Molecule protects neurons during ischemia

In an article published in PLoS One, researchers from USP’s Chemistry Institute demonstrate that bradykinin interrupts the process of cell apoptosis in the brain tissue of rats.

By Karina Toledo

Agência FAPESP – In an article published in the journal PLoS One, a group of researchers from Universidade de São Paulo’s Chemistry Institute (IQ-USP) demonstrated that bradykinin – a peptide with known anti-hypertension action – is capable of reversing the process of cell death in conditions that occur during brain ischemia. The study was conducted in collaboration with scientists from Puerto Rico.

“When arterial occlusion occurs and the flow of oxygen is interrupted, cells die and release a substance called glutamate. This stimulates glutamate receptors, including the NMDA (N-methyl D-aspartate) receptor, in neighboring cells, allowing calcium to enter cells in an uncontrolled manner,” explains Alexander Henning Ulrich, coordinator of the Thematic Project funded by FAPESP.

When this calcium excess reaches the mitochondria, it stimulates the formation of reactive oxygen species and induces apoptosis, a form of cell suicide.

“In the experiment with rats, bradykinin was able to reverse the apoptotic process. We took samples from a region in these animals’ brains, the hippocampus, and put them in a physiological solution. Afterwards, we electrically stimulated the samples with electrodes and measured neuronal activity,” said Ulrich.

To simulate what occurs in the brain after ischemia, the researchers treated the tissue with NMDA, causing an influx of calcium into the cells. When the neuronal activity was measured after the NMDA treatment, 80% of pyramidal neurons in the hippocampus had begun the process of apoptosis. However, when the brain tissue was treated with bradykinin after exposure to NMDA, the majority of the cells were rescued from death.

“We are still investigating the exact mechanism that gives bradykinin this neuroprotective effect. Our hypothesis is that it activates a signal that interrupts the apoptotic process,” says Ulrich.

According to the researcher, despite the promising results, it is not likely that bradykinin can be used to treat brain ischemia. Some studies indicate that the resulting subproducts of bradykinin degradation, such as des-arg9-bradykinin, can induce adverse effects, aggravating the damage caused by ischemia.

“Our objective is to discover a substance that is analogous to bradykinin and has the neuroprotective effects without the undesired reactions,” he said.

Versatile

Bradykinin was discovered more than 50 years ago by Brazilian researchers. They observed that the venom of Bothrops jararaca increased the presence of this peptide in the blood of mammals.

The substances responsible for increasing the concentration of bradykinin – known as bradykinin-potentiating peptides (BPPs) – served as a base for the development of captopril and an entire class of anti-hypertension medicines.

In the thematic study conducted by Ulrich, the objective was to discover new uses for the molecule. Using in vitro cellular models, the team verified that the substance stimulated neurogenesis, prompting the brain’s stem cells to develop into new neurons. The discovery paves the way for new treatments for degenerative diseases such as Alzheimer’s disease and Parkinson’s disease.

In another experiment conducted with rat models of Parkinson’s disease, Ulrich and Telma Tiemi Schwindt Diniz Gomes, a professor at the USP Biomedical Sciences Institute, managed to reverse similar states to those found in patients with advanced stages of Parkinson’s disease.

The results were presented during the 27^th Annual Meeting of the Federation of Experimental Biology Societies, held in Águas de Lindoia, São Paulo, this past August.

“We induced the death of dopaminergic neurons in one of the brain hemispheres of animals, and the animals began to display motor function disorders, which were observed as rotational behavior, after the induction of the dopaminergic system by apomorphine,” explains Ulrich.

“Fifty-six days after bradykinin was administered, the compromised motor function was reversed in the majority of animals. In fact, the histological analysis suggests that the improvement was caused by the neurogenesis induced by the drug,” he affirms.

The article “Kinin-B2 Receptor Mediated Neuroprotection after NMDA Excitotoxicity Is Reversed in the Presence of Kinin-B1 Receptor Agonists” can be read at: www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0030755.