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Pregnenolone
Update
By David Jay Brown
Eugene Roberts, Ph.D., has been a
leading figure in neurochemistry for more than half a century.
Currently a Distinguished Scientist at the City of Hope, in
California, he received his doctorate in biochemistry in 1943.
In the intervening years, he worked on the Manhattan Project,
determining the safe levels of exposure to uranium dust,
performed cancer research a Washington University in St. Louis,
where he discovered the neurotransmitter gamma-aminobutyric acid
(GABA), and in 1954, he founded the Department of Biochemistry
and the division of Neurosciences at the City of Hope.
For much of the last decade, he
has been studying steroid metabolism and has been instrumental
in reviving interest in pregnenolone and DHEA as potential
therapeutic agents. At age 78, he remains an active researcher,
theoretician, and member of the National Academy of Sciences,
still trying to climb such "Mount Everests of science" as cancer
and schizophrenia.
I spoke with Dr. Roberts about
his latest research in the biochemistry of pregnenolone and its
therapeutic effects. I was impressed by his very lively mind,
which easily leaps from one idea to the next, and the vast range
of his knowledge. He's also a warm and perceptive person, with a
highly creative perspective, who seems to really be having fun
in life.
David:
What aroused your interest in pregnenolone?
Dr. Roberts:
Originally, I was interested in DHEA and DHEA sulfate because
these steroids have been shown to decrease monotonically with
age in both males and females after a peak in their early
twenties. About 30% of DHEA sulfate and DHEA in the blood of the
male comes from the testes, and the rest comes primarily from
the adrenals. In females, it comes largely from the adrenals. In
both sexes, small contributions of blood levels of these
substances may be made from other tissues.
Subsequently I got
interested in pregnenolone, the substance from which all other
steroidal substances are formed. That's how it came about, sheer
curiosity.
I looked into the
early history of pregnenolone, which was very interesting. It's
a shame it was dropped so soon as a potential therapy for
rheumatoid arthritis, but it probably was a function of the
sensational effects of cortisone, which was discovered about
that time.
Generally, the
clinical reports of yesteryear indicated that pregnenolone could
exert marked ameliorative effects on various symptoms of
rheumatoid arthritis. It also seemed to affect other autoimmune
conditions, e.g., lupus. The results were interesting in that
they indicated that pregnenolone or substances formed from it
could exert pleiotropic effects.
The work of Hoagland
and his colleagues on the effect of pregnenolone on fatigability
was most interesting, particularly since fatigability often
precedes the occurrence of symptoms in rheumatoid arthritis.
Normal individuals showed significantly decreased fatigability
when working under stress when they were receiving small oral
doses of pregnenolone, and their performances improved, as well.
Individuals working under relaxed conditions showed little
effect.
After oral
administration of pregnenolone, pregnenolone sulfate is formed
rapidly in the intestine and liver and enters the bloodstream.
Thus, oral administration of pregnenolone largely results in an
elevation in blood pregnenolone sulfate.
In many
physiological tests in animals, it was found that pregnenolone
sulfate has excitatory effects on nerves and enhances the
excitatory effects of a known excitatory neurotransmitter such
as glutamate. If pregnenolone sulfate should penetrate the
blood-brain barrier, it would, therefore, have an excitatory
effect. Since the blood-brain barrier is incomplete in regions
of the hypothalamus and pituitary gland, at the minimum, it
would be expected that it could have major action on the release
of various hormones, such as those arising from the thyroid,
adrenal, and pituitary glands.
It is possible that
an alerting effect of pregnenolone ingestion may occur for the
latter reason. However, the effects must be much more
complicated because pregnenolone sulfate, pregnenolone, and the
substances from them are known to have effects at many sites,
from the membrane to gene transcription.
David:
What are you working on currently?
Dr. Roberts:
There are two major areas related to pregnenolone. One is
related to memory. Experiments performed with James Flood gave
results that were just amazing. Weakly trained mice learned to
avoid a foot shock by going to the correct arm of a T-maze.
Immediately after training, small amounts of pregnenolone
sulfate were injected directly into several regions of the
brain, the amygdala, septum, mamillary bodies, hippocampus or
caudate nucleus. The ability of the mice to perform the the task
successfully was measured one week later. When pregnenolone
sulfate was injected into the amygdala, the mice had
significantly enhanced retention of the correct response, when
less than 150 molecules of the substances was given. From this
result, pregnenolone sulfate appears to be the most potent
memory enhancer yet reported in animals, and the amygdala seems
to be the most sensitive brain region for memory enhancement by
any substance.
In order to prove to
ourselves that we hadn't made a mistake, we had separate
dilutions made in another laboratory, and we got the same
results.
Now I'm trying to
figure out how only 150 molecules can have such an influence. It
appears to be similar to a pheromone-like effect, such as when a
few molecules of sex-attractant to a male moth from a female
moth a mile away inform him of her location. There are a number
of possible mechanisms by which a particular substance can
signal a cell to produce the substance in greatly increased
amounts.
Thus, a few
molecules of pregnenolone sulfate liberated endogenously or
furnished exogenously may cause glial cells in the brain to
produce millions of molecules of the substance and liberate them
into the the environment. Solution of this problem may give us a
handle as to how to greatly enhance memory capability with
little or no administration of substances that do not occur
naturally.
A second area of
great current interest for me is that related to the attenuation
of spinal cord damage. Tens of thousands of individuals injured
in the last earthquake in China are today hospitalized as
paraplegics or quadriplegics. There is urgency in developing a
practical means for avoiding this in California, which may have
a major quake at any time.
Lloyd Guth and I
found that pregnenolone, when combined with nonsteroidal
anti-inflammatory drug (NSAID) Indomethacin and a stimulator of
cytokine secretion, (bacterial lipopolysaccharide), could
attenuate damage to the spinal cord when rats were treated
immediately after the injury. Control animals receiving saline
alone showed marked spinal cord degeneration and paralysis.
The combined
treatment reduced histopathological changes, spared tissue from
secondary injury, and increased restoration of motor function.
In fact of the 16 animals we treated, 11 were able to stand and
walk within 21 days after the injury; 4 of them nearly normal.
This kind of effect had never been seen in experiments in which
pregnenolone was not included in the treatment regimen.
It now has been
found elsewhere (unpublished, personal communication) in similar
experiments that continuous administration only of a
pregnenolone sulfate solution via a mini-pump gave better
protection than any ever observed previously. This approach may
prove to be applicable not only to spinal cord injury, but also
to nervous system injury in general and perhaps to injury to
other tissues as well.
We are now exploring
means to develop a transdermal preparation that will be
effective, since spinal cord-injured individuals often have
difficulty in swallowing and under chaotic post quake conditions
injection of solutions of substances is problematic. Our goal is
the revisal of a preparation of pregnenolone or pregnenolone
sulfate that can be dispensed from a tube contained in widely
distributed earthquake first aid kits. Anybody in the
environment should be able to apply a cream or gel to the spinal
cord of an injured individual. Of course this approach also
would be applicable to injuries resulting from accidents of all
sorts.
Among other
interests, the above projects are keeping me fully involved. |
