Chronic treatment with AMPA receptor potentiator Org 26576 increases neuronal cell proliferation and survival in adult rodent hippocampus.
BACKGROUND
Currently available antidepressants upregulate hippocampal neurogenesis and prefrontal gliogenesis after chronic administration, which could block or reverse the effects of stress. Allosteric alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiators (ARPs), which have novel targets compared to current antidepressants, have been shown to have antidepressant properties in neurogenic and behavioral models.


OBJECTIVE
This study analyzed the effect of the ARP Org 26576 on the proliferation, survival, and differentiation of neurons and glia in the hippocampus and prelimbic cortex of adult rats.


METHODS
Male Sprague-Dawley rats received acute (single day) or chronic (21 day) twice-daily intraperitoneal injections of Org 26576 (1-10 mg/kg). Bromodeoxyuridine (BrdU) immunohistochemistry was conducted 24 h or 28 days after the last drug injection for the analysis of cell proliferation or survival, respectively. Confocal immunofluorescence analysis was used to determine the phenotype of surviving cells.


RESULTS
Acute administration of Org 26576 did not increase neuronal cell proliferation. However, chronic administration of Org 26576 increased progenitor cell proliferation in dentate gyrus (approximately 40%) and in prelimbic cortex (approximately 35%) at the 10-mg/kg dosage. Cells born in response to chronic Org 26576 in dentate gyrus exhibited increased rates of survival (approximately 30%) with the majority of surviving cells expressing a neuronal phenotype.


CONCLUSIONS
Findings suggest that Org 26576 may have antidepressant properties, which may be attributed, in part, to upregulation of hippocampal neurogenesis and prelimbic cell proliferation.
Su
Xiaowei W
XW
Division of Molecular Psychiatry, Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, Yale University School of Medicine, New Haven, CT 06508, USA.
Li
Xiao-Yuan
XY
Banasr
Mounira
M
Koo
Ja Wook
JW
Shahid
Mohammed
M
Henry
Brian
B
Duman
Ronald S
RS
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects*; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000819:agonists*; D013997:Time Factors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology
D000928:Antidepressive Agents; C545643:Org 26576; D018091:Receptors, AMPA; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D001973:Bromodeoxyuridine