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Eugene Roberts Ph.D.

Pregnenolone Update

with Eugene Roberts Ph.D.

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.