University of São Paulo: Research in mice identifies substance with potential to prevent worsening of Parkinson’s

Research by the Institute of Biomedical Sciences (ICB) at USP brings a promising perspective for the development of new therapeutic targets for the treatment of Parkinson’s disease, characterized by the early death or degeneration of cells in the substantia nigra region of the brain, responsible for the of dopamine (a neurotransmitter.) The absence or decrease of dopamine affects the motor system, causing tremors, slowness of movement, muscle stiffness, imbalance, as well as changes in speech and writing. There are also non-motor symptoms, such as gastrointestinal, respiratory and psychiatric changes, for example. There is no cure, only symptom control.

Published in the Molecular Neurobiology journal , the research was developed at the Cell Neurobiology Laboratory, under the coordination of Professor Luiz Roberto G. Britto, together with researchers from the Institute of Chemistry (IQ) at USP and the University of Toronto, Canada. “In mice, we were able to decrease about 60% of cell death by inhibiting TRPM2 – one of the calcium entry channels in brain cells. This was done with a substance based on the tyrphostine molecule, called AG-490”, says Britto. “Mice not given the substance performed 70% worse on behavioral tests,” he adds.

The strategy, according to him, interfered with one of the four aspects known to science by which Parkinson’s promotes the death of neurons. “Among the causes are some metabolic dysfunctions and abnormal accumulation of proteins, neuroinflammation of the brain, oxidative stress caused by the accumulation of reactive oxygen species and an increase in the activity of calcium input channels – which we managed to prevent at least in part. ”, explains Britto. “In all the cells of the organism, when these channels are very active, the tendency is for an overload of calcium to occur. This activates a series of enzymes that degrade cell structures, leading to their death,” he adds.

“With the study, we came to the conclusion that when we blocked the channel, the degeneration of neurons, specifically in those regions where neurons are killed by the disease, greatly decreased. The same happened in the places where those neurons project and have synaptic contacts, which helped to preserve dopamine, a fundamental neurotransmitter for movements, among other functions”, he explains.

The tests were carried out on mice that were injected with the toxin 6-hydroxydopamine, which mimics the effects of Parkinson’s disease. The animals were then divided into two groups. In one of them, the substance AG-490 was applied; in the other, no. After six days, tests were carried out to assess the animals’ ability to balance and other motor behaviors. After they were sacrificed, the neurons that produce dopamine in the substantia nigra were counted, which is classically involved with the disease. The region where they connect, the striatum, has also been studied in terms of the presence of dopaminergic synapses. In both regions, there was less damage with the administration of AG-490, both in behavioral terms and in terms of the number of cells and degenerated terminals.

Next steps
According to Britto, before moving on to clinical trials, many more studies will be needed. “For us to have a drug based on AG-490, we need to make sure that this substance works after the application of the toxin, since, for now, it was administered at the same time as the injection of the toxin that produces the Parkinson’s model. We will also test genetically modified animals for TRPM2, hoping that they will be more resistant in terms of neuronal death in this model. In addition, it is necessary to study the possible side consequences of injecting the substance.”

The study is the result of a line of research by Britto, who has been investigating the subject for over ten years. This stage of the research was developed

during the doctoral thesis of the biologist Ana Flávia Fernandes Ferreira. In a previous study by the same group, a similar result was obtained with another substance, carvacrol, to block another cellular channel, TRPM7, which is part of the same family of calcium ion channels as TRPM2.

Advances in studies that seek to cure Parkinson’s disease are urgent. According to the World Health Organization (WHO), the condition affects 1% of people over 65 years old and reaches 4% among the population over 80 years old. A study published in the Lancet magazine shows that between 1990 and 2015, Parkinson’s cases doubled due to the aging of the world’s population, jumping from about 26,000 to about 62,000 per million inhabitants.

“In this sense, the prospects for the future are not good, because it is imagined that by 2050 a considerable part of the elderly will be living up to 120 years. Solutions then need to be immediate for the second most common neurodegenerative disease after Alzheimer’s. Today, Medicine only deals with the symptoms of the disease to try to improve the patient’s quality of life, but it does not prevent them from progressing over time and the degeneration of brain cells from continuing and worsening the disease.”