Society for Neuroscience Conference – More to Report

A very interesting poster at the SfN meeting described experiments with the antihypertensive medicine Telmisartan and its ability to protect brain cells from dying from an overdose of neurotransmitters.

During a stroke, dead or dying neurons tend to dump enormous quantities of neurotransmitters into their surrounding environment, and these excessive concentrations of neurotransmitters are deleterious for the surrounding neurons. This phenomenon is called “excitoxicity,” and it is an important killer of neurons in a stroke.

In this poster, a Chinese scientist used Telmisartan to pre-treat cultured neurons that were then given large quantities of the neurotransmitter glutamate. The drug protected the neurons from dying from the excessive concentrations of glutamate. Telmisartan also profected cells by binding to the AT[1A] receptor, and activating the PPAR[gamma] transcription factor. While these results may sound cryptic, PPAR[gamma] is a target for a group of anti-diabetic drugs called the triglitazones. By activating this transcription factor, telmisartan rescued these cultured neurons from certain death, and Dr. Wang (the poster presenter) suggested that Telmisartan could potentially be prescribed to delay the effects of stroke are even Alzheimer’s disease.

I also attended a series of short oral presentations at this meeting, and one symposium included modeling diseases with induced pluripotent stem cells. That was a fascinating symposium and I felt like a kid in a candy store. One Japanese researchers discussed his successes at using induced pluripotent stem cells (iPSCs) to make brain “organics.” These organoids contain multiple organ-specific cell types, recapitulate some function of the organ, and share at least some of the cellular organization of the organ. Brain organoids were made by deriving iPSCs from cells taken from human volunteers, which were ten grown in embryonic stem cell medium for one week to expand the cells. Then the cells were for about another week in Neural Induction Medium, and then shaken for four more weeks. The cells self-organized into minibrains that exhibited cortical organization with the layered structure of a brain that expressed many of the same genes as the layers of a developing brain. These minibrains also showed glutamate-induced calcium mobilization. Thus these minibrains qualify as a brain organoid.

Next, he used this same procedure to make minibrains from iPSCs derived from patients with fragile X syndrome, which, besides Down Syndrome, is the leading cause of mental retardation, globally speaking. Minibrains from these Fragile X Syndrome patients formed and looked normal. However, they showed abnormal connections between neurons. This tremendous model system can provide ways to study neurological diseases at very detailed levels.

The next talk was by Haruhisa Inoue from Kyoto University who examined the use of iPSCs as a way to treat neurological diseases. In particular, Dr. Inoue was interested in Amyotrophic Lateral Sclerosis or ALS. In the case of ALS, a cells called astrocytes are the problem. The astrocytes generate a foul environment that causes the neurons in the spinal cord to die off.

Dr. Inoue used iPSC technology to derive mature astrocytes from non-ALS and ALS patients. The two sets of astrocytes showed profound functional differences. When he transplanted normal astrocytes into the spinal cords of ALS mice, her also discovered that the mice showed rather significant functional improvements. Thus, Dr. Inoue thinks that transplantation of astrocytes made from iPSCs derived from the cells of healthy volunteers might provide an excellent way to delay or even reverse the effects of ALS.

Human Menstrual Blood Stem Cells Treat Premature Ovarian Failure in Mice

Premature ovarian failure (POF) or primary ovarian insufficiency is a condition characterized by loss of normal ovarian function before age 40. POF causes low levels of the hormone estrogen and irregular ovulation (release of eggs). POF causes infertility.

Some medical professional call POF premature menopause, even though these two conditions are not exactly the same. Women with POF may have irregular or occasional menstrual cycles for years and may even become pregnant. However, women with premature menopause cease having periods and can’t become pregnant.

The symptoms of POF are similar to those of menopause: irregular or skipped periods (amenorrhea), which may be present for years or may develop after a pregnancy or after stopping birth control pills; hot flashes, night sweats, vaginal dryness, irritability or difficulty concentrating, and decreased sexual desire.

In women with POF, infertility is very hard to treat, but restoring estrogen levels can avert many of the complications.

There are several causes of POF. Particular chromosomal defects such as Turner’s syndrome, in which a woman has only one X chromosome instead of the usual two, and fragile X syndrome, a major cause of intellectual disability can cause POF. Likewise, exposure to various toxins can also cause POF. Chemotherapy and radiation therapy are probably the most common causes of toxin-induced POF. Other toxins such as cigarette smoke, industrial chemicals, pesticides and viruses may also hasten POF. If the immune system mounts an immune response to ovarian tissue (autoimmune disease), then it might produce antibodies against the woman’s own ovarian tissue. Such antibodies will harm the egg-containing follicles and damage the egg. What triggers the immune response is unclear, but exposure to certain viruses is one possibility. Also various sundry unknown factors may also contribute to it.

There are no treatments for POF that restore the ovaries. For this reason a recent paper in the journal Stem Cells and Development represents a great advance in POF treatment.

Te Liu from the Shanghai Institute of Chinese Medicine and colleagues have used stem cells isolated from human menstrual blood to treat toxin-induced POF in mice.

Human endometrial stem cells exhibit stem cell properties in culture. These human endometrial stem cells are easily isolated from human menstrual blood. Other laboratories have even used them to treat heart conditions in clinical trials.

In this present study, Liu and colleagues treated female mice with the anti-cancer/anti-organ rejection drug cyclophosphamide. This drug pushed the mice into POF. Then one group of mice had human menstrual stem cells injected into their ovaries whereas another group received an injection of phosphate-buffered saline.

After 14 days, ovaries from those mice injected with human menstrual stem cells expressed higher levels of ovarian-specific proteins. Also, the blood levels of estrogen of the stem cell-injected mice were also higher. Postmortem examination also showed that the average ovarian weight of the stem cell-injected mice was much higher, as was the number of normal follicles. Follicles contain eggs surrounded with follicle cells and their absence is indicative of an ovary from a woman who is in menopause. That fact that the stem cell-treated POF mice had normal follicles and more of them suggests that the injected stem cells beefed up the supply of existing eggs and helped them survive and flourish.

These results suggest that these human menstrual stem cells, which are derived from the endometrium, can survive when introduced into a living organism and promote the regeneration of ovaries. There is no evidence that these cells differentiate into eggs, but instead they probably create an environment where the existing moribund eggs are rejuvenated and revitalized. This treatment for POF might be a viable option for human patients; all without destroying human embryos.