Sertraline slows disease progression and increases neurogenesis in N171-82Q mouse model of Huntington's disease.
Huntington's disease (HD) is an inherited progressive neurodegenerative disorder resulting from CAG repeat expansion in the gene that encodes for the protein huntingtin. To identify neuroprotective compound (s) that can slow down disease progression and can be administered long term with few side effects in Huntington's disease, we investigated the effect of sertraline, a selective serotonin reuptake inhibitor (SSRI) which has been shown to upregulate BDNF levels in rodent brains. We report here that in HD mice sertraline increased BDNF levels, preserved chaperone protein HSP70 and Bcl-2 levels in brains, attenuated the progression of brain atrophy and behavioral abnormalities and thereby increased survival. Sertraline also enhanced neurogenesis, which appeared to be responsible for mediating the beneficial effects of sertraline in HD mice. Additionally, the effective levels of sertraline are comparable to the safe levels achievable in humans. The findings suggest that sertraline is a potential candidate for treatment of HD patients.
Duan
Wenzhen
W
Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, MD 21287, USA. Electronic address: wduan2@jhmi.edu.
Peng
Qi
Q
Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, MD 21287, USA.
Masuda
Naoki
N
Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, MD 21287, USA.
Ford
Eric
E
Department of Radiology, Johns Hopkins University School of Medicine, USA.
Tryggestad
Erik
E
Department of Radiology, Johns Hopkins University School of Medicine, USA.
Ladenheim
Bruce
B
Molecular Neuropsychiatry Branch, National Institute on Drug Abuse, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA.
Zhao
Ming
M
Oncology Analytical Pharmacology Core, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Cadet
Jean Lud
JL
Molecular Neuropsychiatry Branch, National Institute on Drug Abuse, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA.
Wong
John
J
Department of Radiology, Johns Hopkins University School of Medicine, USA.
Ross
Christopher A
CA
Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, MD 21287, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
D000818:Animals; D001216:Asparagine / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D005973:Glutamine / Q000235:genetics; D006816:Huntington Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology* / Q000187:drug effects* / Q000502:physiology; D020280:Sertraline / Q000494:pharmacology / Q000627:therapeutic use*
D005973:Glutamine; D001216:Asparagine; D020280:Sertraline