US 20100184806A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0184806 A1 Barlow et al. (43) Pub. Date: Jul. 22, 2010 (54) MODULATION OF NEUROGENESIS BY PPAR (60) Provisional application No. 60/826,206, filed on Sep. AGENTS 19, 2006. (75) Inventors: Carrolee Barlow, Del Mar, CA (US); Todd Carter, San Diego, CA Publication Classification (US); Andrew Morse, San Diego, (51) Int. Cl. CA (US); Kai Treuner, San Diego, A6II 3/4433 (2006.01) CA (US); Kym Lorrain, San A6II 3/4439 (2006.01) Diego, CA (US) A6IP 25/00 (2006.01) A6IP 25/28 (2006.01) Correspondence Address: A6IP 25/18 (2006.01) SUGHRUE MION, PLLC A6IP 25/22 (2006.01) 2100 PENNSYLVANIA AVENUE, N.W., SUITE 8OO (52) U.S. Cl. ......................................... 514/337; 514/342 WASHINGTON, DC 20037 (US) (57) ABSTRACT (73) Assignee: BrainCells, Inc., San Diego, CA (US) The instant disclosure describes methods for treating diseases and conditions of the central and peripheral nervous system (21) Appl. No.: 12/690,915 including by stimulating or increasing neurogenesis, neuro proliferation, and/or neurodifferentiation. The disclosure (22) Filed: Jan. 20, 2010 includes compositions and methods based on use of a peroxi some proliferator-activated receptor (PPAR) agent, option Related U.S. Application Data ally in combination with one or more neurogenic agents, to (63) Continuation-in-part of application No. 1 1/857,221, stimulate or increase a neurogenic response and/or to treat a filed on Sep. 18, 2007. nervous system disease or disorder. Patent Application Publication Jul. 22, 2010 Sheet 1 of 9 US 2010/O184806 A1 Figure 1: Human Neurogenesis Assay Ciprofibrate Neuronal Differentiation (TUJ1) 100 8090 Ciprofibrates 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 Conc(M) Patent Application Publication Jul. 22, 2010 Sheet 2 of 9 US 2010/O184806 A1 Figure 2: Human Neurogenesis Assay Clofibrate Neuronal Differentiation (TUJ1) 100 90 Clofibrate 80 10-8.5 10-8.0 107.5 10-7.0 10-6.5 10-6.0 10-5.5 10-50 10-4.5 Conc(M) Patent Application Publication Jul. 22, 2010 Sheet 3 of 9 US 2010/O184806 A1 Figure 3: Human Neurogenesis Assay Rosiglitazone Neuronal Differentiation (TUJ1) 130 120 110 Rosiglitazone 100 90 8O 70 60 50 40 30 2O 10 1, -8.5 10-8.0 107.5 10-7.0 10-6.5 10-6.0 10-5.5 10-5.0 Conc(M) Patent Application Publication Jul. 22, 2010 Sheet 4 of 9 US 2010/O184806 A1 Figure 4: Human Neurogenesis Assay TOO70907 Neuronal Differentiation (TUJ1) 1 OO 90 TOO70907 80 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. 22, 2010 Sheet 5 of 9 US 2010/O184806 A1 Figure 5: Human Neurogenesis Assay: Rosiglitazone + Tacrine Neuronal Differentiation (TUJ1) 140 - O - Rosiglitazone IP Tacrine 115 -0- Combination 90 65 40 s & Exx 83e & 8 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. 22, 2010 Sheet 6 of 9 US 2010/0184806 A1 Figure 6: Human Neurogenesis Assay: Rosiglitazone + N-Acetylcysteine (1:3) Neuronal Differentiation 110 c 100 o Rosiglitazone C E 0.6 E 90 A. N-Acetylcysteine 3 80. Rosiglitazone + N-Acetylcysteine p 70 C 60 : 50 5 40 E 30 20 9 10 8 L O ge gas stage " ' A. 0-9.0 108.5 0-8.0 0-7.5 10-7.0 10-6.5 10-6.0 10-5.5 10-5.0 104.5 ge assessioneers sessessmeless 0-8. 0-8.0 10-7. 0-7.0 (8.5 0-8.0 0-. 0-5.0 0-. 0-40 Conc (M) Patent Application Publication Jul. 22, 2010 Sheet 7 of 9 US 2010/O184806 A1 Figure 7: Human Neurogenesis Assay: Ciglitazone + N-Acetylcysteine (1:30) Neuronal Differentiation 10 100 go Ciglitazone C E 0.14 9 O & N-Acetylcysteine Ciglitazone + N-Acetylcysteine 25 sOO -1 10-10.0 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 gressessess assag & says assassis 8.5 -8.0 -. -7.0 -8. 6.0 0-5. 0-5. 1-4. 4.0 Conc (M) Patent Application Publication Jul. 22, 2010 Sheet 8 of 9 US 2010/O184806 A1 Figure 8: Human Neurogenesis Assay: Pioglitazone + N-Acetylcysteine (1:10) Neuronal Differentiation O OO {o Pioglitazone C E 0.6 9 O A. N-Acetylcysteine Poglitazone + N-Acetylcysteine 15 OO -1 8 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 (8.5 0-8.0 0-7.5 07.0 0-8.5s 10-8.0's (-5.5 0-5. 10-4.5 y Conc (M) Patent Application Publication Jul. 22, 2010 Sheet 9 of 9 US 2010/0184806 A1 Figure 9: Human Neurogenesis Assay: Troglitazone + N-Acetylcysteine (1:3) Neuronal Differentiation 110 100--0. Troglitazone C E 0.04 A. N-Acetylcysteine Troglitazone + N-Acetylcysteine 10 -1 g 10-9.5 10-9.0 10-8.5 0-8.0 10-7.5 0-7.0 106.5 10-6.0 10-5.5 10-5.0 104.5 sales ressesassasse-memories (8. 