The therapeutic effects of Rho-ROCK inhibitors on CNS disorders

Abstract

Rho-kinase (ROCK) is a serine/threonine kinase and one of the major downstream effectors of the small GTPase Rho. The Rho-ROCK pathway is involved in many aspects of neuronal functions including neurite outgrowth and retraction. The Rho-ROCK pathway becomes an attractive target for the development of drugs for treating central nervous system (CNS) disorders, since it has been recently revealed that this pathway is closely related to the pathogenesis of several CNS disorders such as spinal cord injuries, stroke, and Alzheimer's disease (AD). In the adult CNS, injured axons regenerate poorly due to the presence of myelin-associated axonal growth inhibitors such as myelin-associated glycoprotein (MAG), Nogo, oligodendrocyte-myelin glycoprotein (OMgp), and the recently identified repulsive guidance molecule (RGM). The effects of these inhibitors are reversed by blockade of the Rho-ROCK pathway in vitro, and the inhibition of this pathway promotes axonal regeneration and functional recovery in the injured CNS in vivo. In addition, the therapeutic effects of the Rho-ROCK inhibitors have been demonstrated in animal models of stroke. In this review, we summarize the involvement of the Rho-ROCK pathway in CNS disorders such as spinal cord injuries, stroke, and AD and also discuss the potential of Rho-ROCK inhibitors in the treatment of human CNS disorders.

Keywords: Rho; Rho-kinase; axonal regeneration; central nervous system disorder; neuron.

Figure 1

schematic drawing of ROCKI and ROCK activation by Rho. (A) ROCKI has the kinase domain at the amino terminus, followed by a coiled-coil domain containing the Rho-binding site (RBD), and a pleckstrin-homology domain (PH) with an internal cysteine-rich domain (CRD). ROCKII has a very similar structure. (B) A proposed mechanism of ROCK activation by GTP-bound Rho is shown (Amano et al 1999). The carboxyl terminal domain forms an autoinhibitory loop that folds back onto the kinase domain and inhibits the kinase activity of ROCK. GTP-bound Rho binds to the RBD region in ROCK and renders the catalytic domain of ROCK to be accessible to its substrates, which results in the activation of ROCK.

Figure 2

Intracellular signal cascades of myelin-associated neurite outgrowth inhibitors. Myelin-associated neurite outgrowth inhibitors such as Nogo, MAG, and OMgp bind to the same receptor, namely, NgR. A receptor complex containing p75^NTR mediates the inhibitory signals such as growth cone collapse and neurite outgrowth inhibition via the activation of Rho and ROCK. NgR is reported to be only involved in the pathway resulting in growth cone collapse (I), but not in the pathway resulting in neurite outgrowth inhibition (II), which suggests that an unknown receptor for the neurite outgrowth inhibitors mediates the latter pathway (Chivatakarn et al 2007). In some neurons, TROY might be involved in this cascade instead of p75^NTR. RGMa binds to a different receptor, namely, neogenin and also activates the Rho-ROCK pathway. Other neurite outgrowth inhibitors such as chondroitin sulfate proteoglycans (CSPGs) and members of the semaphorin and ephrin families are also reported to activate the Rho-ROCK pathway for their inhibitory functions (not shown).

Figure 3

The chemical structures of ROCK inhibitors. Two typical ROCK inhibitors, ie, fasudil and Y-27632, and their derivatives are shown. Isoquinoline derivatives, including fasudil, hydroxyfasudil, and dimethylfasudil, are represented on the upper side. 4-Aminopyridine derivatives such as Y-27632 and Y-39983 are shown on the lower side.