Rspecialized regions in the membrane of nervous system cells, rich in cholesterol and known as lipid rafts – lipid rafts, in English – may be the key to understanding the action of antidepressant drugs. In a study with the participation of the Ribeirão Preto School of Medicine (FMRP) at USP, scientists found that the level of cholesterol in these regions of the cell membrane determines the structure and functioning of a receptor, a protein that serves as a target for antidepressants in neurons. The research is described in an article published in the scientific journal Cell .
“For the study, several classes of antidepressants were used, including classic drugs, such as fluoxetine and imipramine, and the fast-acting antidepressants, discovered more recently, such as ketamine,” says researcher Cassiano Ricardo Alves to Jornal da USP Faria Diniz, who is doing post-doctoral studies at FMRP and participated in the work. “From in vitro, laboratory, and in silico approaches, using high-performance computer simulations, it was found that in lipid rafts, antidepressants bind directly to the TRKB receptor, thus being able to modulate the activity of the receptor while stabilize its three-dimensional structure. ”
“The TRKB protein, when activated, leads to a cascade of intracellular pathways responsible, in general, for the refinement and reinforcement of synaptic connections, that is, between the cells of the nervous system”, explains Faria Diniz. “The action of TRKB then regulates the activity of specific regions of the central nervous system, such as the hippocampus and the prefrontal cortex, which are involved in modulating our behavioral responses to stress.”
The data obtained in the research indicate that TRKB can assume different conformations, depending on the amount of cholesterol in the membrane. “Antidepressants, in turn, stabilize the conformation of the receptor in a state more prone to activation”, reports the researcher. “We observed experimentally that the same change in the TRKB region that impaired its interaction with fluoxetine, as determined by computer simulation, also reduced the interaction of TRKB with several other antidepressants in vitro. “
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This same change in TRKB, when present in mice, makes animals less responsive to antidepressants, whether they are fast-acting or slow-acting. “Therefore, in vivo experiments [in animals] corroborate the data in vitro and in silico by suggesting that, in fact, the potential direct action on TRKB is important for the action of antidepressants”, highlights Cassiano Diniz, “even when the their effect is put to the test within complex biological organisms ”.
According to the FMRP researcher, it was believed that the difference in the primary mechanism of action between classic and new drugs would be responsible for differences in effect latency, that is, in the time required for clinical effects to be detected. “The result of our work leads us to believe that, in addition to the primary mechanisms, the action of antidepressants depends on a direct action on TRKB”, he points out. “The latency for this effect would be due to the delay by classic antidepressants, but not by new compounds such as ketamine, in reaching sufficient concentrations in the central nervous system to act on TRKB.”
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The study’s conclusions could direct the development of new molecules capable of binding to TRKB with greater affinity, modulating its response and at the same time being able to quickly overcome the blood-brain barrier, evaluates the researcher. The blood-brain barrier is a natural protection of the body, a kind of “cordon of isolation” that prevents viruses, fungi, bacteria and other foreign bodies from reaching the central nervous system.
“Remembering that millions of people around the world use antidepressants daily, and that these drugs are used in the treatment of various psychiatric disorders, in addition to being important also for the treatment of other diseases, such as chronic pain,” he says . “Thus, better understanding the mechanism of action of these drugs would facilitate the development of new molecules with a better therapeutic profile and, therefore, is of great interest to the medical clinic.”
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The study was led by Plínio Casarotto and Caroline Biojone, currently hired as researchers in the group of Professor Eero Castrén, from the University of Helsinki (Finland), both graduates of the Department of Pharmacology at FMRP and former fellows of the State Research Support Foundation from São Paulo (Fapesp), including an internship at the University of Helsinki through the BEPE program. The work counted on the collaboration of Faria Diniz, also from the FMRP Pharmacology Department, while on internship through the BEPE program (via Fapesp postdoctoral fellowship).
Researchers from the Universities of Freiburg (Germany) and Bergen (Norway) also participated in the study, in addition to the Department of Physics at the University of Helsinki, responsible for molecular modeling. The article Antidepressant drugs act by directly binding to TRKB neurotrophin receptors was published in the scientific journal Cell on March 4.