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.