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Targeting the membrane positioning of aquaporin 4 is expected to treat central nervous system edema

2021-05-07
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Targeted aquaporin 4 (AQP4) is abundantly distributed in the central nervous system, and is involved in the reabsorption of cerebrospinal fluid, osmotic pressure regulation, etc., and is related to the occurrence of cerebral edema and spinal cord edema. Recently, it was published in the latest issue of the scientific journal Cell that targeting aquaporin-4 subcellular localization, rather than directly inhibiting the activity of AQP4, is expected to treat central nervous system edema. The researchers used the licensed drug trifluoperazine to inhibit calmodulin in the rat spinal cord injury model. Pharmacological studies have shown that trifluoperazine has an antagonistic effect on calmodulin.

Many brain diseases, severe systemic infections, or acute hypoxia can cause brain edema. Brain edema increases in brain volume and intracranial pressure. Aquaporin is a special membrane protein that is permeable to water. AQP4 is one of the main aquaporins in the mammalian brain. The large distribution of AQP4 in the brain and the distribution on astrocytes show obvious polarity. That is, it is abundantly expressed on astrocytes close to vascular endothelial cells, suggesting that AQP4 is an important structural basis for water transport and regulation between glial cells, cerebrospinal fluid and blood vessels.

AQP4 plays an important role in maintaining the water balance of the brain and is a key molecule in the occurrence and development of brain edema. The phosphorylation of Ser111 is also a potential pharmacological target to increase the water permeability of AQP4. Pharmacological research can clarify the structure-activity relationship of drugs and guide the development of new drugs. After years of accumulated experience, multi-party verification and long-term practical tests, Medicilon’s pharmacology service department has established a complete animal model library, which can provide various effective animal models according to customer needs to test the effectiveness of drugs.

Recently from Aston University (UK), Harvard Medical School (USA), University of Birmingham (UK), University of Calgary (Canada), Lund University (Sweden), University of Copenhagen (Denmark) and University of Wolverhampton An international team of scientists (UK) has developed a new treatment. Researchers used a licensed antipsychotic drug trifluoperazine (TFP) to change the behavior of tiny water pores in aquaporin cells. Trifluoperazine (TFP) has a good effect on hallucinations and delusions in schizophrenia. It not only has a strong blocking effect on dopamine-2 (DA2) receptors, but also has specificity for calmodulin The inhibitory effect.

The researchers tested the treatment of injured rats. The researchers found that after a single dose of the drug was administered to the injured site of the rat, the rats recovered complete movement and sensitivity in just 2 weeks, while the control group did not receive the drug. The rats still showed motor and sensory disturbances six weeks after the injury.

The role of this therapy is to counteract the normal response of cells to the hypoxia of the brain and spinal cord in the central nervous system caused by trauma. In this state, the cells quickly become “salter” due to the accumulation of ions, causing a stream of water to pass through the water channels, swelling the cells, and putting pressure on the skull and spine. This accumulation of pressure can damage the fragile brain and spinal cord tissue, and disrupt the flow of electrical signals from the brain to the body, and vice versa.

But the researchers found that trifluoperazine can prevent this from happening. The researchers focused their research on the important star-shaped brain and spinal cord cells (called astrocytes). They found that trifluoperazine prevented a protein called calmodulin from interacting with aquaporin. Combine. Compared with untreated animals, using trifluoperazine to inhibit calmodulin in the rat spinal cord injury model can inhibit the localization of AQP4 in the blood spinal cord barrier, reduce CNS edema, and lead to faster functional recovery. Therefore, the researchers suggested that the mechanism of calmodulin-mediated cell surface localization of AQP4 is a feasible strategy for the development of CNS edema therapy.

Trifluoperazine has been used to treat patients with schizophrenia and other mental health conditions, and long-term use will be accompanied by side effects, but the researchers said that their experiments have shown that a single dose may have significant effects on patients with central nervous system edema Long-term impact. Trifluoperazine has been approved for use in humans by the US Federal Drug Administration (FDA) and the UK National Institute of Health and Healthcare (NICE). It can be used as a rapid treatment for brain injury. But the researchers also emphasized that based on the understanding of the properties of trifluoperazine, they will further develop new and good drugs.

In short, the researchers said that this novel treatment method brings hope to patients suffering from central nervous system damage and has huge therapeutic potential. Their research results show that in the near future, it can be put into clinical application at a reduced cost.

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