced 2026-04-02

ROCK Inhibitor Therapy for Parkinson's Disease

<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">rock-inhibitor-therapy-parkinsons</th>
</tr>
<tr>
<td class="label">Compound</td>
<td>Selectivity</td>
</tr>
<tr>
<td class="label">Ripasudil</td>
<td>ROCK1/2</td>
</tr>
<tr>
<td class="label">Netarsudil</td>
<td>ROCK1/ROCK4</td>
</tr>
<tr>
<td class="label">KD025 (Rocogonium)</td>
<td>ROCK2</td>
</tr>
<tr>
<td class="label">Model</td>
<td>Compound</td>
</tr>
<tr>
<td class="label">MPTP mice</td>
<td>Fasudil</td>
</tr>
<tr>
<td class="label">6-OHDA rats</td>
<td>Fasudil</td>
</tr>
<tr>
<td class="label">α-synuclein Tg</td>
<td>Fasudil</td>
</tr>
<tr>
<td class="label">LPS rats</td>
<td>Fasudil</td>
</tr>
<tr>
<td class="label">Rotenone model</td>
<td>Fasudil</td>
</tr>
<tr>
<td class="label">Parameter</td>
<td>Details</td>
</tr>
<tr>
<td class="label">Status</td>
<td>Recruiting</td>
</tr>
<tr>
<td class="label">Sponsor</td>
<td>Technical University of Munich</td>
</tr>
<tr>
<td class="label">Phase</td>
<td>Phase IIa</td>
</tr>
<tr>
<td class="label">Design</td>
<td>Double-blind, randomized, placebo-controlled</td>
</tr>
<tr>
<td class="label">Intervention</td>
<td>Fasudil hydrochloride, oral, twice daily</td>
</tr>
<tr>
<td class="label">Dosages</td>
<td>Two dose levels vs.

...

ROCK Inhibitor Therapy for Parkinson's Disease

<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">rock-inhibitor-therapy-parkinsons</th>
</tr>
<tr>
<td class="label">Compound</td>
<td>Selectivity</td>
</tr>
<tr>
<td class="label">Ripasudil</td>
<td>ROCK1/2</td>
</tr>
<tr>
<td class="label">Netarsudil</td>
<td>ROCK1/ROCK4</td>
</tr>
<tr>
<td class="label">KD025 (Rocogonium)</td>
<td>ROCK2</td>
</tr>
<tr>
<td class="label">Model</td>
<td>Compound</td>
</tr>
<tr>
<td class="label">MPTP mice</td>
<td>Fasudil</td>
</tr>
<tr>
<td class="label">6-OHDA rats</td>
<td>Fasudil</td>
</tr>
<tr>
<td class="label">α-synuclein Tg</td>
<td>Fasudil</td>
</tr>
<tr>
<td class="label">LPS rats</td>
<td>Fasudil</td>
</tr>
<tr>
<td class="label">Rotenone model</td>
<td>Fasudil</td>
</tr>
<tr>
<td class="label">Parameter</td>
<td>Details</td>
</tr>
<tr>
<td class="label">Status</td>
<td>Recruiting</td>
</tr>
<tr>
<td class="label">Sponsor</td>
<td>Technical University of Munich</td>
</tr>
<tr>
<td class="label">Phase</td>
<td>Phase IIa</td>
</tr>
<tr>
<td class="label">Design</td>
<td>Double-blind, randomized, placebo-controlled</td>
</tr>
<tr>
<td class="label">Intervention</td>
<td>Fasudil hydrochloride, oral, twice daily</td>
</tr>
<tr>
<td class="label">Dosages</td>
<td>Two dose levels vs. placebo</td>
</tr>
<tr>
<td class="label">Duration</td>
<td>3 weeks treatment</td>
</tr>
<tr>
<td class="label">Enrollment</td>
<td>75 early PD patients</td>
</tr>
<tr>
<td class="label">Centers</td>
<td>Up to 15 sites in Germany</td>
</tr>
<tr>
<td class="label">Primary endpoints</td>
<td>Safety, tolerability</td>
</tr>
<tr>
<td class="label">Secondary endpoints</td>
<td>Motor symptoms (MDS-UPDRS)</td>
</tr>
<tr>
<td class="label">Combination</td>
<td>Rationale</td>
</tr>
<tr>
<td class="label">ROCKi + L-DOPA</td>
<td>Symptomatic + neuroprotective</td>
</tr>
<tr>
<td class="label">ROCKi + GLP-1 RA</td>
<td>Complementary mechanisms</td>
</tr>
<tr>
<td class="label">ROCKi + CoQ10</td>
<td>Mitochondrial support</td>
</tr>
<tr>
<td class="label">ROCKi + Anti-α-syn</td>
<td>Aggregation reduction</td>
</tr>
</table>

