The goal of this placebo-controlled double-blind Phase 2 clinical trial is to test in people with early Alzheimer's Disease.
The main questions it aims to answer are:
* Does treatment with fasudil, a ROCK-inhibitor, lead to significant improvement in working memory (based on computer-based working memory composite scores) compared to placebo in individuals with early Alzheimer's disease (AD) over 12 months?
* What is the effect of fasudil treatment for 12 months on other cognitive functions, brain metabolism measured by Fluorodeoxyglucose Positron Emission Tomography (FDG-PET), and other relevant clinical functions and biomarkers in individuals with early Alzheimer's disease (AD)?
* Treatment will be escalated to a maintenance dose of 120 mg total daily dose for up to 50 weeks, with regular clinic visits for efficacy and safety evaluations.
* Assessments will include cognitive tests, FDG-PET scans, and biomarker analyses, with follow-up by the Data and Safety Monitoring Board for ongoing safety review.
The study will compare participants receiving fasudil with those receiving placebo to see if fasudil treatment leads to improvements in cognitive functions, brain metabolism measured by FDG-PET.

Start Date01 Aug 2024

Sponsor / Collaborator

Helse Stavanger HF

[+2]

CTIS2024-517413-33-00 / RecruitingIIT

Safety, Tolerability and Symptomatic Efficacy of the ROCK-Inhibitor Fasudil in Patients with Parkinson's Disease (ROCK-PD) - ROCK-PD-0000-LIN-007

Start Date11 Sep 2023

Sponsor / Collaborator-

JPRN-jRCTs041220024 / SuspendedPhase 1IIT

A Phase 1 study of Fasudil in combination with Methotrexate, Adriamycin and Cisplatin (MAP) targeting cancer stem cell.

Start Date31 May 2022

Sponsor / Collaborator-

100 Clinical Results associated with VDCCs x ROCK1

100 Translational Medicine associated with VDCCs x ROCK1

0 Patents (Medical) associated with VDCCs x ROCK1

Literatures (Medical) associated with VDCCs x ROCK1

01 Dec 2023·European Journal of Pharmacology

Pinocembrin attenuates susceptibility to atrial fibrillation in rats with pulmonary arterial hypertension

Article

Author: Bo, Yang ; Weiguo, Wan ; Cui, Zhang ; Tianxin, Ye ; Yi, Yu ; Zhangchi, Liu

BACKGROUNDPulmonary arterial hypertension (PAH) is a disease characterized by pulmonary vascular remodeling that triggers fibrosis and excessive myocardium apoptosis, ultimately facilitating atrial fibrillation (AF). In various rat models, Pinocembrin has anti-fibrotic and anti-apoptotic effects, reducing arrhythmia vulnerability. However, whether pinocembrin alleviates to AF in a PAH model remains unclear. The experiment aims to investigate how pinocembrin affects AF susceptibility in PAH rats and the possible mechanisms involved.METHODSThe PAH model was induced by monocrotaline (MCT; i. p. 60 mg/kg). Concurrently, rats received pinocembrin (i.p.50 mg/kg) or saline. Hemodynamics parameters, electrocardiogram parameters, lung H.E. staining, atrial electrophysiological parameters, histology, Western blot, and TUNEL assay were detected.RESULTSCompared to the control rats, MCT-induced PAH rats possessed prominently enhancive mPAP (mean pulmonary artery pressure), pulmonary vascular remodeling, AF inducibility, HRV, right atrial myocardial fibrosis, apoptosis, atrial ERP, APD, and P-wave duration. Additionally, there were lowered protein levels of Cav1.2, Kv4.2, Kv4.3, and connexin 40 (CX40) in the MCT group in right atrial tissue. However, pinocembrin reversed the above pathologies and alleviated the activity of the Rho A/ROCKs signaling pathway, including the expression of Rho A, ROCK1, ROCK2, and its downstream MYPT-1, LIMK2, BCL-2, BAX, cleaved-caspase3 in right atrial and HL-1 cells.CONCLUSIONPresent data exhibited pinocembrin attenuated atrial electrical, ion-channel, and autonomic remodeling, diminished myocardial fibrosis and apoptosis levels, thereby reducing susceptibility to AF in the MCT-induced PAH rats. Furthermore, we found that pinocembrin exerted inhibitory action on the Rho A/ROCK signaling pathway, which may be potentially associated with its anti-AF effects.

