Y-39983, a Selective Rho-Kinase Inhibitor, Attenuates Experimental Autoimmune Encephalomyelitis via Inhibition of Demyelination (2024)

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Volume 20, Issue 6

September 2013

Research Articles| August 30 2013

Subject Area: Endocrinology , Immunology and Allergy , Neurology and Neuroscience

Cong Gao;

Cong Gao

Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Institute of Neuroscience and Second Affiliated Hospital of Guangzhou Medical University, and Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

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Li Huang;

Li Huang

Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Institute of Neuroscience and Second Affiliated Hospital of Guangzhou Medical University, and Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

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Youming Long;

Youming Long

Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Institute of Neuroscience and Second Affiliated Hospital of Guangzhou Medical University, and Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

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Jianzheng Zheng;

Jianzheng Zheng

Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Institute of Neuroscience and Second Affiliated Hospital of Guangzhou Medical University, and Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

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Jie Yang;

Jie Yang

Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Institute of Neuroscience and Second Affiliated Hospital of Guangzhou Medical University, and Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

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Shuxiang Pu;

Shuxiang Pu

Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Institute of Neuroscience and Second Affiliated Hospital of Guangzhou Medical University, and Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

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Longchang Xie

Longchang Xie

Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Institute of Neuroscience and Second Affiliated Hospital of Guangzhou Medical University, and Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

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Neuroimmunomodulation (2013) 20 (6): 334–340.

Article history

Received:

February 27 2013

Accepted:

June 05 2013

Published Online:

August 30 2013

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Citation

Cong Gao, Li Huang, Youming Long, Jianzheng Zheng, Jie Yang, Shuxiang Pu, Longchang Xie; Y-39983, a Selective Rho-Kinase Inhibitor, Attenuates Experimental Autoimmune Encephalomyelitis via Inhibition of Demyelination. Neuroimmunomodulation 1 September 2013; 20 (6): 334–340. https://doi.org/10.1159/000353568

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Abstract

Objective: Rho-associated kinase (ROCK) is a serine/threonine kinase and a major downstream effector of the small GTP-binding protein, Rho. Rho-ROCK triggers an intracellular signaling cascade that controls actin cytoskeleton and is essential for cell motility and adhesion, neurite outgrowth and retraction. In chronic disabling disease, multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), demyelination and axonal damage are the major pathological changes contributing to neurological disability. We investigated the protective effect of a specific ROCK inhibitor, Y-39983, on demyelination and axonal damage in chronic EAE. Methods: Western blotting for myelin proteins, electron microscopy and solochrome cyanine staining was performed to evaluate demyelination while neurofilament proteins and cytoskeletal proteins including β-actin and β-tubulin were used to determine axonal damage in a chronic mouse model of EAE treated with Y-39983. Results: Y-39983 significantly suppressed clinical symptoms of EAE and prevented its relapse while increasing the amount of myelin proteins. No significant changes in neurofilaments and cytoskeletal proteins were observed compared with control EAE mice. The inhibition of demyelination by Y-39983 was confirmed by solochrome cyanine staining and electron microscopy. To further study the effect of Y-39983 on demyelination in EAE, we tested three major ROCK substrates, including myosin light chain phosphorylation, LIMK2 and collapsin response mediator protein-2. The activity of these molecules was decreased in EAE animals treated with Y-39983. Conclusion: The inhibitory effect of Y-39983 on demyelination is probably due to the inactivation of ROCK substrates, which are important for neurite outgrowth, growth cone collapse and demyelination of oligodendrocytes.

Keywords:

Axonal regeneration, Experimental autoimmune encephalomyelitis, Multiple sclerosis, Myelination, Neurite outgrowth inhibitors, Rho-kinase inhibitor, ROCK , Y-39983

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© 2013 S. Karger AG, Basel

2013

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FAQs

What is rho kinase inhibitor drugs for? ›

The use of ROCK inhibitors (RKIs) has been shown to improve corneal wound healing and endothelial regeneration. Because of this, RKIs are a promising therapeutic agent for corneal disease, but have also found applications in glaucoma and vitreoretinal disease.

What is the function of the Rho-kinase? ›

Rho-associated kinase (Rho-kinase/ROCK/ROK) is an effector of the small GTPase Rho and belongs to the AGC family of kinases. Rho-kinase has pleiotropic functions including the regulation of cellular contraction, motility, morphology, polarity, cell division, and gene expression.

How do rho kinase inhibitors reduce IOP? ›

The mechanism of ROCK inhibitors' ability to decrease IOP is through direct action on the trabecular meshwork and Schlemm's canal cells (increases permeability), which play a large role in the resistance of aqueous humor outflow.

