The results of research headed by a team at the University of Birmingham suggest that inflammatory conditions in the brain, including traumatic brain injury (TBI) and degenerative diseases such as Alzheimer’s disease and Parkinson’s disease, could be targeted with an existing developmental drug.
Using live cultures of human brain cells and slices of brain tissue obtained during neurosurgery, the researchers, headed by Nicholas Barnes, PhD, professor at the University of Birmingham College of Medicine and Health, investigated the role of the P2X7 receptor, which is responsible for triggering inflammatory signaling. Their findings revealed that these P2X7 receptors drive the release of cytokines involved in controlling inflammation. By blocking this receptor with a specific antagonist, the team was able to significantly reduce the inflammatory response in human brain tissue.
The team suggests that their results could open the door to treating a wide spectrum of chronic neurological conditions, including TBI, neurodegenerative diseases, and even psychiatric disorders such as depression and psychosis, which are increasingly understood to have a neuroinflammatory component.
Barnes said, “This exciting discovery marks a major step toward repurposing existing therapeutics to combat neuroinflammation at its source. The identification of this receptor could have far-reaching implications for some of the most debilitating and widespread brain disorders such as Alzheimer’s disease, Parkinson’s, and multiple sclerosis, or inflammation-linked psychiatric conditions like schizophrenia and depression.”
Barnes is senior and corresponding author of the team’s published paper in Brain, titled “P2X7 receptor-mediated IL-1β release by human brain tissue: the impact of CNS-penetrant potential therapeutics,” in which they concluded “Our findings provide direct relevant evidence for the use of P2X7R antagonism to inhibit human microglia-mediated inflammation, with arising potential benefits for patients with TBI and other neuroinflammatory diseases.”
TBI is a major cause of death globally, and there are currently there are no approved therapeutic drugs to improve clinical outcomes, “… emphasizing the clear unmet substantial clinical need,” the authors wrote.
The mechanical damage associated with TBI drives a neuroinflammatory response. “The purinergic P2X7 receptor (P2X7R) is a key driver of neuroinflammation in a range of animal models of traumatic brain injury,” the team continued. P2X7R is expressed by microglia, the resident immune cells in the CNS that are involved in many developmental, homeostatic and pathological roles. “It is well recognized that microglial activation and the hostile neuroinflammatory response arising after the initial insult provide a therapeutic window for pharmacological intervention,” the investigators further stated.
For their reported study investigating how brain cells respond to and manage inflammation, the team developed a way of turning a type of white blood cell into microglia, replicating a normal cellular transformation that has recently been identified to occur in the brain as a natural part of human aging. These microglia are the central coordinators of the immune system in the brain.
Using readily accessible human peripheral monocytes taken from blood samples, the researchers converted them into microglia-like cells—human monocyte-derived microglia (hMDM)—that were used to see how microglia are likely to respond to the inflammation signals. “This enabled us to demonstrate the ability of clinically relevant P2X7R antagonists, including brain-penetrant molecules, to curtail pro-inflammatory cytokine release,” they wrote.
The team showed that administering a P2X7 receptor antagonist interrupted the triggers that these microglia give off as they are damaged and die. Barnes said, “Studying human microglia has long been a major challenge: once removed from their native brain environment, they rapidly lose their defining characteristics, likely due to the absence of critical regulatory signals. Our approach involved the use of monocyte-derived microglia which provide a powerful, scalable, and virtually unlimited platform for studying human microglial biology with unprecedented precision.”
The team confirmed their results using adult human precision-cut brain slices that had been generated subsequent to neurosurgical resections. “Having identified the response in the human monocyte-derived microglia, this provided the impetus to translate these findings with human brain obtained following neurosurgical procedures, Barnes continued. “This successful translation means the next stage for this research is the development of clinical trials in patients with neurodegenerative conditions and patients with TBI where there are no effective pharmacological treatments to reduce the neuroinflammation and arising damage.”
In their paper the authors concluded, “The present study provides direct translational evidence from human cellular and brain tissue models to support the clinical use of P2X7R antagonists to limit secondary ATP-driven neuroinflammatory events, such as those that occur in TBI, and thus might improve the clinical outcomes for patients.”
