Nortriptyline delays disease onset in models of chronic neurodegeneration

Abstract

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.

Chronic Amitriptyline Treatment Attenuates Nigrostriatal Degeneration and Significantly Alters Trophic Support in a Rat Model of Parkinsonism

“…More recently, AMI was shown to mediate changes in hippocampal BDNF and GDNF, resulting in reduced neuroinflammation and alpha-synuclein accumulation in a mouse model of multiple systems atrophy (Valera et al, 2014). Finally, nortriptyline (a metabolite of AMI), was shown to delay the onset of neurodegeneration in mouse models of ALS and Huntington's disease (Wang et al, 2007). Collectively, these studies provide evidence that antidepressants, and AMI specifically, afford neuroprotection in multiple animal models of neurodegeneration.…”

Therapeutic progress in amyotrophic lateral sclerosis-beginning to learning

“…Inhibitors of mPT are neuroprotective in nature, for example nortriptyline, an FDA-approved tricyclic antidepressant [144] delays the disease onset and reduces motor neuronal loss in ALS mice [145]. Another mPT inhibitor, cyclosporine, an immunosuppressant, prevents the assembly of mPT and stabilizes mitochondrial membranes, thereby preventing apoptosis.…”

Amitriptyline Improves Motor Function via Enhanced Neurotrophin Signaling and Mitochondrial Functions in the Murine N171-82Q Huntington Disease Model

“…They found that nortriptyline significantly delayed disease onset and extended the life span of HD mice by extending the presymptomatic portion of the disease without affecting mortality. In an established cellular model of HD, they also reported that nortriptyline inhibited mitochondrion-mediated cell death and decreased loss of mitochondrial membrane potential (25).…”