Health

A new class of highly effective inhibitors prevent neurodegeneration-ScienceDaily

Neurobiologists at the University of Heidelberg have discovered that special receptors at neural junctions, which normally activate protective gene programs, can lead to neuronal cell death when they are outside synapses. Their basic discoveries on the process of neurodegeneration have at the same time led researchers at the Interdisciplinary Center for Neuroscience (IZN) to a whole new principle of therapeutics. In experiments with mouse models, they discovered a new class of highly effective inhibitors for protecting nerve cells. As Dr. Hilmer Bading points out, this new class of drugs opens up the prospects-for the first time-to combat the currently incurable diseases of the nervous system. The results of this study are Science..

The research by Professor Bading and his team focuses on the so-called NMDA receptors. This receptor is an ion channel protein activated by the biochemical messenger neurotransmitter glutamate. It allows calcium to flow into the cells. Calcium signals initiate a plastic process at synapses, but also propagate to the cell nucleus, where they activate protective genetic programs. Glutamate-activated NMDA receptors at the junction of nerve cells have important functions in the brain and contribute to learning and memory processes and neuroprotection. However, the same receptors can be found outside synapses. These extrasynaptic NMDA receptors pose a threat because their activation can lead to cell death. However, glutamate’s efficient cell uptake system usually ensures that these receptors are not activated and that nerve cells are not damaged.

This situation can change dramatically in the presence of the disease. For example, if a part of the brain is not supplied with enough oxygen after a stroke, interruption of circulation disables the glutamate uptake system. Extrasynaptic glutamate levels are elevated, which activates extrasynaptic NMDA receptors. The result is nerve cell damage and death with limited brain function. Elevated extrasynaptic glutamate levels are not limited to cerebral circulatory disorders. “Evidence suggests that the toxicity of extrasynaptic NMDA receptors plays a central role in many neurodegenerative diseases,” explains Professor Bading. According to scientists, this is especially true for Alzheimer’s disease and amyotrophic lateral sclerosis, resulting in weakness and muscle wasting, retinal degeneration, and even brain damage after infection with viruses and parasites. Cause

Glutamate-activated NMDA receptors in the nerve junction help build a protective shield, but outside synapses change from Dr. Jekyll to Mr. Hyde. “Understanding why extrasynaptic NMDA receptors cause neuronal cell death is the key to developing neuroprotective therapies,” continues Professor Bading. That’s where Heidelberg researchers are focusing. Experiments with mouse models have demonstrated that NMDA receptors outside synapses form a type of “death complex” with another ion channel protein. This protein, called TRPM4, has a variety of functions in the body that are involved in the cardiovascular system and immune response. TRPM4 is toxic to extrasynaptic NMDA receptors, according to the latest findings by Hilmar Bading and his research team.

Scientists have used molecular and protein biochemical methods to identify the contact surfaces of two interacting proteins. Based on this knowledge, they used a structure-based search to identify substances that could break this bond itself, thereby disassembling and inactivating the “death complex”. .. This new class of inhibitors, which Heidelberg researchers call “interface inhibitors” to break the bond formed on the contact surface between the extrasynaptic NMDA receptor and TRPM4, is highly effective in nerve cells. Proven to be a protective agent. “We are working on a whole new principle of therapeutics. Interface inhibitors provide tools that can selectively eliminate the toxicity of extrasynaptic NMDA receptors,” explains Professor Bading.

Professor Bading and his team have already demonstrated the effectiveness of the new inhibitor in a mouse model of stroke or retinal degeneration. According to Heidelberg researchers, there is good reason to expect such interface inhibitors (orally administered as broad-spectrum neuroprotective agents) to provide treatment options for currently incurable neurodegenerative diseases. “But it will take a few more years to be approved as a drug for human use, as the new substance must first successfully pass many preclinical and clinical trial stages.”

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