8.0 0-7.5 07.0 0-6.5 0-8.0 0-5. 0-3.0 0-. 0-40 Conc (M) US 2010/0184806 A1 Jul. 22, 2010 MODULATION OF NEUROGENESIS BY PPAR to the applicant and does not constitute any admission as to AGENTS the correctness of the dates or contents of these documents. SUMMARY OF THE INVENTION RELATED APPLICATIONS 0006 Disclosed herein are compositions and methods for 0001. This application is a continuation-in-part applica the prophylaxis and treatment of diseases, conditions and tion of U.S. application Ser. No. 1 1/857,221, filed Sep. 18, injuries of the central and peripheral nervous systems and for 2007, currently pending, which claims benefit of priority stimulating or increasing neurogenesis. The present invention from U.S. Provisional Applications 60/826,206, filed Sep.19, provides in one aspect compositions of one or more PPAR 2006, now expired, all of which are incorporated by reference agent preferably in combination with a neurogenic agent, a as if fully set forth. neurogenic sensitizing agent or an anti-astrogenic agent, for stimulating or increasing neurogenesis. Embodiments of the methods, and activities of the compositions, include increas FIELD OF THE INVENTION ing or potentiating neurogenesis in cases of a disease, disor der, or condition of the nervous system. Embodiments of the 0002 The instant disclosure relates to compositions and disclosure include methods of treating a neurodegenerative methods for treating diseases and conditions of the central disorder, neurological trauma including brain or central ner and peripheral nervous system by, for example, stimulating or Vous system trauma and/or recovery therefrom, an affective increasing a neurogenic response using a peroxisome prolif disorder including depression and anxiety, psychosis, learn erator activated receptor (PPAR) modulator, optionally in ing and memory disorders, and ischemia of the central and/or combination with one or more neurogenic agents. The dis peripheral nervous systems. In another embodiment, the dis closure includes methods based on the application of the closed compositions and methods are used to improve cog modulator and/or the combination to stimulate or increase a nitive outcomes and mood disorders. neurogenic response, and/or the formation of new nerve cells 0007. In one aspect, the compositions contain one or more and/or neuro differentiation. PPAR agents optionally in combination with one or more neurogenic agents, neurogenic sensitizing agents and/or anti astrogenic agents. The PPAR agent may be PPAR-gamma BACKGROUND OF THE INVENTION agonist Such as a glitaZone, encompassing rosiglitaZone, ciglitaZone, pioglitaZone, troglitaZone, balaglitaZone or other 0003) Neurogenesis is a vital process in the brains of ani members of the glitaZone family of compounds including mals and humans, whereby new nerve cells are continuously pharmaceutically acceptable salts and Solvates thereof. generated throughout the lifespan of the organism. The newly 0008. In another aspect the neurogenic, neurogenic sensi born cells are able to differentiate into functional cells of the tizing and anti-astrogenic agents include antioxidants and central nervous system and integrate into existing neural cir pharmaceutically acceptable salts, Solvates and analogs cuits in the brain. Neurogenesis is known to persist through thereof as non-limiting examples. The antioxidant may be out adulthood in two regions of the mammalian brain: the represented by N-acetylcysteine (N-acetyl-L-csyteine, ace subventricular Zone (SVZ) of the lateral ventricles and the tylcysteine, NAC), as a non-limiting example. Furthermore, dentate gyrus of the hippocampus. In these regions, multipo the combination of agents may be administered in one phar tent neural progenitor cells (NPCs) continue to divide and maceutically acceptable formulation, or concurrently or give rise to new functional neurons and glial cells (for review sequentially in more than one formulation. Jacobs Mol. Psychiatry. 2000 May: 5(3):262-9). It has been 0009. Thus the invention includes PPAR agents in combi shown that a variety of factors can stimulate adult hippocam nation with neurogenic, neurogenic sensitizing and anti-as pal neurogenesis, e.g., adrenalectomy, Voluntary exercise, trogenic agents, PPAR agents in combination with an anti enriched environment, hippocampus dependent learning and oxidant, PPAR-gamma agonists in combination with anti-depressants (Yehuda.