| (+)-trans-4-(1-aminoethyl)-1-(4-pyridycarbamoyl)-cyclohexane and method for promoting neural growth in the central nervous system and in a patient at a site of neuronal lesion -> Monitor Keywords |
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(+)-trans-4-(1-aminoethyl)-1-(4-pyridycarbamoyl)-cyclohexane and method for promoting neural growth in the central nervous system and in a patient at a site of neuronal lesionRelated Patent Categories: Chemistry: Molecular Biology And Microbiology, Measuring Or Testing Process Involving Enzymes Or Micro-organisms; Composition Or Test Strip Therefore; Processes Of Forming Such Composition Or Test Strip(+)-trans-4-(1-aminoethyl)-1-(4-pyridycarbamoyl)-cyclohexane and method for promoting neural growth in the central nervous system and in a patient at a site of neuronal lesion description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070128585, (+)-trans-4-(1-aminoethyl)-1-(4-pyridycarbamoyl)-cyclohexane and method for promoting neural growth in the central nervous system and in a patient at a site of neuronal lesion. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation-in-part application of U.S. application Ser. No. 09/184,572 filed on Nov. 2, 1998. FIELD OF INVENTION [0002] This invention relates to the regulation of growth of neurons in the Central Nervous System. BACKGROUND [0003] Following trauma in the adult central nervous system (CNS) of mammals, injured neurons do not regenerate their transected axons. An important barrier to regeneration is the axon growth inhibitory activity that is present in CNS myelin and that is also associated with the plasma membrane of oligodendrocytes, the cells that synthesize myelin in the CNS (see Schwab M. E., et al., (1993) Ann. Rev. Neurosci. 16, 565-595, for review). The growth inhibitory properties of CNS myelin have been demonstrated in a number of different laboratories by a wide variety of techniques, including plating neurons on myelin substrates or cryostat sections of white matter, and observations of axon contact with mature oligodendrocytes (Schwab, M. E., et al., (1993) Annu. Rev. Neurosci. 16, 565-595). Therefore, it is well documented that adult neurons cannot extend neurites over CNS myelin in vitro. [0004] It has also been well documented that removing myelin in vivo improves the success of regenerative growth over the native terrain of the CNS. Regeneration occurs after irradiation of newborn rats, a procedure that kills oligodendrocytes and prevents the appearance of myelin proteins (Savio and Schwab, (1990) Neurobiology 87, 4130-4133). After such a procedure in rats is combined with a corticospinal tract lesion, some corticospinal axons regrow long distances beyond the lesions. Also, in a chick model of spinal cord repair, the onset of myelination correlates with a loss of its regenerative ability of cut axons (Keirstead, et al., (1992) Proc. Nat. Acad. Sci. (USA) 89, 11664-11668). The removal of myelin with anti-galactocerebroside and complement in the embryonic chick spinal cord extends the permissive period for axonal regeneration. These experiments demonstrate a good correlation between myelination and the failure of axons to regenerate in the CNS. [0005] Myelin inhibits axon growth because it contains at least several different growth inhibitory proteins. It has been well documented by us and by others that myelin-associated glycoprotein (MAG) has potent growth inhibitory activity, both in vitro and in vivo (McKerracher, L., et al., (1994) Neuron 13, 805-811; Mukhopadhyay, G., et al., (1994) Neuron 13, 805-811; Li, M., et al., (1996) J Neurosci. Res. 46, 404-414; Schafer, M., et al., (1996) Neuron 16, 1107-1113). A high molecular weight inhibitory activity has been characterized by Schwab and collaborators, and neutralization of this activity with the IN-1 antibody allows some axons to regenerate in white matter (Schwab, M. E., et al., (1993) Ann. Rev. Neurosci. 16 565-595; Bregman, B., et al., (1995) Nature 378, 498-501.). We also have evidence that there is an additional growth inhibitory protein in myelin (Xiao, Z., et al., (1997) Soc. Neurosci. Absts. 23, 1994). Clearly, there are multiple inhibitory proteins that stop axon regeneration in mammalian CNS myelin. [0006] In addition to the myelin-derived inhibitors there are also other growth inhibitory molecules expressed in the adult mammalian CNS. Tenacin is a growth inhibitory protein that is expressed in some unmyelinated regions of the CNS (Bartsch, U., et al., (1994) J Neurosci. 