A recent research study discovered that an ion transporter protein can regulate the pH of certain brain cells and help repair the blood-brain barrier after an ischemic stroke. This could potentially restore normal brain function. This study has identified new therapeutic targets for ischemic stroke and related brain conditions, for which there are currently no specific treatments available. Ischemic stroke is a leading cause of death and disability, affecting approximately 15 million people worldwide each year. One of the contributing factors to this condition is the loss of the blood-brain barrier, which is a highly selective protective cell.A new study conducted by Dr. Hyun Kyoung Lee, an associate professor at Baylor College of Medicine and a researcher at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital, has discovered an ion transporter protein that plays a crucial role in maintaining the integrity of the blood-brain barrier. This barrier is responsible for preventing harmful chemicals from entering the brain through the bloodstream. The findings of this study could potentially lead to the development of strategies to repair and reverse brain damage, which would greatly benefit patients suffering from stroke and other neurological conditions.The pH of certain brain cells can be adjusted to fix the blood-brain barrier and return the brain to normal functioning after an ischemic stroke, according to a study published in Cell Reports. This study is the first to identify new and specific treatment targets for ischemic stroke and related brain conditions that currently have no targeted treatments available.
In stroke and other neurological conditions, the blood-brain barrier and pH regulation are disrupted. Dr. Lee, a Cynthia and Anthony G. PeTrello, a neurology researcher, explained, “When the blood-brain barrier gets damaged, it can have serious consequences like brain swelling, nerve damage, and eventually, problems with movement and thinking. We didn’t know much about how stroke affects the blood-brain barrier before this study.”
While endothelial cells are the main part of the blood-brain barrier, there is growing evidence that astrocytes, which are the most common and diverse type of support cells in the central nervous system, also play a crucial role in keeping this structure strong.
On top of this barrier, it’s important to keep the pH level (a measure of acidity) in balance.The balance of pH (acidity or alkalinity of a solution) in the brain cells and their environment is crucial for optimal brain function. Problems with pH regulation in the brain are often linked to various neurological conditions. Ischemic stroke injury is connected to a significant decrease in pH, but the exact cause of this change and the involvement of astrocytes in this process were unknown until this study. Astrocytic Slc4a4 is crucial for maintaining the blood-brain barrier. Earlier research has shown that a sodium-carbonate cotransporter has a role in regulating pH levels in astrocytes.The gene Slc4a4, found in astrocytes, helps to move acid-base ions across cell membranes in both directions to control pH levels inside and outside the cell in response to various stimuli. Mutations in Slc4a4 have been linked to several brain disorders, including ischemic stroke.
This study is the first to examine how Slc4a4 affects the interaction between astrocytes and endothelial cells in maintaining and repairing the blood-brain barrier after a stroke.
To investigate the role of Slc4a4, the Duncan NRI team created a conditional mouse model of Slc4a4.the Slc4a4 gene in astrocytes. This was observed both during the development and in adult mice. The researchers used a mouse model to carry out their study and discovered that removing Slc4a4 from astrocytes led to changes in their structure and function. Specifically, they noted an increase of over 40% in the diameter of the brain blood vessels, a three-fold increase in the number of small molecules that could enter the brain, and the loss of junctional markers. These findings strongly suggested that the blood-brain barrier was compromised when astrocytic Slc4a4 was absent.Dr. Qi Ye, the leading author and postdoctoral fellow in the Lee lab, stated that astrocytic Slc4a4 is crucial in these mice. They also found that Slc4a4 plays a critical role in remodeling the blood-brain barrier after an ischemic stroke. To test this, they used a cortical photothrombotic stroke model in Slc4a4 animal models, which closely resembles the size, location, and reactive gliosis seen in human brains after ischemic stroke. This model involved multi-omics analysis.
Scientists discovered that the absence of astrocytic Slc4a4 led to an increase in the release of a pro-inflammatory molecule called CCL2. This molecule activated the CCR2 receptor on nearby endothelial cells, causing damage to the blood-brain barrier and leading to increased leakage between the two cell types. Furthermore, they observed that this breakdown of the blood-brain barrier was influenced by higher levels of specific metabolites (arginine and nitrous oxide) due to changes in astrocytic pH levels.
This study has uncovered a potential new avenue for preventing the breakdown of the blood-brain barrier after a stroke by identifying the precise mechanism and key players involved.Dr. Lee noted that there are promising treatment options for ischemic stroke and brain pathologies. He also mentioned that key players in this pathway, such as the Slc4a4 transporter protein, the CCL2-CCR2 axis, and metabolites, are “druggable” and can potentially be developed into therapeutic targets.
