Discovery of a proneurogenic, neuroprotective chemical.
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:
Pieper
Andrew A
AA
Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA. andrew.pieper@utsouthwestern.edu
Xie
Shanhai
S
Capota
Emanuela
E
Estill
Sandi Jo
SJ
Zhong
Jeannie
J
Long
Jeffrey M
JM
Becker
Ginger L
GL
Huntington
Paula
P
Goldman
Shauna E
SE
Shen
Ching-Han
CH
Capota
Maria
M
Britt
Jeremiah K
JK
Kotti
Tiina
T
Ure
Kerstin
K
Brat
Daniel J
DJ
Williams
Noelle S
NS
MacMillan
Karen S
KS
Naidoo
Jacinth
J
Melito
Lisa
L
Hsieh
Jenny
J
De Brabander
Jef
J
Ready
Joseph M
JM
McKnight
Steven L
SL
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
D051792:Basic Helix-Loop-Helix Proteins; D002227:Carbazoles; D018696:Neuroprotective Agents; C492587:Npas3 protein, mouse; C552520:P7C3 compound