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(12) United States Patent (10) Patent No.: US 9,339,508 B2 Baulieu Et Al

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(12) United States Patent (10) Patent No.: US 9,339,508 B2 Baulieu Et Al US0093395.08B2 (12) United States Patent (10) Patent No.: US 9,339,508 B2 Baulieu et al. (45) Date of Patent: May 17, 2016 (54) USE OF 3-METHOXY-PREGNENOLONE FOR OTHER PUBLICATIONS THE PREPARATION OF A DRUG FOR TREATING ATRAUMATIC BRAIN INURY Kolb et al., Nerve Growth Factor Treatment Prevents Dendritic Atro phy and Promotes Recovery of Function. After Cortical Injury, (71) Applicant: MAPREG, Le Kremlin Bicetre (FR) Neuroscience, vol. 76, No. 4, pp. 1139-1151. (1996). Zhanget al., “Cytoskeletal Disruption Following Contusion Injury to (72) Inventors: Etienne-Emile Baulieu, the Rat Spinal Cord”, Journal of Neuropathology and Experimental Neuilly-sur-Seine (FR); Esther Fellous, Neurology, vol. 59, No. 4, pp. 287-296, (2000). Schumacher et al., “Pretreatment with Calpain Inhibitor CPE-4143 Paris (FR); Paul Robel, Paris (FR) Inhibits Calpain I Activation and Cytoskeletal Degradation, Improves Neurological Function, and Enhances AXonal Survival (73) Assignee: MAPREG, Le Kremlin Bicetre (FR) After Traumatic Spinal Cord Injury”. Journal of Neurochemistry, vol. (*) Notice: Subject to any disclaimer, the term of this 74, No. 4, pp. 1646-1655, (2000). Springer et al., “Rapid Calpain I Activation and Cytoskeletal Protein patent is extended or adjusted under 35 Degradation Following Traumatic Spinal Cord Injury: Attenuation U.S.C. 154(b) by 287 days. with Riluzole Pretreatment”, Journal of Neurochemistry, vol. 69, No. 4, pp. 1592-1600, (1997). (21) Appl. No.: 13/666,663 Matus, “MAP2, Microtubules, pp. 155-166, (1994). Sanchez et al., “Phosphorylation of Microtubule-Associated Protein (22) Filed: Nov. 1, 2012 2 (MAP2) and its Relevance for the Regulation of the Neuronal (65) Prior Publication Data Cytoskeleton Function”. Progress in Neurobiology, vol. 61, pp. 133 168, (2000). US 2013/0244991 A1 Sep. 19, 2013 Caceres, et al., “Suppression of MAP2 in Cultured Cerebeller US 2014/OO458O7 A2 Feb. 13, 2014 Macroneurons Inhibits Minor Neurite Formation'. Neuron, vol. 9, US 2014/0228336 A2 Aug. 14, 2014 pp. 607-618, (1992). Harada et al., “MAP2 is Required for Dendrite Elongation, PKA Anchoring in Dendrites, and Proper PKA Signal Transduction'. The Related U.S. Application Data Journal of Cell Biology, vol. 158, No. 3, pp. 541-549, (2002). Reyna-Neyra et al., “Estradiol and Progesterone Modify Microtubule (63) Continuation-in-part of application No. 12/232,993, Associated Protein 2 Content in the Rat Hippocampus', Brain filed on Sep. 26, 2008, now Pat. No. 8,334.278, which Research Bulletin, vol. 58. No. 6, pp. 607-612. (2002). is a continuation-in-part of application No. Nakatomi et al., “Regeneration of Hippocampal Pyramidal Neurons 10/542,495, filed aS application No. after Ischemic Brain Injury by Recruitment of Endogenous Neural PCT/FR2004/000086 on Jan. 16, 2004, now Pat. No. Progenitors”. Cell. vol. 110, pp. 429-441. (2002). 8,034,798. Garcia-Estrada et al., “Dehydroeplandrosterone, Pregnenolone and Sex Steroids Down-Regulate Reactive Astroglia in the Male Rat (30) Foreign Application Priority Data Brain after a Penetrating Brain Injury'. Int. J. Devil. Neuroscience, vol. 17, No. 2, pp. 145-150, (1999). Legrand et al., “Pregnenolone Reverses the Age-Dependent Accu Jan. 17, 2003 (FR) ....................................... 0300507 mulation of Glial Fibrillary Acidic Protein within Astrocytes of Spe cific Regions of the Rat Brain”. Brain Research, vol. 802, pp. 125 (51) Int. Cl. 132, (1998). A6 IK3I/56 (2006.01) Guth et al., “Key Role for Pregnenolone in Combination Therapy that AOIN 45/00 (2006.01) Promotes Recovery after Spinal Cord Injury”. Proc. Natl. Acad. Sci. A 6LX3/57 (2006.01) USA, vol. 91, pp. 12308-12311, (1994). A6 IK3I/58 (2006.01) Gursoy et al., “Pregnenolone Protects Mouse Hippocampal (HT-22) (52) U.S. Cl. Cells Against Glutamate and Amyloid Beta Protein Toxicity'. CPC ................. A61 K3I/57 (2013.01); A61 K3I/58 Neurochemical Research, vol. 26, No. 1, pp. 15-21, (2001). (2013.01) (Continued) (58) Field of Classification Search CPC ............................... A61K 31/56; A61K 3 1/57 USPC .................................................. 