14, 4756-4768) and after lesion tenascin is expressed by astrocytes that border the lesion site (Ajemain and David (1994) J Comp. Neurol. 340, 233-242). Also growth inhibitory proteins that are proteoglycans are expressed by reactive astrocytes, and these proteins form a barrier to regeneration at the glial scar (McKeon and Silver (1995) Exp. Neurol. 136, 32-43). [0007] While axons damaged in the CNS in vivo do not typically regrow, there have been some reports of long distance axon extension in adult white matter. Such growth has been observed following transplantation of grafted neural tissue (Wictorin, K., et al., (1990) Nature 347, 556-558; Davies, S. J. A., et al., (1994) J Neurosci. 14, 1596-1612; Isacson, O. and Deacon, T. W. (1996) Neuroscience 75, 827-837), suggesting that embryonic neurons primed for rapid extension of axons may be less susceptible to growth inhibition. Some embryonic neurons are not susceptible to MAG (Mukhopadhyay, G., et al., (1994) Neuron 13, 805-811), but most embryonic neurons are inhibited by the other myelin inhibitors (Schwab, M. E., et al., (1993) Ann. Rev. Neurosci. 16, 565-595). Therefore, in the cases when axons are able to extend on myelin, signaling through intracellular pathways may play an important role in stimulating, or blocking the inhibition of axon growth. For example, it is known that laminin is able to stimulate rapid neurite growth (Kuhn, T. B., et al., (1995) Neuron 14, 275-285), and we have documented that when laminin is present in sufficient concentration, neurites can extend directly on myelin substrates. These findings suggest the possibility that the stimulation of the integrins, the receptors for laminin, is sufficient to allow axon growth on myelin. Similarly, it has been documented that when the adhesion molecule L1 is expressed ectopically on astrocytes, it can partially overcome their non-permissive substrate properties (Mohajeri, M. H., et al., (1996) Eur. J. Neurosci. 8, 1085-1097). Therefore, neurons can, under appropriate conditions, grow axons on inhibitory substrates, suggesting that the balance of positive to negativegrowth cues is a critical determinant for the success or failure of axon regrowth after injury. [0008] Growth inhibitory proteins typically cause growth cone collapse, a process that causes dramatic rearrangements to the growth cone cytoskeleton (Bandtlow, C. E., et al., (1993) Science 259, 80-83; Fan, J., et al., (1993) J Cell Biol. 121, 867-878; Li, M., et al., (1996) J Neurosci. Res. 46, 404-414). One family of proteins that has been implicated in receptor-medicated signaling to the cytoskeleton is the small GTPases of the Rho family (Hall, A. (1996) Ann. Rev. Cell Biol. 10, 31-54). In non-neuronal cells it has been clearly documented that mutations in Rho family members that include Rho, Rac and cdc42, affect adhesion, actin polymerization, and the formation of lamellipodia and filopodia, which are all processes important to motility (Nobes, C. D. and Hall, A. R. (1995) Cell 81, 53-62). There is now good evidence that members of the Rho family regulate axon outgrowth in development. Mutations in Rho-related family members block the extension of axons in Drosophila (Luo, L., et al., (1994) Genes Dev. 8, 1787-1802) and disrupt axonal pathfinding in C. elegans (Zipkin, I. L., et al., (1997) Cell 90, 883-894). More recently it has been shown that the guidance molecule collapsin acts through a Rac-dependent mechanism (Jin, Z. and Strittmatter, S. M. (1997) J. Neurosci. 17, 6256-6263). In transgenic mice that express constitutively active Rac in Purkinje cells, there are alterations in the development of axon terminals and dendritic arborizations (Luo, L., et al., (1996) Nature 379, 837-840). Consistent with the observations in vivo, it was found that dominant negative Rac expressed in PC12 cells disrupts neurite outgrowth in response to NGF (Hutchens, J. A., et al., (1997) Molec. Biol. Cell 8, 481-500). Also, treatment of PC12 cells with lysophosphatidic acid, a mitogenic phospholipid, causes neurite retraction that is mediated by Rho (Tigyi, G., et al., (1996) J. Neurochem. 66, 537-548). Therefore, different members of the Rho family can exert distinct effects on neurite growth, and in PC12 cells the activation of Rho is correlated with growth cone collapse. In non-neuronal cells, Rho participates in integrin-dependent signaling (Laudanna, C., et al., (1996) Science 271, 981-983; Udagawa, T. and McIntyre, B. W. (1996) J. Biol. Chem. 271, 12542-12548). The possibility that Rho might play a role within the myelin-derived growth inhibitory system has been studied (Jin, Z. and Strittmatter, S. M. (1997) J. Neurosci. 