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I was saddened to hear Sir James Black has died. He was a pioneering
pharmacologist who, among other accomplishments, created the widely used
and highly influential beta blocking drug, propranolol. This drug has not
only improved the health of thousands if not millions of people, but has
also been widely used for research purposes, yielding basic information
about the signaling molecule norepinephrine (NE) and its receptors.
In a recent series of papers (Fitzgerald 2009a1,b2; Fitzgerald
2010a3,b4), I put forth the novel hypothesis that NE is an etiological
factor in a number of diseases, including some types of cancer,
osteoarthritis, rheumatoid arthritis, asthma, open-angle glaucoma,
diabetes mellitus, epilepsy, and Alzheimer's disease. The basic idea is
that elevated NE can function as a general pathological entity throughout
the body. This is an unusual hypothesis because NE is a neurotransmitter
in the brain and sympathetic nervous system, although it innervates most
if not all of the organs of the body and could thereby affect a broad
range of diseases.
My papers1-4 largely reviewed data on pharmaceutical manipulation of
the NE system in both humans and animal models. Direct evidence for
elevated NE or its metabolites was also examined. Additional lines of
evidence assessed the relationship between the diseases and
pheochromocytoma, bipolar disorder, hypertension, obesity, and
psychological stress, which may all involve elevated NE.
Why might NE affect the various diseases in the first place? Since
NE is a “stress hormone” that helps mediate the body’s “fight or flight”
response to environmental stressors, perhaps having (largely genetic)
elevated NE tone keeps the body in a state of diminished maintenance or
homeostatic processing, resulting in an increased probability of
developing disease.
Resveratrol, a naturally occurring molecule in some plants, has been
associated with benefits in a wide range of diseases5. One possibility is
that resveratrol achieves its putative therapeutic effects by blocking NE
receptors, since it bears structural similarity to NE.
The most important point of this letter is that use of existing
pharmaceutical drugs that either lower the level of NE (such as clonidine)
or block NE receptors (such as propranolol and prazosin) may lower the
probability of an individual developing the various diseases (and possibly
treat those diseases), and this could be tested epidemiologically.
If elevated NE plays an etiological role in a number of diseases in a
large number of individuals, then chronically taking a single drug that
weakens NE signaling systemically, such as clonidine or propranolol, may
prevent or treat many different diseases simultaneously. This would mean
Sir James Black's drug is of even greater importance and value.
Acknowledgements
This work was conceived of while I was employed by Johns Hopkins
University, and I am now employed by the National Institute on Alcohol
Abuse and Alcoholism. The work was not supported by any funding source or
agency. I have no conflicts of interest to disclose.
References
1. Fitzgerald PJ. Is norepinephrine an etiological factor in some
types of cancer? Int J Cancer 2009a; 124:257-263.
2. Fitzgerald PJ. Is elevated noradrenaline an aetiological factor
in a number of diseases? Auton Autacoid Pharmacol 2009b; 29:143-156.
3. Fitzgerald PJ. Is elevated norepinephrine an etiological factor
in some cases of epilepsy? Seizure 2010a; in press.
4. Fitzgerald PJ. Is elevated norepinephrine an etiological factor
in some cases of Alzheimer’s disease? Curr Alzheimer Res 2010b; in press.
5. Marques FZ, Markus MA, Morris BJ. Resveratrol: cellular actions
of a potent natural chemical that confers a diversity of health benefits.
Int J Biochem Cell Biol 2009; 41:2125-2128.
Competing interests:
None declared
Competing interests:
No competing interests
23 May 2010
Paul J. Fitzgerald
postdoc
Johns Hopkins University, Baltimore, Maryland, USA, 21218
It is ironic that the issue that publishes an obituary of Sir james
Black, '...a vocationally oriented professional, uninterested in money;
should also carry a feature on Clinical Excellence Awards, that describes
today's Consultants striving to demonstrate their excellence, with the
sole aim of winning an award with a sizeable financial component!
Norepinephrine: new diseases for an old signaling molecule?
I was saddened to hear Sir James Black has died. He was a pioneering
pharmacologist who, among other accomplishments, created the widely used
and highly influential beta blocking drug, propranolol. This drug has not
only improved the health of thousands if not millions of people, but has
also been widely used for research purposes, yielding basic information
about the signaling molecule norepinephrine (NE) and its receptors.
In a recent series of papers (Fitzgerald 2009a1,b2; Fitzgerald
2010a3,b4), I put forth the novel hypothesis that NE is an etiological
factor in a number of diseases, including some types of cancer,
osteoarthritis, rheumatoid arthritis, asthma, open-angle glaucoma,
diabetes mellitus, epilepsy, and Alzheimer's disease. The basic idea is
that elevated NE can function as a general pathological entity throughout
the body. This is an unusual hypothesis because NE is a neurotransmitter
in the brain and sympathetic nervous system, although it innervates most
if not all of the organs of the body and could thereby affect a broad
range of diseases.
My papers1-4 largely reviewed data on pharmaceutical manipulation of
the NE system in both humans and animal models. Direct evidence for
elevated NE or its metabolites was also examined. Additional lines of
evidence assessed the relationship between the diseases and
pheochromocytoma, bipolar disorder, hypertension, obesity, and
psychological stress, which may all involve elevated NE.
Why might NE affect the various diseases in the first place? Since
NE is a “stress hormone” that helps mediate the body’s “fight or flight”
response to environmental stressors, perhaps having (largely genetic)
elevated NE tone keeps the body in a state of diminished maintenance or
homeostatic processing, resulting in an increased probability of
developing disease.
Resveratrol, a naturally occurring molecule in some plants, has been
associated with benefits in a wide range of diseases5. One possibility is
that resveratrol achieves its putative therapeutic effects by blocking NE
receptors, since it bears structural similarity to NE.
The most important point of this letter is that use of existing
pharmaceutical drugs that either lower the level of NE (such as clonidine)
or block NE receptors (such as propranolol and prazosin) may lower the
probability of an individual developing the various diseases (and possibly
treat those diseases), and this could be tested epidemiologically.
If elevated NE plays an etiological role in a number of diseases in a
large number of individuals, then chronically taking a single drug that
weakens NE signaling systemically, such as clonidine or propranolol, may
prevent or treat many different diseases simultaneously. This would mean
Sir James Black's drug is of even greater importance and value.
Acknowledgements
This work was conceived of while I was employed by Johns Hopkins
University, and I am now employed by the National Institute on Alcohol
Abuse and Alcoholism. The work was not supported by any funding source or
agency. I have no conflicts of interest to disclose.
References
1. Fitzgerald PJ. Is norepinephrine an etiological factor in some
types of cancer? Int J Cancer 2009a; 124:257-263.
2. Fitzgerald PJ. Is elevated noradrenaline an aetiological factor
in a number of diseases? Auton Autacoid Pharmacol 2009b; 29:143-156.
3. Fitzgerald PJ. Is elevated norepinephrine an etiological factor
in some cases of epilepsy? Seizure 2010a; in press.
4. Fitzgerald PJ. Is elevated norepinephrine an etiological factor
in some cases of Alzheimer’s disease? Curr Alzheimer Res 2010b; in press.
5. Marques FZ, Markus MA, Morris BJ. Resveratrol: cellular actions
of a potent natural chemical that confers a diversity of health benefits.
Int J Biochem Cell Biol 2009; 41:2125-2128.
Competing interests:
None declared
Competing interests: No competing interests