title: Discovery of a proneurogenic, neuroprotective chemical.
abstract: An in vivo screen was performed in search of chemicals capable of enhancing neuron formation in the hippocampus of adult mice. Eight of 1000 small molecules tested enhanced neuron formation in the subgranular zone of the dentate gyrus. Among these was an aminopropyl carbazole, designated P7C3, endowed with favorable pharmacological properties. In vivo studies gave evidence that P7C3 exerts its proneurogenic activity by protecting newborn neurons from apoptosis. Mice missing the gene encoding neuronal PAS domain protein 3 (NPAS3) are devoid of hippocampal neurogenesis and display malformation and electrophysiological dysfunction of the dentate gyrus. Prolonged administration of P7C3 to npas3(-/-) mice corrected these deficits by normalizing levels of apoptosis of newborn hippocampal neurons. Prolonged administration of P7C3 to aged rats also enhanced neurogenesis in the dentate gyrus, impeded neuron death, and preserved cognitive capacity as a function of terminal aging. PAPERCLIP:
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA. andrew.pieper@utsouthwestern.edu
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Pieper
authors.forename: Shanhai
authors.initials: S
authors.lastname: Xie
authors.forename: Emanuela
authors.initials: E
authors.lastname: Capota
authors.forename: Sandi Jo
authors.initials: SJ
authors.lastname: Estill
authors.forename: Jeannie
authors.initials: J
authors.lastname: Zhong
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Long
authors.forename: Ginger L
authors.initials: GL
authors.lastname: Becker
authors.forename: Paula
authors.initials: P
authors.lastname: Huntington
authors.forename: Shauna E
authors.initials: SE
authors.lastname: Goldman
authors.forename: Ching-Han
authors.initials: CH
authors.lastname: Shen
authors.forename: Maria
authors.initials: M
authors.lastname: Capota
authors.forename: Jeremiah K
authors.initials: JK
authors.lastname: Britt
authors.forename: Tiina
authors.initials: T
authors.lastname: Kotti
authors.forename: Kerstin
authors.initials: K
authors.lastname: Ure
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Brat
authors.forename: Noelle S
authors.initials: NS
authors.lastname: Williams
authors.forename: Karen S
authors.initials: KS
authors.lastname: MacMillan
authors.forename: Jacinth
authors.initials: J
authors.lastname: Naidoo
authors.forename: Lisa
authors.initials: L
authors.lastname: Melito
authors.forename: Jenny
authors.initials: J
authors.lastname: Hsieh
authors.forename: Jef
authors.initials: J
authors.lastname: De Brabander
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Ready
authors.forename: Steven L
authors.initials: SL
authors.lastname: McKnight
mesh_terms: D000375:Aging / Q000187:drug effects; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects; D018891:Dentate Gyrus / Q000166:cytology / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000166:cytology*; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002227:Carbazoles; D018696:Neuroprotective Agents; C492587:Npas3 protein, mouse; C552520:P7C3 compound