US 2008O167363A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0167363 A1 Barlow et al. (43) Pub. Date: Jul. 10, 2008 (54) MODULATION OF NEUROGENESIS BY (22) Filed: Dec. 27, 2007 MELATONNERGICAGENTS Related U.S. Application Data (75) Inventors: as: ey Mat 5. (60) Provisional application No. 60/882,434, filed on Dec. CA (US); Andrew Morse, San 28, 2006, provisional application No. 60/882,440, Diego, CA (US); Kai Treuner, San filed on Dec. 28, 2006. Diego, CA (US); Kym I. Lorrain, San Diego, CA (US); Jeff Redwine, Publication Classification San Diego, CA (US); Christine (51) Int. Cl. Hoffmaster, El Cajon, CA (US) A63L/403 (2006.01) A6IP 25/24 (2006.01) Correspondence Address: (52) U.S. Cl. ........................................................ 514/411 TOWNSEND AND TOWNSEND AND CREW, LLP (57) ABSTRACT TWO EMBARCADERO CENTER, EIGHTH FLOOR The present disclosure describes methods for treating dis SAN FRANCISCO, CA 94111-3834 eases and conditions of the central and peripheral nervous system by stimulating or increasing neurogenesis. The dis (73) Assignee: BrainCells, Inc, San Diego, CA closure includes compositions and methods based on use of (US) melatonin or other melatoninergic agent, optionally in com bination with one or more other neurogenic agents, to stimu (21) Appl. No.: 11/965,110 late or activate the formation of new nerve cells. Human Neurogenesis ASSay: Ramelteon Neuronal Differentiation (TUJ1) 130 120 Ramelteon 110 100 90 80 70 60 50 40 30 20 1O O -10 10-8.5 10-8.0 10-7.5 10-7.0 10-6.5 10-6.0 10-5.5 10-5.0 10-4.5 10-40 Conc(M) Patent Application Publication Jul. 10, 2008 Sheet 1 of 13 US 2008/0167363 A1 Figure 1: Human Neurogenesis Assay: Ramelteon Neuronal Differentiation (TUJ1) 130 120 Ramelteon 110 100 90 80 70 60 50 40 30 20 10 O -10 10-8.5 10-8.0 10-7.5 10-7.0 10-6.5 10-6.0 10-5.5 10-5.0 10-4.5 10-40 Conc(M) Patent Application Publication Jul. 10, 2008 Sheet 2 of 13 US 2008/0167363 A1 Figure 2: Human Neurogenesis Assay: GR 135,531 Neuronal Differentiation (TUJ1) 130 120 GR 135,531 110 100 90 80 70 60 50 40 30 20 10 O -10 10-9.5 10-9.0 10-8.5 10-8.0 10-7.5 10-7.0 10-6.5 10-6.0 10-5.5 10-5.0 Conc(M) Patent Application Publication Jul. 10, 2008 Sheet 3 of 13 US 2008/0167363 A1 Figure 3: Human Neurogenesis Assay: Captopril + Melatonin Neuronal Differentiation (TUJ1) E. Captopril Melatonin 110 -- Captopril 100 - - - MelatOnin Conc (M) Patent Application Publication Jul. 10, 2008 Sheet 4 of 13 US 2008/0167363 A1 Figure 4: Human Neurogenesis Assay: 5-HT + MelatOnin Neuronal Differentiation (TUJ1) 5-HT Melatonin 110 - - - - 5-HT 100 - - - MelatOnin 90 80 70 60 50 40 30 20 10 O -10 10-8.5 10-8.0 10-7.5 10-7.0 10-6.5 10-6.0 10-5.5 10-5.0 10-4.5 10-40 Conc (M) Patent Application Publication Jul. 10, 2008 Sheet 5 of 13 US 2008/0167363 A1 Figure 5: Human Neurogenesis Assay: Buspirone + Melatonin Neuronal Differentiation (TUJ1) 110 100 - Buspirone + Melatonin 90- "Buspirone 80- --Melatonin 10-8.5 10-8.0 10-7.5 10-7.0 10-6.5 10-6.0 10-5.5 10-5.0 10-4.5 10-40 Conc (M) Patent Application Publication Jul. 10, 2008 Sheet 6 of 13 US 2008/0167363 A1 Figure 6: Human Astrocyte Assay: Buspirone + Melatonin Astrocyte Differentiation (GFAP) 110 100 - Buspirone + Melatonin 90- "BuspirOne 80- --Melatonin 10-8.5 10-8.0 10-7.5 10-7.0 10-6.5 10-6.0 10-5.5 10-5.0 10-4.5 10-40 Conc (M) Patent Application Publication Jul. 10, 2008 Sheet 7 of 13 US 2008/0167363 A1 Figure 7: Buspirone + Melatonin, Novelty Suppressed Feeding Novelty Suppressed Feeding (at 21 days) 1 2 O - 1 4.68OOOOO 2 O Vehicle Melatonin Buspirone Melatonin Buspirone Patent Application Publication Jul. 10, 2008 Sheet 8 of 13 US 2008/0167363 A1 Figure 8: In Vivo Neurogenesis Buspirone + Melatonin BrdU Positive Cells in Dorsal Granule Cell Layer 1 2 O9% 1 10% 100% 90%; 80% 70% 60% 50% Vehicle Melatonin Buspirone Melatonin 3 mg/kg 0.5 mg/kg -- Buspirone p < 0.01 (11% increase) Patent Application Publication Jul. 10, 2008 Sheet 9 of 13 US 2008/0167363 A1 Figure 9: Human Neurogenesis Assay: Buspirone + Ramelteon Neuronal Differentiation (TUJ1) Buspirone + Ramelteon "Buspirone O Ramelteon 10-8.5 10-8.0 107.5 10-7.0 10-6.5 10-6.0 10-5.5 10-5.0 10-4.5 10-40 Conc(M) Patent Application Publication Jul. 10, 2008 Sheet 10 of 13 US 2008/0167363 A1 Figure 10: Human Astrocyte Assay: Buspirone + Ramelteon Astrocyte Differentiation (GFAP) 10595 Buspirone + Ramelteon as "Buspirone 75 Rameteon 65 55 45 35 25 15 5 . 