Nortriptyline delays disease onset in models of chronic neurodegeneration.
This study was to characterize the neuroprotective effects of nortriptyline, a tricyclic antidepressant, in mouse models of chronic neurodegeneration [amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD)]. Nortriptyline was originally selected from a library screening of 1040 FDA-approved drugs by using isolated mitochondria. It emerged as a strong inhibitor of mitochondrial permeability transition (mPT). Our results showed that nortriptyline significantly delayed disease onset and extended the lifespan of ALS mice although its effect on mortality was less than that on onset. We also tested promethazine, another compound which emerged from the same screening, in ALS mice. Promethazine-treated ALS mice exhibited a significant delay in disease onset but not in mortality. Histochemistry analysis found that nortriptyline treatment indeed protected motor neurons from death and reduced ventral horn atrophy in ALS mice. Furthermore, release of cytochrome c and activation of caspase 3, two molecular phenomena associated with mitochondrial-pathway-mediated cell death, were inhibited by nortriptyline. We also demonstrated similar beneficial effects of nortriptyline in HD mice: it extended the presymptomatic portion of the disease but had no effect on mortality. In an established cellular model of HD, nortriptyline inhibited cell death and decreased loss of mitochondrial membrane potential. In summary, this study indicated the potential therapeutic usefulness of nortriptyline in ALS and HD. In addition, our data suggested a role for mPT in chronic neurodegeneration, particularly at the early rather than the advanced disease stages.
Wang
Hongyan
H
Neuroapoptosis Laboratory, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, LMRC 113, Boston, MA 02115, USA.
Guan
Yingjun
Y
Wang
Xin
X
Smith
Karen
K
Cormier
Kerry
K
Zhu
Shan
S
Stavrovskaya
Irina G
IG
Huo
Chunfeng
C
Ferrante
Robert J
RJ
Kristal
Bruce S
BS
Friedlander
Robert M
RM
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002908:Chronic Disease; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009661:Nortriptyline / Q000494:pharmacology*; D013997:Time Factors; D016896:Treatment Outcome
D000929:Antidepressive Agents, Tricyclic; D018696:Neuroprotective Agents; D009661:Nortriptyline