Rho-ROCK inhibitors for the treatment of CNS injury.
Injured axons in the adult central nervous system (CNS) exhibit almost no regeneration. Several myelin-associated proteins such as myelin-associated glycoprotein (MAG), Nogo, and oligodendrocyte-myelin glycoprotein (OMgp) have been identified as inhibitors of CNS axonal regeneration in the CNS. Recently, repulsive guidance molecule (RGM) was identified as a potential myelin-derived neurite outgrowth inhibitor in vitro and in vivo. These axonal growth inhibitors transmit inhibitory signals through common intracellular molecules such as RhoA and its effector Rho kinases (ROCK). The effects of these axonal growth inhibitors are blocked by inhibition of the Rho-ROCK pathway in vitro. Injuries to the adult CNS induce the activation of the Rho-ROCK pathway, and the inhibition of this pathway promotes axonal regeneration and functional recovery in the injured CNS. Therefore, the Rho-ROCK pathway is a promising target for drug development for the treatment of human CNS injuries such as spinal cord injuries. This review also discusses recent patents and future developments which are useful in the treatment of human CNS injuries.
Kubo
Takekazu
T
Department of Neurobiology, Graduate School of Medicine, Chiba University, Chiba, Japan. kubo@restaff.chiba-u.jp
Yamashita
Toshihide
T
D000818:Animals; D002493:Central Nervous System Diseases / Q000188:drug therapy* / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D008954:Models, Biological; D009186:Myelin Sheath / Q000187:drug effects; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D004791:Enzyme Inhibitors; D054460:rho-Associated Kinases