ALISKIREN MODULATION OF NEUROGENESIS
The disclosure provides compositions and methods for treating diseases and conditions of the central and peripheral nervous system by stimulating or increasing neurogenesis by use of a renin inhibitor in combination with one or more neurogenic agents. The disclosure also includes compositions and methods for stimulating or activating the formation of new nerve cells based on the application of a renin inhibitor in combination with one or more neurogenic agents.
1 . A composition comprising a renin inhibitor in combination with one or more neurogenic agents.
2 . The composition of claim 1 , wherein the renin inhibitor is aliskiren or a pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof; and the one or more neurogenic agents is a 5-HT 3 receptor antagonist, a PDE inhibitor, an anti-viral agent, a dopamine modulator, a Rho kinase inhibitor or an alpha2-adrenergic receptor antagonist.
3 . The composition of claim 2 , wherein the 5-HT 3 receptor antagonist is azasetron, granisetron, ondansetron, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, the PDE inhibitor is ibudilast or a pharmaceutically acceptable salt, solvate or N-oxide thereof, the antiviral agent is ribavirin or a pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof, the dopamine modulator is methylphenidate or a pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof; the Rho kinase inhibitor is fasudil or a pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof; and the alpha2-adrenergic receptor antagonist is yohimbine or a pharmaceutically acceptable salt, solvate or N-oxide thereof.
4 . The composition of claim 1 , wherein the renin inhibitor in combination with one or more neurogenic agents is in a pharmaceutically acceptable formulation.
5 . A method of stimulating or increasing neurogenesis in a cell or tissue, the method comprising contacting the cell or tissue with an effective amount of the composition of claim 1 , to stimulate or increase neurogenesis in said cell or tissue.
6 . The method of claim 5 , wherein the cell or tissue is in an animal or human subject.
7 . The method of claim 6 , wherein the subject has a condition affecting normal neurogenesis whereby stimulating or increasing neurogenesis improves the condition.
8 . A method of claim 7 , wherein the condition causes decreased neurogenesis in the subject.
9 . A method of claim 7 , wherein the condition causes aberrant neurogenesis in the subject.
10 . A method of claim 7 , wherein the subject had been exposed to an agent causing decreased neurogenesis.
11 . A method of claim 5 , wherein the neurogenesis comprises differentiation of neural stem cells (NSCs) along a neuronal lineage.
12 . A method of claim 5 , wherein the neurogenesis comprises differentiation of neural stem cells (NSCs) along a glial lineage.
13 . A method of claim 6 , wherein the neurogenesis occurs in the hippocampus of the subject.
14 . A method of decreasing the level of astrogenesis in a cell or tissue due to an agent that induces or produces astrogenesis, the method comprising contacting the cell or tissue with an effective amount of the composition of claim 1 , to decrease the level of astrogenesis in a cell or tissue.
15 . The method of claim 14 , wherein the agent that induces or produces astrogenesis is also neurogenic.
16 . A method claim 14 wherein the cell or tissue is in an animal or human subject.
17 . A method of treating a subject suffering from a nervous system disorder comprising administering to the subject an effective amount of the composition of claim 1 .
18 . A method of claim 17 , wherein the subject is an animal or human.
19 . A method of claim 17 , wherein the nervous system disorder is a mental disorder or a disease of the central nervous system.
20 . A method of claim 19 , wherein the mental disorder is an affective disorder.
21 . A method of claim 19 , wherein the disease of the central nervous system causes cognitive impairment.
22 . A method of claim 21 , wherein the cognitive impairment is the result of chronic infection, toxic disorders, neurodegenerative disorders, or combinations thereof.
23 . A method of treating a subject suffering from cognitive impairment due to a non-disease state comprising administering to the subject a therapeutically-effective amount of the composition of claim 1 .
24 . The method of claim 23 , wherein the non-disease state is aging.
25 . The method of claim 23 , wherein the cognitive impairment is a result of chemotherapy or radiation therapy.