17, 6256-6263). It was concluded, however, that the inhibitory effects of myelin are not mediated by Rho family members. [0009] A need remains for a means of inactivating the multiple inhibitory proteins present in myelin that prevent axonal regrowth after injury in the CNS. [0010] This background information is provided for the purpose of making known information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should be construed, that any of the preceding information constitutes prior art against the present invention. SUMMARY OF THE INVENTION [0011] The present invention relates to antagonists and inhibitors to members of the Rho family of proteins and diagnostic, therapeutic, and research uses for each of these aspects. In particular, members of the Rho family of proteins serve as a therapeutic target to foster regrowth of injured or degenerating axons in the CNS. [0012] In accordance with the present invention, a preferred embodiment relates to antagonists and inhibitors of members of the Rho family of proteins and their use as a means of blocking a common signaling pathway used by the diverse growth inhibitory molecules. The antagonists and inhibitors may be mutated forms of Rho and biologically active (Rho family-inhibitory) fragments, peptides, C3 and biologically active (Rho family-inhibitory) fragments, or small molecules such as Y-27632. [0013] In yet a further aspect of the present invention, Rho family member proteins can be used to design small molecules that antagonize and inhibit Rho family proteins, to block inhibition of neurite outgrowth. In another aspect of the present invention Rho family members can be used to design antagonist agents that suppress the myelin growth inhibitory system. These antagonist agents can be used to promote axon regrowth and recovery from trauma or neurodegenerative disease. [0014] In a further aspect of the present invention, inhibitors of the Rho family of proteins can be used to block inhibition of neurite outgrowth and to suppress the myelin growth inhibitory system. Such inhibitors could block exchange of the GTP/GDP cycle of Rho activation/inactivation. [0015] A further embodiment involves a method of suppressing the inhibition of neuron growth, comprising the steps of delivering to the nerve growth environment, antibodies directed against Rho family members in an amount effective to reverse said inhibition. [0016] In accordance with another aspect of the present invention, there is provided an assay method useful to identify Rho family member antagonist agents that suppress inhibition of neuron growth, comprising the steps of: [0017] a) culturing neurons on a growth permissive substrate that incorporates a growth-inhibiting amount of a Rho family member; and [0018] b) exposing the cultured neurons of step a) to a candidate Rho family member antagonist agent in an amount and for a period sufficient prospectively to permit growth of the neurons; thereby identifying as Rho family antagonists the candidates of step b) which elicit neurite outgrowth from the cultured neurons of step a). [0019] In accordance with another aspect of present invention, there is provided a method to suppress the inhibition of neuron, comprising the steps of delivering, to the nerve growth environment, a Rho family antagonist in an amount effective to reverse said inhibition. [0020] In another embodiment, kinases activated by Rho, such as Rho-associated kinase, are antagonist candidates. Thus, compounds such as Y-27632 (U.S. patent Ser. No. 04/997,834), that block Rho-associated kinase activity, thereby inactivating the Rho signaling pathway, are also embodiments of this invention. Thus, the use of other compounds within this family of compounds as described in U.S. patent Ser. No. 04/997,834 that inhibit Rho kinase are also considered within the scope of this invention. [0021] In another embodiment, the nucleic acids encoding Rho family members can be used in antisense techniques and therapies. [0022] In yet another embodiment, a kit is provided comprising components necessary to conduct the assay method useful to screen Rho family antagonist agents. Continue reading about (+)-trans-4-(1-aminoethyl)-1-(4-pyridycarbamoyl)-cyclohexane and method for promoting neural growth in the central nervous system and in a patient at a site of neuronal lesion... 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