Protection from Parkinsonism
Transcription factor inhibitor protects mice from Parkinson's disease
Anastasia Kuznetsova-Fantoni, N+1
Biologists from three countries have developed a drug for the treatment of Parkinson's disease that protects neurons from death by preventing oxidative stress. In experiments on mice, the drug allowed neurons to survive even if it was administered after exposure to the neurotoxin. The study was published in the journal Proceedings of the National Academy of Sciences (Bach1 derepression is neuroprotective in a mouse model of Parkinson's disease).
Parkinson's disease is still an incurable disease: patients are prescribed medications to relieve symptoms and slow the progression of the disease. Many researchers are trying to develop a new treatment method to improve the quality of life of patients. For example, they inject stem cells into their brains and reprogram astrocytes into dopamine-producing neurons.
Another potential method of treating Parkinson's disease is activation of signaling pathways and transcription factors. One of the application points chosen by the researchers was the Keap1-Nrf2 signaling pathway. It activates the expression of genes that protect neurons from inflammation and oxidative stress. This is important in Parkinson's disease, since it is oxidative stress that contributes to the death of neurons in this pathology. In experiments with the Keap1-Nrf2 signaling pathway, researchers encountered a problem: activation of Nrf2 caused many side effects due to the fact that this transcription factor non-specifically reacts with other proteins, and not only with Keap1.
A team of scientists from Russia, the USA and Japan, led by Bobby Thomas from the Medical University of South Carolina, decided to approach the problem from the other side. They focused on the Nrf2 — Bach1 repressor. First, the researchers turned off Bach1 expression in mice and found that their neurons were protected from neurotoxin-induced inflammatory stress.
Inspired by the results, the researchers developed a Bach1 inhibitor called HPPE. The drug was tested in two modes of administration: before exposure to neurotoxin and eight hours after treatment with it (six mice in each group). In both experimental groups, it was possible to significantly reduce the death of dopamine-producing neurons compared with the control group of six animals to which the drug was not administered (p<0.05).
Neurons of mice from the control group (Veh) and the group of the drug HPPE, which was administered after exposure to neurotoxin (MPTP). A drawing from an article in PNAS.
In future studies, the authors of the work will have to study the side effects of long-term use of the drug, as well as assess whether it can be used for other diseases of the nervous system.
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