01 Feb 2019·Cardiovascular Research

Y-27632 preconditioning enhances transplantation of human-induced pluripotent stem cell-derived cardiomyocytes in myocardial infarction mice

Article

Author: Zhou, Lufang ; Zhang, Jianyi ; Tang, Yawen ; Zhao, Meng ; Oduk, Yasin ; Borovjagin, Anton V ; Ernst, Patrick J ; Zhu, Hanxi ; Mattapally, Saidulu ; Fan, Chengming ; Zhu, Wuqiang

AimsThe effectiveness of cell-based treatments for regenerative myocardial therapy is limited by low rates of cell engraftment. Y-27632 inhibits Rho-associated protein kinase (ROCK), which regulates the cytoskeletal changes associated with cell adhesion, and has been used to protect cultured cells during their passaging. Here, we investigated whether preconditioning of cardiomyocytes, derived from human-induced pluripotent stem cells (hiPSC-CM), with Y-27632 improves their survival and engraftment in a murine model of acute myocardial infarction (MI).Methods and resultsAfter MI induction, mice were subjected to intramyocardial injections of phosphate-buffered saline, hiPSC-CM cultured under standard conditions (hiPSC-CM-RI), or Y-27632-preconditioned hiPSC-CM (hiPSC-CM+RI). The resulting engraftment rate calculated 4 weeks after implantation was significantly higher and the abundance of apoptotic transplanted cells was significantly lower in hiPSC-CM+RI recipients than in hiPSC-CM-RI animals. In cultured hiPSC-CM, Y-27632-preconditioning reversibly reduced contractile activity and the expression of troponin genes, while increasing their attachment to an underlying mouse cardiomyocyte (HL1) monolayer. Y-27632 preconditioning also increased the expression of N-cadherin and integrin ß1, the two cell junction proteins. hiPSC-CM+RI were also larger in cell area with greater cytoskeletal alignment and a more rod-like shape than hiPSC-CM-RI, both after transplantation (in vivo) and in culture. The effects of Y-27632 preconditioning on contractile activity and morphology of hiPSC-CMs in culture, as well as on their engraftment rate and apoptotic death in MI mouse grafts, could be recapitulated by hiPSC-CM treatment with the L-type calcium-channel blocker verapamil.ConclusionPreconditioning with the ROCK inhibitor Y-27632 increased the engraftment of transplanted hiPSC-CM in a murine MI model, while reversibly impairing hiPSC-CM contractility and promoting adhesion.

01 Aug 2017·Cardiovascular Research

RHOA-ROCK signalling is necessary for lateralization and differentiation of the developing sinoatrial node

Article

Author: deRuiter, Marco C ; Gittenberger-de Groot, Adriana C ; Tertoolen, Leon G ; Jongbloed, Monique R M ; Pijnappels, Daniël A ; Schalij, Martin J ; Poelmann, Robert E ; Kelder, Tim P ; Vicente-Steijn, Rebecca ; Wisse, Lambertus J

AIMSRHOA-ROCK signalling regulates cell migration, proliferation, differentiation, and transcription. RHOA is expressed in the developing cardiac conduction system in chicken and mice. In early development, the entire sinus venosus myocardium, including both the transient left-sided and the definitive sinoatrial node (SAN), has pacemaker potential. Later, pacemaker potential is restricted to the right-sided SAN. Disruption of RHOA expression in adult mice causes arrhythmias including bradycardia and atrial fibrillation, the mechanism of which is unknown but presumed to affect the SAN. The aim of this study is to assess the role of RHOA-ROCK signalling in SAN development in the chicken heart.METHODS AND RESULTSROCK signalling was inhibited chemically in embryonic chicken hearts using Y-27632. This prolonged the immature state of the sinus venosus myocardium, evidenced by up-regulation of the transcription factor ISL1, wide distribution of pacemaker potential, and significantly reduced heart rate. Furthermore ROCK inhibition caused aberrant expression of typical SAN genes: ROCK1, ROCK2, SHOX2, TBX3, TBX5, ISL1, HCN4, CX40, CAV3.1, and NKX2.5 and left-right asymmetry genes: PITX2C and NODAL. Anatomical abnormalities in pulmonary vein development were also observed. Patch clamp electrophysiology confirmed the immature phenotype of the SAN cells and a residual left-sided sinus venosus myocardium pacemaker-like potential.CONCLUSIONSRHOA-ROCK signalling is involved in establishing the right-sided SAN as the definitive pacemaker of the heart and restricts typical pacemaker gene expression to the right side of the sinus venosus myocardium.

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