Abbott GmbH & Co. KG, Knollstrasse 50, D-67061 Ludwigshafen, Germany Correspondence to B.K.M. e-mail: bernhard. mueller@abbott.com doi:10.1038/nrd1719 RHO KINASE, A PROMISING DRUG TARGET FOR NEUROLOGICAL DISORDERS Bernhard K. Mueller, Helmut Mack and Nicole Teusch 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. 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. One of the best-characterized effectors of the small GTP-binding proteins of the Rho subfamily (Rho GTPases) is Rho-associated coiled-coil-containing protein kinase (hereafter simply referred to as ROCK). RhoGTPases, a subfamily of the Ras superfamily of GTPases, function as molecular devices that control multiple signalling pathways in a very precise and coordinated way by switching between a biochemically inactive (GDP-bound) and an active (GTP-bound) state 1–3 . The cycling between GDP- and GTP-bound states is controlled by two classes of proteins: GTPase- activating proteins (GAPs), which enhance intrinsic GTPase activity; and guanine nucleotide-exchange factors (GEFs), which catalyse the exchange of GDP to GTP 4 . Furthermore, a third set of regulatory pro- teins, the guanine nucleotide-dissociation inhibi- tors (GDIs), sequester GTPases in the cytosol in the inactive, GDP-bound state. In the active, GTP-bound state, RhoGTPases acti- vate numerous downstream effectors. In this review, we concentrate on one of these effectors, ROCK. The current understanding of the pathophysiological con- sequences of ROCK activation in the central nervous system (CNS) is summarized and we highlight the potential therapeutic use of ROCK inhibitors for the treatment of various neurological disorders, including spinal-cord injury, Alzheimer`s disease, stroke, multiple sclerosis and NEUROPATHIC PAIN. ROCK isoforms and tissue distribution ROCK is a serine/threonine (Ser/Thr) protein kinase that was identified about ten years ago as a RhoGTP- binding protein with a molecular mass of ~160 kDa 5–7 . Two isoforms encoded by two different genes of ROCK have been described: ROCKI (also known as ROKβ or p160ROCK) and ROCKII (which is also known as ROKα) 8 . These two proteins share an overall sequence similarity at the amino-acid level of 65% and in their kinase domains of 92% 9,10 . ROCKs are most homo- logous to other members of the group of AGC KINASES, such as myotonic dystrophy kinase (DMPK), myotonic dystrophy kinase-related CDC42-binding kinase (MRCK) and citron kinase. In general, the catalytic domain of all these kinases is located at the amino ter- minus, followed by a coiled-coil-forming region and a pleckstrin-homology domain with a cysteine-rich NATURE REVIEWS | DRUG DISCOVERY VOLUME 4 | MAY 2005 | 387 REVIEWS