ROCK

2022-06-20: reference:

ROCK (Rho-associated Kinase) #

• ROCK2 is eexpressed in brain and muscle tissue.
• Rho-Kinase Mediates Hypoxia-Induced Downregulation of Endothelial Nitric Oxide Synthase
  • Stabilizes eNOS mRNA. The treatment they did increased ENOS’s half life 2-fold.
• Perspectives on ROCK2 as a Therapeutic Target for Alzheimer’s Disease (there are many studies as AD therapy)
  • (Negatively) regulates autophagy, such as during the accumulation of tau.
• ROCK and PDE5 Inhibitors for the Treatment of Dementia: Literature Review and Meta-Analysis
• Applications for ROCK kinase inhibition
  • Stimulated by Caspase 3 and PDK1, inhibited by Gem and RhoE. ROCK2 is inhibited by Rad.
• Peripheral Delivery of a ROCK Inhibitor Improves Learning and Working Memory
  • GWAS for memory (specifically retention of non-semantic material) found associations with the KIBRA gene (Kidney and brain expressed protein/WWC1). Interacts with synaptopodin, Dendrin, PKMζ. Colocalizes with SHANK3
  • ROCK is activated by proxy of Protein Kinase Cζ pathways, and then goes to interact with KIBRA.
    • Atypical PKCzeta is involved in RhoA-dependent mitogenic signaling by the P2Y(12) receptor in C6 cells, etc.
• Distinct and Complementary Functions of Rho kinase isoforms ROCK1 and ROCK2 in Prefrontal Cortex Structural Plasticity (ROCK1 vs ROCK2)

Effectors #

• It activates M1 phenotype microglia and inhibits M2. As such, it activates IL-6, TNF-α, IL-1β ROS, NO and inhibits IL-4, IL-10, IL-13.
  • Rho Kinase Inhibitor Fasudil Regulates Microglia Polarization and Function
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  • Inhibits MYPT1, an activator of MLC.
  • rhoA-KO-MLC-actin.JPG so ROCK->Myosin light chain 20 leads to formation of Actin arcs. I’m guessing they kinetically restrain the microtubule somehow.
  • Many effects are amplified by phosphorylating ZIPK, which phosphorylates many of the same substrates.
• Induces Growth Cone collapse by activating actomyosin contractility and by phosphorylating (inhibiting) CRMP2.
  • TLR4 promotes the phosphorylation of CRMP2 via the activation of Rho‑kinase in MCAO rats

• Loss of ROCK leads to loss of tight junction integrity in endothelial cells; by inhibiting actomyosin leading to disinhibition of E-Cadherin.
  • RhoA/ROCK-2 Pathway Inhibition and Tight Junction Protein Upregulation by Catalpol Suppresses Lipopolysaccaride-Induced Disruption of Blood-Brain Barrier Permeability
• ROCK2 knockout lowers Calpain, Caspase 3, and raises p-AKT and CRMP2
• Activates ERK, which degrades p27Kipe, a CDK inhibitor which down-regulates the cell cycle via binding cyclin-CDK complex. Thus, ROCK has proliferative effects.
  • Fasudil inhibits platelet-derived growth factor-induced human pulmonary artery smooth muscle cell proliferation by up-regulation of p27kip¹ via the ERK signal pathway

Inhibitors #

• Fasudil is taken orally. It’s an inhibitor and also vasodilator.
  • ROCK is important for vasoconstriction and vascular remodeling in the pathogenesis of plmonary hypertension: induces Vasoconstriction via phosphorylating myosin-binding subunit of myosin light chain (MLC) phosphatase.
    • Rho kinase inhibitor HA-1077 prevents Rho-mediated myosin phosphatase inhibition in smooth muscle cells
  • ROCK increases Angiotensin-converting enzyme (ACE) activity in pulmonary hypertension.
  • Fasudil attenuates aggregation of α-synuclein in models of Parkinson’s disease
  • Antidepressant-relevant behavioral and synaptic molecular effects of long-term fasudil treatment in chronically stressed male rats
    • Increases p-GSK-3β, p-4E-BP1, p-MTOR, and decreases p-Ser831. Note, this is in stressed animals, so perhaps this is protective.
  • Allostasist tried it and didn’t really notice anything. But tolerated it decently.
• BA-1049 aka NRL-1049: Fausidil analog. 86x ROCK2:ROCK1 affinity.
  • No off-target effects it seems. Better safety profile than Fasudil R
• Rxc007
  • 11 hour half life; 40mg dose.a
• Belumosudil (aka KD025). 200x ROCK2:ROCK1 affinity.
  • Treatment attenuates spatial learning and memory deficits induced by traumatic brain injury.
• I think ibuprofen has similar actions.
• Novel Dual AChE and ROCK2 Inhibitor Induces Neurogenesis via PTEN/AKT Pathway in Alzheimer’s Disease Model