514/169, 182 Primary Examiner — Sue Liu See application file for complete search history. Assistant Examiner — Helen Chui (74) Attorney, Agent, or Firm — Finnegan, Henderson, (56) References Cited Farabow, Garrette and Dunner, L.L.P. U.S. PATENT DOCUMENTS (57) ABSTRACT 6,245,757 B1* 6/2001 Choppet al. .................. 514,177 2002fOO72509 A1* 6/2002 Stein et al. .................... 514,169 A method for the treatment of a traumatic brain lesion com prises administering to the patient an effective quantity of FOREIGN PATENT DOCUMENTS 3-methoxy-pregna-5-ene-20-one (3-methoxy-PREG). EP 1310258 A1 5, 2003 WO WOO1,68068 A2 9, 2001 WO WOO2,36128 A1 5, 2002 6 Claims, 27 Drawing Sheets US 9,339,508 B2 Page 2 (56) References Cited Bianchi et al., Cytoskeletal Changes in the Hippocampus Following Restraint Stress: Role of Serotonin and Microtubules, (2003) SYN OTHER PUBLICATIONS APSE 49:188-194. Bianchietal. Fluoxetine Administration Modulates the Cytoskeletal Parveen Sra et al., “Evaluation of Locomotor Rating Scales Follow Microtubular System in the Rat Hippocampus, (2009) SYNAPSE ing Spinal Cord Injury in Rats'. Orthopaedic Research Society, Feb. 63:359-364. 1-4, 1999, p. 982, Anaheim, California. S.W. Scheff, "A statistical method for analyzing rating scale data: the Meieran et al., Chronic pregnenolone effects in normal humans: BBB locomotor score”. J. Neurotrauma, Oct. 19, 2002, pp. 1251 attenuation of benzodiazepine-induced sedation, (2004) 1260, Lexington, Kentucky. Psychoneuroendocrinology 29, 486-500. D. M. Basso et al., “A sensitive and reliable locomotor rating scale for Miyamoto et al., Effects of long-term treatment with desipramine on open field testing in rats'. J. Neurotrauma, Feb. 12, 1995, pp. 1-21. microtubule proteins in rat cerebral cortex, (1997) European Journal Columbus, Ohio. of Pharmacology 333, 279-287. D. M. Basso et al., “MASCIS evaluation of open field locomotor scores: effects of experience and teamwork on reliability. Multicenter Murakami et al., Pregnenolone binds to microtubule-associated pro Animal Spinal Cord Injury Study”. J. Neurotrauma, Jul. 13, 1996, pp. tein 2 and stimulates microtubule assembly, (2000) PNAS Mar. 28, 343-359, Columbus, Ohio. 2000 vol. 97 No. 7:3579-3584. Murakami et al., “Pregnenolone Binds to Microtubule-Associated Donati et al., Chronic Antidepressant Treatment Prevents Accumu Protein 2 and Stimulates Microtubule Assembly”. PNAS, vol.97, No. lation of GSO in Cholesterol-Rich, Cytoskeletal-Associated, Plasma 7, pp. 3579-3584 (2000). Membrane Domains (Lipid Rafts), (2005) Neuropsychopharmacol Campbell et al., The role of the hippocampus in the pathophysiology ogy 30, 1238-1245. of major depression, (2004) J Psychiatry Neurosci 29(6):417-26. Fontaine-Lenoir et al., Microtubule-associated protein 2 (MAP2) is a Serra, et al., Social isolation-induced increase in the sensitivity of rats neurosteroid receptor, (2006) PNAS 103:4711-4716. to the steriodogenic effect of ethanol. (2003) Journal of Bianchi et al., Neuronal Plasticity, Stress and Depression: Involve Neurochemistry 85,257-263. ment of the Cytoskeletal Microtubular System. (2005) Current Drug Warner-Schmidt, et al., Hippocampal Neurogenesis: Opposing Targets CNS & Neurological Disorders 4,597-611. Effects of Stress and Antidepressant Treatment, (2006) Hippocampus Bianchi et al., Isolation rearing induces recognition memory deficits 16:239-249. accompanied by cytoskeletal alterations in rathippocampus, (2006) European Journal of Neuroscience vol. 24, 2894-2902. * cited by examiner U.S. Patent May 17, 2016 Sheet 1 of 27 US 9,339,508 B2 0.35 : 3 : 0.25 8.2 0.5 * & Contro 0.1 ya. 8888& -8-. 83-8 ,0s - s s sites Figure 1 U.S. Patent May 17, 2016 Sheet 2 of 27 US 9,339,508 B2 7 : 5 100 8 a. -A - 30 it - A 20 8 0 V x 8 a 88 k 4. s 8 ther of days in culture Figure 3 U.S. Patent May 17, 2016 Sheet 3 of 27 US 9,339,508 B2 Sites.g. Figure 4 U.S. Patent May 17, 2016 Sheet 4 of 27 US 9,339,508 B2 SO 13 '... 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