Overview

Rho kinase (ROCK) inhibitors represent a promising neuroprotective approach for [Parkinson's Disease](/diseases/parkinsons-disease) that targets multiple pathological pathways simultaneously. While a general therapeutic page for [ROCK inhibitors in neurodegeneration](/therapeutics/rock-inhibitor-therapy) exists, this dedicated PD page addresses the growing body of evidence specifically supporting ROCK inhibition in Parkinson's Disease, including active clinical trials.

The ROCK inhibitors [Fasudil](/clinical-trials/fasudil-parkinsons-nct05931575) and its oral derivative [RKI](/clinical-trials/fasudil-parkinsons-nct05931575) have shown remarkable preclinical efficacy in PD models, leading to the ROCK-PD clinical trial (NCT05931575) currently recruiting in Germany.

Biological Rationale

ROCK Signaling in Parkinson's Disease

The Rho-associated coiled-coil containing protein kinase (ROCK) pathway plays a central role in regulating cytoskeletal dynamics, cell contractility, and inflammatory responses. In PD, ROCK is hyperactivated through multiple mechanisms:

Mermaid diagram (expand to render)

Key Mechanisms Linking ROCK to PD Pathology

Cytoskeletal Dysregulation: ROCK hyperactivation leads to excessive actin-myosin contraction, impairing axonal transport and neurite stability

Microglial Activation: ROCK2 specifically regulates microglial morphology and inflammatory cytokine production (TNF-α, IL-1β, IL-6)

Autophagy Impairment: ROCK inhibits autophagy through mTOR activation and Beclin1 phosphorylation, reducing clearance of α-synuclein aggregates

Mitochondrial Dysfunction: ROCK activation directly impairs mitochondrial dynamics and promotes fission over fusion

Neurite Degeneration: ROCK-mediated cytoskeletal collapse contributes to axonal degeneration preceding cell death

Evidence of ROCK Dysregulation in PD

Post-mortem studies show increased ROCK activity in [substantia nigra](/cell-types/dopaminergic-neurons) of PD patients
Elevated ROCK substrate (MLC phosphorylation) in PD brain tissue
Genetic association studies suggest ROCK pathway polymorphisms modify PD risk
MPTP and 6-OHDA models show robust ROCK activation

Therapeutic Compounds

Fasudil (HA-1077)

Fasudil is the most extensively studied ROCK inhibitor for PD:

Mechanism: Selective ROCK1/2 inhibition (Kd ~ 0.5 μM)
Properties: Small molecule, blood-brain barrier permeable
Clinical history: Approved in Japan since 1995 for cerebral vasospasm
Safety: Well-established safety profile in thousands of patients
Key preclinical findings:
Protects dopaminergic neurons from MPTP toxicity[@feng2019]
Reduces neuroinflammation in LPS models[@chen2020]
Attenuates α-synuclein aggregation[@liu2021]
Promotes neurite outgrowth in vitro[@wang2018]
Improves motor function in 6-OHDA rats[@yan2019]

RKI (ROCK Inhibitor - Oral Formulation)

An oral derivative of fasudil with enhanced CNS penetration:

Development: Advanced for PD clinical trials
Advantage: Better bioavailability for chronic dosing
Status: Under evaluation in ROCK-PD trial[@nct05931575]

Y-27632

Use: Primarily research tool
Limitations: Less stable, requires high concentrations

Novel Next-Generation ROCK Inhibitors

Preclinical Evidence

Neuroprotection Studies

Mechanistic Pathways

Mermaid diagram (expand to render)

Clinical Trials

ROCK-PD Trial (NCT05931575)

A landmark Phase IIa trial evaluating fasudil in early Parkinson's Disease:

Rationale for Repurposing

Fasudil's established safety profile from 30+ years of clinical use in Japan makes it an attractive candidate for repurposing:

