Medicines currently available on the market act generically on the brain and can cause serious side effects.
Researchers from the State University of Campinas (Unicamp) mapped brain proteins with the aim of unraveling the molecular bases of schizophrenia. The results of the study, published in the European Archives of Psychiatry and Clinical Neuroscience, may guide the search for more specific and effective treatments against the disease. The medications currently available on the market act generically on the brain and can cause serious side effects.
The work was led by the team from the Neuroproteomics Laboratory at the Institute of Biology (IB-Unicamp), which used brain tissue samples from patients with the disease collected postmortem. Two types of nerve cells – neurons and oligodendrocytes – were treated in culture with MK-801, a drug that alters the neurotransmitter function of glutamate and mimics in vitro what occurs in people with schizophrenia. In this way, the group was able to study the biological processes associated with the disorder that are specific to each cell type.
The neurons treated with the substance showed oxidative stress (one of the factors that can lead to brain degeneration) and apoptosis (a type of programmed cell death). Oligodendrocytes, cells responsible for the formation and maintenance of the myelin sheath (fatty layer that facilitates the transmission of nerve impulses), showed differences associated with protein synthesis and membrane organization.
“We cultivated oligodendrocytes and neurons in the laboratory and treated them with MK-801. Then we analyzed the proteins in the brain and in each of the cells, crossing the data. We were thus able to unravel which differences are specific to neurons, which are linked to oligodendrocytes and which are common to both cell types”, explains Professor Daniel Martins-de-Souza, supervisor of the work and coordinator of the laboratory, financed by Fapesp.
PhD candidate Giuliana da Silva Zuccoli, first author of the article, highlights that the potential lack of myelin or dysfunction in the formation of the sheath may be related to cognitive or memory dysfunction in the disease.
Myelin "wraps" the axon – part of the neuron, similar to an arm, that connects to another neuron at a synapse. This prevents the loss of energy in the transmission of impulses from one neuron to another.
Last year, other research conducted at the Neuroproteomics Laboratory, with support from FAPESP, had already linked schizophrenia to a disorder of oligodendrocytes, which end up producing weak myelin sheaths.
Previous research has described that the brains of patients with schizophrenia have abnormal levels of the neurotransmitter glutamate. They also pointed out a link between the dysfunction of glutamatergic neurotransmission and the hypofunction of the NMDA receptor (NMDAr, which is activated by glutamate). Glutamatergic neurotransmission is essential for human cognition, learning and memory.
“Treatment of neural cells with MK-801 revealed that neurons, oligodendrocytes and astrocytes are affected but show different responses in NMDAr hypofunction. NMDAr activation in oligodendrocytes is involved in their maturation, metabolic modulation and myelination around axons. Thus, understanding the effects of glutamatergic dysregulation on neurons and oligodendrocytes is crucial to understanding the role of these cellular counterparts in schizophrenia, especially in the hippocampal context,” the researchers write in the article.
And they conclude: “We were able to find proteomic signatures in common between the hippocampus and neurons treated with MK-801, as well as between the hippocampus and oligodendrocytes treated with MK-801.” These data will be important for the development of treatments more targeted at different dysfunctional biological processes in different brain cells.
The study was conducted in collaboration with Professor Helder Nakaya's group, from the Faculty of Pharmaceutical Sciences at the University of São Paulo (FCF-USP). FAPESP support was provided through six projects (18/14666-4, 17/25588-1, 19/00098-7, 17/50137-3, 12/19278-6 and 13/08216-2).
Cases
Considered a serious and debilitating mental disorder, schizophrenia affects around 23 million people worldwide, 1,5 million of whom are Brazilians, according to the Pan American Health Organization (PAHO).
It is characterized by thoughts or experiences that seem out of touch with reality, disorganized speech or behavior, and reduced participation in everyday activities. Treatment involves a combination of medication, psychotherapy and specialized care. To detect schizophrenia, a clinical assessment is carried out.
A methodology developed by Brazilian researchers last year showed promise in creating a blood test capable of diagnosing the disease. The method was developed by groups from the Federal University of São Paulo (Unifesp) and Unicamp and is the first capable of differentiating the disorder through the analysis of biochemical and molecular changes involved in the pathologies (read more at: agencia.fapesp.br/ 33824/).
The article Linking proteomic alterations in schizophrenia hippocampus to NMDAr hypofunction in human neurons and oligodendrocytes, by authors Giuliana S. Zuccoli, Guilherme Reis-de-Oliveira, Bruna Garbes, Peter Falkai, Andrea Schmitt, Helder I. Nakaya and Daniel Martins-de- Souza, can be read at https://link.springer.com/article/10.1007/s00406-021-01248-w.
original article published on the Agência Fapesp website.
