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  • Review Article
  • Published:

Rho kinase, a promising drug target for neurological disorders

Nature Reviews Drug Discovery volume 4, pages 387–398 (2005)Cite this article

Key Points

  • A large number of Rho kinase (ROCK) inhibitors have been developed during the past decade, and to our knowledge none of these distinguish between the two ROCK isoforms, ROCKI and ROCKII. In addition, the commercially available inhibitors (fasudil, Y-27632 and H-1152) target other closely related kinases. Despite this, the reasonably selective ROCK inhibitor fasudil has been marketed in Japan since 1995 for the treatment of cerebral vasospasm after subarachnoid haemorrhage and is currently undergoing clinical evaluation in angina pectoris.

  • Most interestingly, knockouts of either ROCK genes yielded the surprising result that despite their embryonic phenotypes, homozygous mice are able to develop to maturity and are fertile and healthy.

  • In different animal models of spinal-cord injury, ROCK inhibitors induced neurite outgrowth and sprouting and enhanced tissue preservation. Both mechanisms account for the improved regeneration and functional recovery of the inhibitor-treated animals in comparison to control animals. These results turn ROCK inhibitors into the currently most potent small-molecule stimulators of neuroregeneration.

  • In a transgenic mouse model of Alzheimer's disease, the ROCK inhibitor Y-27632 decreased the amount of toxic Aβ42, thereby interfering with the pathological degenerative process. In animal models of neuropathic pain and in multiple sclerosis models, data have shown that inhibiting the Rho–ROCK pathway has positive effects, which indicate an excellent therapeutic opportunity.

  • No crystallographic structural data of the kinase domain of ROCKs are currently available but a structural surrogate kinase approach with protein kinase A yielded valuable information that explains the binding mode of three different ROCK inhibitors (fasudil, Y-27632 and H-1152). Crystallographic data on the ROCK kinase structure will help to design more selective and more potent ROCK inhibitors.

Abstract

Rho kinases (ROCKs), the first Rho effectors to be described, are serine/threonine kinases that are important in fundamental processes of cell migration, cell proliferation and cell survival. Abnormal activation of the Rho/ROCK pathway has been observed in various disorders of the central nervous system. Injury to the adult vertebrate brain and spinal cord activates ROCKs, thereby inhibiting neurite growth and sprouting. Inhibition of ROCKs results in accelerated regeneration and enhanced functional recovery after spinal-cord injury in mammals, and inhibition of the Rho/ROCK pathway has also proved to be efficacious in animal models of stroke, inflammatory and demyelinating diseases, Alzheimer's disease and neuropathic pain. ROCK inhibitors therefore have potential for preventing neurodegeneration and stimulating neuroregeneration in various neurological disorders.

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Figure 1: Molecular structure of Rho kinase (ROCK) I and II.
Figure 2: Activation mechanism of Rho kinase (ROCK).
Figure 3: Major ROCK substrates.
Figure 4: Spinal-cord injury.
Figure 5: Growth-cone collapse.
Figure 6: Structures of Rho kinase (ROCK) inhibitors.

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Authors and Affiliations

  1. Abbott GmbH & Co. KG, Knollstrasse 50, Ludwigshafen, D-67061, Germany

    Bernhard K. Mueller, Helmut Mack & Nicole Teusch

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  1. Bernhard K. Mueller
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  2. Helmut Mack
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Correspondence to Bernhard K. Mueller.

Related links

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DATABASES

Entrez Gene

APP

CRMP2

DMPK

GFAP

LIMK1

LIMK2

MAG

MAP2

MAPKAPK1b

MLCP

MRCK

MSK1

NgR1

NgR2

NOGO-A

OMgp

p21CIP1/WAF1

PKN2

ROCKI

ROCKII

TROY

FURTHER INFORMATION

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CareCure Community

Christopher and Dana Reeve Paralysis Resource Center

MedicinePlus - Alzheimer's Disease

National Institute of Neurological Disorders and Stroke

National Multiple Sclerosis Society

NeuroTrauma Registry Spinal Cord Map

Glossary

NEUROPATHIC PAIN

A pain state initiated or caused by a primary lesion or dysfunction in the nervous system.

AGC KINASES

A group of kinases with a high degree of amino-acid sequence conservation in their kinase domains.

OMPHALOCOELE

Inability to close the ventral body wall during ontogenetic development, which causes the protrusion of intestinal organs.

HAEMORRHAGE

Excessive bleeding, with increased blood release from blood vessels into surrounding tissues or organs.

SUBARACHNOID SPACE

The brain and spinal cord are enclosed by three layers of connective tissue called the meninges.The space below (or under) the outermost meningeal layer and the middle arachnoid meningeal layer is the subarachnoid space.

ISCHAEMIA

Insufficient blood supply of organs or tissues, very often caused by a thrombus or a clot blocking a blood vessel.

REPERFUSION

Restoration of blood flow after obstruction of blood vessels.

EXCITOTOXICITY

The fundamental concept that neurons can be damaged by overstimulation or overexcitation with excitatory amino acids such as glutamate.

NEURONAL GROWTH CONES

Hand-like structures at the tip of growing neurites, axons and dendrites.

RETRACTION BULB

Large bulbs at the ends of injured nerve fibres in humans suffering from brain injury or spinal-cord injury.

CHONDROITIN SULPHATE PROTEOGLYCAN

(CSPG). The most abundant proteoglycan found in the mammalian CNS, CSPG consists of a protein core and long, unbranched polysaccharides comprising chondroitin sulphate (CS) disaccharide unit repeats.

C3 TRANSFERASE

Bacterial exoenzyme produced by a diverse group of bacteria that inactivates Rho proteins by covalently attaching an ADP-ribose to certain amino acids.

PDAPP MICE

Transgenic mice that express mutated human amyloid precursor protein under control of the platelet-derived growth factor promoter. These mice develop extracellular fibrils and plaques.

LYSOPHOSPHATIDIC ACID (LPA)

A natural phospholipid and a major active constituent of serum that induces growth-factor-like activities in many cell types by binding to specific G-protein-coupled cell-surface receptors.

ALLODYNIA

Abnormal pain state, in which normally non-painful stimuli evoke painful responses.

HYPERALGESIA

An increased or excessive pain response to noxious stimuli.

RHIZOTOMY

Surgical transection of a spinal nerve root.

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Mueller, B., Mack, H. & Teusch, N. Rho kinase, a promising drug target for neurological disorders. Nat Rev Drug Discov 4, 387–398 (2005). https://doi.org/10.1038/nrd1719

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