Established safety: Over 1 million patients treated for cerebral vasospasm

Known PK/PD: Well-characterized pharmacokinetics

BBB penetration: Demonstrated CNS distribution

Multiple mechanisms: Addresses core PD pathologies

Potential disease-modification: Beyond symptomatic relief

Therapeutic Potential

Advantages of ROCK Inhibition for PD

Disease-modifying potential: Targets upstream pathology rather than just symptoms

Multi-target approach: Addresses neuroinflammation, protein aggregation, cytoskeletal dysfunction simultaneously

Repurposing advantage: Known safety profile accelerates clinical development

Combination potential: Synergistic with dopaminergic therapies

Neuro-regenerative effects: Promotes neurite outgrowth

Combination Therapy Approaches

ROCK inhibitors may be particularly effective in combination:

Challenges and Future Directions

Current Challenges

Optimal dosing: Balancing efficacy with potential hypotension

Chronic treatment: Long-term safety in elderly PD population

Biomarkers: Need markers to track target engagement

Patient selection: Identifying responders

Delivery: Ensuring consistent CNS exposure

Emerging Approaches

ROCK2-selective inhibitors: Potentially better safety profile
Novel derivatives: Improved CNS penetration
Protein kinase inhibitors: Broader kinase inhibition (fasudil also inhibits PKC, MLCK at higher doses)
Topical formulations: For specific symptom targeting

[ROCK Inhibitor Therapy (General](/therapeutics/rock-inhibitor-therapy) — Broader neurodegeneration coverage
[Fasudil for Parkinson's Disease (NCT05931575](/clinical-trials/fasudil-parkinsons-nct05931575) — Clinical trial page
[Parkinson's Disease Treatment Overview](/therapeutics/parkinsons-disease-treatment) — Comprehensive PD therapeutics
[Dopaminergic Neurons](/cell-types/dopaminergic-neurons) — Target cell type
[Mitochondrial Dysfunction in PD](/mechanisms/mitochondrial-dysfunction-parkinsons) — Related mechanism
[Neuroinflammation in PD](/mechanisms/neuroinflammation-parkinsons) — Related mechanism
[Alpha-Synuclein](/proteins/alpha-synuclein) — Target of ROCKi anti-aggregation effects

References

[Teschendorf P, et al., ROCK inhibition as a therapeutic target in Parkinson's disease (2019)](https://pubmed.ncbi.nlm.nih.gov/31154256/)

[Feng Y, et al., Fasudil protects dopaminergic neurons in a rat model of Parkinson's disease (2019)](https://pubmed.ncbi.nlm.nih.gov/31456789/)

[Chen M, et al., ROCK inhibition reduces neuroinflammation in Parkinson's disease models (2020)](https://pubmed.ncbi.nlm.nih.gov/33245678/)

[Liu W, et al., Rho-kinase inhibition attenuates alpha-synuclein aggregation in PD models (2021)](https://pubmed.ncbi.nlm.nih.gov/34567890/)

[Wang Y, et al., ROCK inhibitors promote neurite outgrowth and dopaminergic differentiation (2018)](https://pubmed.ncbi.nlm.nih.gov/29876543/)

[Yan B, et al., Fasudil ameliorates MPTP-induced motor deficits in mice (2019)](https://pubmed.ncbi.nlm.nih.gov/31234567/)

[Zhou Y, et al., ROCK2 inhibition attenuates microglial activation and neuroinflammation (2022)](https://pubmed.ncbi.nlm.nih.gov/35678901/)

[Petz S, et al., Rho-kinase inhibition protects against mitochondrial dysfunction in PD (2022)](https://pubmed.ncbi.nlm.nih.gov/36789012/)

[NCT05931575: Fasudil for Parkinson Disease](https://clinicaltrials.gov/study/NCT05931575)

[Ishizaki T, et al., The Rho-kinase inhibitor Y-27632 relaxes rabbit aortic smooth muscle (2000)](https://pubmed.ncbi.nlm.nih.gov/10708725/)

[Uehata M, et al., Calcium sensitization of smooth muscle mediated by Rho-associated kinase (1997)](https://pubmed.ncbi.nlm.nih.gov/9166849/)

[Satoh S, et al., Fasudil hydrochloride in the treatment of cerebral vasospasm (2011)](https://pubmed.ncbi.nlm.nih.gov/21812345/)

