An antidepressant developed over 40 years ago has been found to reverse the muscle enlargement and weakened pumping function associated with heart failure, say researchers.
In an animal study, John Hopkins researchers found that antidepressant clorgyline, which is no longer in use in humans, blocked the action of enzyme monoamine oxidase-A (MAO-A) and stopped its breakdown of a key neurohormone.
AdvertisementNorepinephrine controls the pace of blood pumping and makes the heart pump harder and faster in response to stress.
The findings showed that mice with failing hearts responded to concurrent low-dose clorgyline treatment, with restoration of normal heart function and only half the harmful changes seen in untreated mice over the same time period.
Heart muscle cell death rates were normal in clorgyline-treated mice, but three and a half times higher in untreated mice.
The team led by Dr Nina Kaludercic, a postdoctoral fellow at Johns Hopkins and the University of Padova in Italy believes that when norepinephrine is not properly stored in the nerves, it overflows into the heart, accelerating the hormone's breakdown by MAO-A.
This in turn leads to the buildup inside the heart of harmful reactive oxygen species, such as hydrogen peroxide, that strain normal muscle cell contraction.
"Our study helps describe heart failure as a vicious chemical circle of stimulant norepinephrine overload and breakdown, and it offers a disease blueprint with monoamine oxidase-A as the target for drugs similar to clorgyline to rein in the disease," said senior study investigator and cardiologist Dr Nazareno Paolocci.
"When norepinephrine is not properly stored and released from the nerves directed to the heart, monoamine oxidase-A breaks it down, generating dangerous chemical species in the nerves and the heart muscle.
"These toxic free radicals produce the same deleterious effects on heart muscle size and pumping function long observed in heart failure.
"Now that we know clorgyline works, we can focus future drug testing on newer, safer MAO-A inhibitors, such as moclobemide, whose chemical bindings are reversible, unlike those of clorgyline," Paolocci added.
The study is published in the journal Circulation Research.
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