What are rho associated protein kinase inhibitors? ›

Rho-kinase inhibitors (rho-associated protein kinase inhibitor or ROCK inhibitor) are a series of compounds that target rho kinase (ROCK) and inhibit the ROCK pathway. Clinical trials have found that inhibition of the ROCK pathway contributes to the cardiovascular benefits of statin therapy.

What are the side effects of protein kinase inhibitors? ›

The protein kinase inhibitors all have some degree of hepatotoxicity and many have been linked to cases of clinically apparent liver injury which can be severe and even fatal.

What are the side effects of rho kinase inhibitor eye drops? ›

The main side effect of ROCK inhibitors is conjunctival hyperemia that is often present in more than half of the patients in certain formulations. Additional clinical trials investigating the reviewed treatment options of Rho kinase inhibitors are necessary to further validate previous findings on the topic.

How is Rho-kinase activated? ›

Rho kinase (ROCK) is a serine/threonine kinase that undergoes activation by interaction with Rho GTPases. The Rho/ROCK signaling pathways control a wide range of fundamental cell functions, including cell adhesion, motility, proliferation, differentiation, and apoptosis.

What are the eye drops for Rho-kinase? ›

Rho kinase (ROCK) inhibitors are a new class of glaucoma drugs with a novel mechanism of action and good safety profile. They exert neuroprotective effects, act on the trabecular tissue, increase the outflow of aqueous humor, and reduce intraocular pressure.

What is a kinase in the body? ›

(KY-nays) A type of enzyme (a protein that speeds up chemical reactions in the body) that adds chemicals called phosphates to other molecules, such as sugars or proteins. This may cause other molecules in the cell to become either active or inactive.

What exercise lowers IOP? ›

Studies show that you can lower your intraocular pressure, or IOP, by doing exercises that raise your pulse by only twenty percent. You can do that easily with a twenty-minute walk, four times a week. If the weather outside is frightful, simple indoor calisthenics or yoga can do the trick, too!

How can I lower my IOP fast? ›

How Do I Lower My Intraocular Pressure
  1. Eat a Healthy Diet. Eating a healthy and balanced diet is helpful when managing your eye pressure. ...
  2. Exercise. Moving your body is important for your health. ...
  3. Reduce Your Caffeine Intake. ...
  4. Elevate Your Head While Sleeping. ...
  5. Medications.
Apr 14, 2020

Can eye drops make you sleepy? ›

you should know that brimonidine eye drops may make you drowsy. Your vision may be blurry for a few minutes after you instill the eye drops. Do not drive a car or operate machinery until you know how this medication affects you. ask your doctor about the safe use of alcohol while you are using brimonidine eye drops.

What was the most common side effect in the Rho-kinase pivotal trials? ›

Local adverse effects, however, including conjunctival hyperemia, subconjunctival hemorrhages and cornea verticillata, are common. Development of Rho kinase inhibitors targeted to the cells of the outflow pathway and the retina may allow these agents to have even greater clinical impact.

What is the FDA approved rho kinase inhibitor? ›

Netarsudil ophthalmic solution (0.02%) is an FDA-approved medication used to treat glaucoma and ocular hypertension. Introduced in December 2017, this therapeutic solution belongs to the class of rho-kinase inhibitors, demonstrating its efficacy in managing these eye conditions.

What does Rho-kinase do in the heart? ›

The RhoA/Rho-kinase pathway is now widely known to play important roles in many cellular functions, including contraction, motility, proliferation, and apoptosis, and its excessive activity induces oxidative stress and promotes the development of cardiovascular diseases.

What are Janus kinase inhibitors used for? ›

These JAK inhibitors (Xeljanz, Cibinqo, Olumiant, Rinvoq and Jyseleca) are used to treat one or more of the following chronic inflammatory disorders: rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis and alopecia areata.

What are kinase inhibitors used for? ›

Certain kinases are more active in some types of cancer cells and blocking them may help keep the cancer cells from growing. Kinase inhibitors may also block the growth of new blood vessels that tumors need to grow. Some kinase inhibitors are used to treat cancer.

What are EGFR inhibitors used for? ›

EGFR is found on the surface of some normal cells and is involved in cell growth. It may also be found at high levels on some types of cancer cells, which causes these cells to grow and divide. Blocking EGFR may keep cancer cells from growing. Some EGFR inhibitors are used to treat cancer.

What is the use of mTOR inhibitor drugs? ›

An mTOR inhibitor immunosuppressant used to prevent organ transplant rejections, treat lymphangioleiomyomatosis, and treat adults with perivascular epithelioid cell tumors.

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