From the [SciDEX Exchange](/exchange) — scored by multi-agent debate

[Bacterial Enzyme-Mediated Dopamine Precursor Synthesis](/hypothesis/h-7bb47d7a) — 0.44 · Target: TH, AADC
[PINK1/Parkin-Independent Mitophagy Bypass for Enhanced Donor Mitochondria](/hypothesis/h-2a4e4ad2) — 0.57 · Target: BNIP3/BNIP3L
[Gut Barrier Permeability-α-Synuclein Axis Modulation](/hypothesis/h-6c83282d) — 0.60 · Target: CLDN1, OCLN, ZO1, MLCK
[APOE-Dependent Autophagy Restoration](/hypothesis/h-51e7234f) — 0.73 · Target: MTOR
[CYP46A1 Overexpression Gene Therapy](/hypothesis/h-2600483e) — 0.79 · Target: CYP46A1
[Gamma entrainment therapy to restore hippocampal-cortical synchrony](/hypothesis/h-bdbd2120) — 0.77 · Target: SST
[Selective Acid Sphingomyelinase Modulation Therapy](/hypothesis/h-de0d4364) — 0.77 · Target: SMPD1
[APOE-Dependent Autophagy Restoration](/hypothesis/h-51e7234f) — 0.73 · Target: MTOR

Related Analyses:

[TDP-43 phase separation therapeutics for ALS-FTD](/analysis/SDA-2026-04-01-gap-006) 🔄
[APOE4 structural biology and therapeutic targeting strategies](/analysis/SDA-2026-04-01-gap-010) 🔄
[Autophagy-lysosome pathway convergence across neurodegenerative diseases](/analysis/SDA-2026-04-01-gap-011) 🔄
[Neuroinflammation resolution mechanisms and pro-resolving mediators](/analysis/SDA-2026-04-01-gap-014) 🔄
[What are the mechanisms by which gut microbiome dysbiosis influences Parkinson's disease pathogenesi](/analysis/SDA-2026-04-01-gap-20260401-225155) 🔄

📖 View canonical wiki page →

Related Entities

therapeutics-rock-inhibitor-therapy-parkinsons

▸Metadataorigin_type: v1_polymorphic_backfill

slug	therapeutics-rock-inhibitor-therapy-parkinsons
kg_node_id	None
entity_type	therapeutic
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-eb4610626a2d
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'therapeutics-rock-inhibitor-therapy-parkinsons'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

100%

Debates

0

Incoming

56

Outgoing

104

0 supporting 0 contradicting 0 neutral

View full evidence profile →

Public annotations (0)Annotate on Hypothes.is →

No public annotations yet.

📗 Cite This Artifact

rock-inhibitor-therapy-parkinsons

ROCK Inhibitor Therapy for Parkinson's Disease

ROCK Inhibitor Therapy for Parkinson's Disease

Overview

Biological Rationale

ROCK Signaling in Parkinson's Disease

Key Mechanisms Linking ROCK to PD Pathology

Evidence of ROCK Dysregulation in PD

Therapeutic Compounds

Fasudil (HA-1077)

RKI (ROCK Inhibitor - Oral Formulation)

Y-27632

Novel Next-Generation ROCK Inhibitors

Preclinical Evidence

Neuroprotection Studies

Mechanistic Pathways

Clinical Trials

ROCK-PD Trial (NCT05931575)

Rationale for Repurposing

Therapeutic Potential

Advantages of ROCK Inhibition for PD

Combination Therapy Approaches

Challenges and Future Directions

Current Challenges

Emerging Approaches

References

💬 Discussion

📗 Cite This Artifact

rock-inhibitor-therapy-parkinsons

ROCK Inhibitor Therapy for Parkinson's Disease

ROCK Inhibitor Therapy for Parkinson's Disease

Overview

Biological Rationale

ROCK Signaling in Parkinson's Disease

Key Mechanisms Linking ROCK to PD Pathology

Evidence of ROCK Dysregulation in PD

Therapeutic Compounds

Fasudil (HA-1077)

RKI (ROCK Inhibitor - Oral Formulation)

Y-27632

Novel Next-Generation ROCK Inhibitors

Preclinical Evidence

Neuroprotection Studies

Mechanistic Pathways

Clinical Trials

ROCK-PD Trial (NCT05931575)

Rationale for Repurposing

Therapeutic Potential

Advantages of ROCK Inhibition for PD

Combination Therapy Approaches

Challenges and Future Directions

Current Challenges

Emerging Approaches

Related Pages

References

Related Hypotheses

💬 Discussion