Many people who suffer a stroke are permanently disabled. Stroke remains the leading cause of long-term disability in the United States. Paralysis of one side of the body, speech and language problems, vision problems and memory loss are some of the major consequences of stroke injury. Every year, nearly 800,000 people in the United States have a stroke. Even with recent advances in treatments to reduce damage and enhance recovery after stroke, solutions are significantly lacking. Recently, UConn School of Medicine researchers published a paper in Experimental Neurology showing how they successfully inhibited an important receptor implicated in post-stroke damage and recovery. The researchers specifically looked at ischemic stroke, which comprises 87% of strokes. Ischemic stroke occurs when there is a blockage in an artery leading to the brain. This reduces the amount of blood and oxygen getting to the brain, causing damage or death of brain cells.
Damaged or dying brain cells release excessive amounts of stored adenosine triphosphate (ATP), a molecule that carries energy within cells, leading to over-stimulation of its receptor P2X4 (P2X4R). When P2X4R is over-active, it causes a cascade of detrimental effects in brain cells, leading to ischemic brain injury. In this study, the researchers found inhibition of P2X4R can regulate the activation of a kind of immune cell that plays a large role in post-stroke inflammation. By partially short-term blocking this receptor, the researchers limited the over-stimulated immune response to improve both acute and chronic stroke recovery. The method presented in this paper is particularly attractive as it only operates during this period of over-activation and does not inhibit normal functions of P2X4R during long-term recovery. Using mouse models, the researchers observed improved balance and coordination, as well as reduced anxiety after their intervention.
The P2X4R inhibitor treatment decreased the total number of infiltrated leukocytes, which are white blood cells that promote ischemic injury when over abundant. This treatment effectively reduced the cell surface expression and activation of P2X4R without reducing its total protein level in brain tissue after stroke injury. One challenge many experimental drugs, including commercially available P2X4R inhibitors, face is insolubility, meaning they cannot enter the body in order to deliver the treatment. The researchers are currently working with team members Dr. Bruce Liang, Dean of the UConn School of Medicine, and Kenneth Jacobson from the National Institutes of Health to develop more soluble and potent novel P2X4R inhibitors. This technology would have a major impact as there is currently no effective drug to target stroke damage on the market aside from a few narrowly applicable treatment to dissolve blood clot or device to remove it.
Another parallel research led by Nicolas Bazan, MD, PhD, Boyd Professor and Director of the Neuroscience Center of Excellence at LSU Health New Orleans School of Medicine, and Ludmila Belayev, MD, LSU Health New Orleans Professor of Neuroscience, Neurology and Neurosurgery, has unlocked a key fundamental mechanism in the communication between brain cells when confronted with stroke. They report that omega-3 fatty acid DHA not only protected neuronal cells and promoted their survival, but also helped maintain their integrity and stability. The discovery provides potential new clinical targets and specific molecules for the treatment of ischemic stroke and other cardiovascular diseases. The researchers found that in the model of stroke, docosahexaenoic acid (DHA) affects the levels of two proteins crucial to communication between brain cells, called MANF and TREM2.
DHA is made from omega-3 very long chain polyunsaturated fatty acids. It is found in fatty, cold-water fish like salmon. Among other benefits, DHA is essential for normal brain function in adults and for the growth and development of the brain in babies. Scientists discovered that treatment with DHA reduced the size of the damaged brain area, initiated repair mechanisms and greatly improved neurological and behavioral recovery. These findings provide a major conceptual advance of broad relevance for neuronal cell survival, brain function and, particularly, stroke and neurodegenerative diseases. These findings advance the understanding of how the complexity and resiliency of the human brain is sustained, mainly when confronted with adversities as in stroke. A key factor is how neurons communicate among themselves. These novel molecules participate in delivering messages to the overall synaptic organization to ensure the accurate flow of information through neuronal circuits.
These findings contribute greatly to our understanding of cellular interactions engaging neurons, astrocytes, and microglia to sustain synaptic circuitry, set neurogenesis in motion, and initiate restoration to pathological derangements. Professor Bazan conclued witha practical comparison: “We know how neurons make synaptic connections with other neurons; however, these connections have to be malleable in order to change to the appropriate strength through experience. It’s like an orchestra. You need a conductor, and this is the role that DHA plays. Such a large-scale complexity first requires violinists, or in this case, synapses, which are highly sensitive sites of stroke injury that become messengers to target vulnerable cells”.
- edited by Dr. Gianfrancesco Cormaci, PHD, specialist in Clinical Biochemistry.
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