10-8.0 10-7.5 10-7.0 10-6.5 10-6-0 10-5.5 10-5.0 10-4.5 10-40 Conc(M) Patent Application Publication Jul. 10, 2008 Sheet 11 of 13 US 2008/0167363 A1 Figure 11: Human Neurogenesis Assay: Luzindole Luzindole Neuronal Differentiation (TUJ1) 120 - LUZindole 110 100 90 80 70 60 50 40 30 20 10 O -10 -8.5 -8.0 -7.5 -7.0 -6.5 -6.0 -5.5 -5.0 -4.5 -4.0 Log Conc (M) Patent Application Publication Jul. 10, 2008 Sheet 12 of 13 US 2008/0167363 A1 Figure 12: Human Neurogenesis Assay: 4-P-PDOT 4-P-PDOT Neuronal Differentiation (TUJ1) 110 m-4-P-PDOT 100 9 O 6 O 25 OO -11 -8.5 -8.0 -7.5 -7.0 -6.5 -6.0 -5.5 -5.0 -4.5 -4.0 Log Conc (M) Patent Application Publication Jul. 10, 2008 Sheet 13 of 13 US 2008/0167363 A1 Figure 13: Human Neurogenesis Assay: 4-P-PDOT AgOmelatine Neuronal Differentiation (TUJ1) 110 100 90 Agomelatine 10-8.5 10-8.0 10-7.5 10-7.0 10-6.5 10-6.0 10-5.5 10-5.0 10-4.5 10-40 Conc (M) US 2008/O167363 A1 Jul. 10, 2008 MODULATION OF NEUROGENESIS BY and MT2 receptors are canonical GPCRs (G-protein coupled MELATONNERGICAGENTS receptors). MT3 has been reported to be quinone reductase 2 (QR2). Another reported mechanism is through interactions CROSS-REFERENCES TO RELATED with nuclear sites corresponding to orphan members of the APPLICATIONS nuclear receptor superfamily, RZR/ROR. 0001. This application claims priority benefit to U.S. Pro 0006 Citation of the above documents is not intended as visional Application No. 60/882,440 titled: “MODULA an admission that any of the foregoing is pertinent prior art. TION OF NEUROGENESIS BY MELATONINERGIC All statements as to the date or representation as to the con tents of these documents is based on the information available LIGANDS” filed Dec. 28, 2006; and U.S. Provisional Appli to the applicant and does not constitute any admission as to cation No. 60/882,434 titled: “MODULATION OF NEURO the correctness of the dates or contents of these documents. GENESIS BY RAMELTEON AND RELATED COM POUNDS also filed Dec.28, 2006, the disclosures of each of which are hereby incorporated by reference in their entirety BRIEF SUMMARY OF THE DISCLOSURE for all purposes. 0007 Disclosed herein are compositions and methods for the prophylaxis and treatment of diseases, conditions and FIELD OF THE DISCLOSURE injuries of the central and peripheral nervous systems by stimulating or increasing neurogenesis. Aspects of the meth 0002 The present disclosure relates to methods for treat ods, and activities of the compositions, include increasing or ing diseases and conditions of the central and peripheral potentiating neurogenesis in cases of a disease, disorder, or nervous system by stimulating or increasing neurogenesis by condition of the nervous system. Embodiments of the disclo use of melatonin or by modulation of melatonin receptor Sure include methods of treating a neurodegenerative disor activity or use of an agent which modulates melatoninactivity der, neurological trauma including brain or central nervous (a melatoninergic agent), optionally in combination with system trauma and/or recovery therefrom, depression, anxi another neurogenic agent. The disclosure includes methods ety, psychosis, learning and memory disorders, and ischemia based on the application of a neurogenesis modulating mela of the central and/or peripheral nervous systems. In other toninergic agent with activity to stimulate or activate the embodiments, the disclosed methods are used to improve formation of new nerve cells. cognitive outcomes and mood disorders. 0008. In one aspect, methods of modulating, such as by BACKGROUND OF THE DISCLOSURE Stimulating or increasing, neurogenesis are disclosed. The 0003) Neurogenesis is a vital process in the brains of ani neurogenesis may be at the level of a cell or tissue. The cellor mals and humans, whereby new nerve cells are continuously tissue may be present in an animal Subject or a human being, generated throughout the lifespan of the organism. The newly or alternatively be in an in vitro or ex vivo setting. In some born cells are able to differentiate into functional cells of the embodiments, neurogenesis is stimulated or increased in a central nervous system and integrate into existing neural cir neural cell or tissue, such as that of the central or peripheral cuits in the brain. Neurogenesis is known to persist through nervous system of an animal or human being.