Inflammatory mediators and stroke: new opportunities for novel therapeutics Brain cells can produce cytokines and chemokines and express adhesion molecules, leading to an inflammatory response after brain injury. Neutrophil accumulation early after injury contributes to brain tissue loss. Inflammation is a promising pharmacologic target due to its rapid onset and progression after stroke, as well as its role in tissue injury. While inflammatory cytokines may contribute to ischemic injury, they can also provide neuroprotection by promoting growth, repair, and functional recovery. Stroke is the third leading cause of death and the leading cause of long-term disability in the U.S. No approved treatment exists beyond tissue plasminogen activator (tPA), which is effective only within 3 hours of stroke onset. Stroke therapies are estimated at $1 billion, with annual healthcare costs of $30 to $50 billion. Stroke incidence is expected to rise, with over 1 million strokes per year in the U.S. by 2050. Stroke is most commonly caused by obstruction of blood flow in a major cerebral vessel, leading to a core of severely ischemic brain tissue. The size of the infarct depends on the penumbra, a zone of tissue around the core where neuronal function is not compromised. Blood flow levels determine the size of the infarct by maintaining cellular energy homeostasis. Ischemia leads to reduced blood flow, causing energy depletion and cellular dysfunction. This results in ionic gradient disruption, leading to cell swelling and cytotoxic edema. Increased extracellular potassium and decreased pH precede other ionic changes. The increase in potassium can release excitotoxic neurotransmitters, leading to sodium/calcium channel activation and further cell swelling. Extracellular calcium influx leads to mitochondrial calcium overload and cellular damage. Inflammatory responses to brain injury include gliosis, characterized by activation and proliferation of mononuclear phagocytic cells. Cytokines activate glial cells, which then produce cytokines, linking inflammation, cytokine production, and gliosis. Inflammatory mediators such as TNF-α and IL-1β are involved in brain injury. Several cell types in the brain can secrete cytokines, and peripherally derived cytokines can also contribute to brain inflammation. The blood-brain barrier is permeable to immune cells, which can contribute to CNS inflammation and gliosis. The inflammatory response to brain injury involves early accumulation of neutrophils, which adhere to the endothelium and migrate into the tissue. Inflammation contributes to lipid-membrane peroxidation, exacerbates tissue injury, and causes cytotoxic products from activated leukocytes. The signaling mechanisms in brain inflammation involve TNF-α, IL-1β, chemotactic cytokines, and adhesion molecules. These mechanisms are crucial for leukocyte adherence and infiltration, and for enhancing endothelial permeability. TNF-α and IL-Inflammatory mediators and stroke: new opportunities for novel therapeutics Brain cells can produce cytokines and chemokines and express adhesion molecules, leading to an inflammatory response after brain injury. Neutrophil accumulation early after injury contributes to brain tissue loss. Inflammation is a promising pharmacologic target due to its rapid onset and progression after stroke, as well as its role in tissue injury. While inflammatory cytokines may contribute to ischemic injury, they can also provide neuroprotection by promoting growth, repair, and functional recovery. Stroke is the third leading cause of death and the leading cause of long-term disability in the U.S. No approved treatment exists beyond tissue plasminogen activator (tPA), which is effective only within 3 hours of stroke onset. Stroke therapies are estimated at $1 billion, with annual healthcare costs of $30 to $50 billion. Stroke incidence is expected to rise, with over 1 million strokes per year in the U.S. by 2050. Stroke is most commonly caused by obstruction of blood flow in a major cerebral vessel, leading to a core of severely ischemic brain tissue. The size of the infarct depends on the penumbra, a zone of tissue around the core where neuronal function is not compromised. Blood flow levels determine the size of the infarct by maintaining cellular energy homeostasis. Ischemia leads to reduced blood flow, causing energy depletion and cellular dysfunction. This results in ionic gradient disruption, leading to cell swelling and cytotoxic edema. Increased extracellular potassium and decreased pH precede other ionic changes. The increase in potassium can release excitotoxic neurotransmitters, leading to sodium/calcium channel activation and further cell swelling. Extracellular calcium influx leads to mitochondrial calcium overload and cellular damage. Inflammatory responses to brain injury include gliosis, characterized by activation and proliferation of mononuclear phagocytic cells. Cytokines activate glial cells, which then produce cytokines, linking inflammation, cytokine production, and gliosis. Inflammatory mediators such as TNF-α and IL-1β are involved in brain injury. Several cell types in the brain can secrete cytokines, and peripherally derived cytokines can also contribute to brain inflammation. The blood-brain barrier is permeable to immune cells, which can contribute to CNS inflammation and gliosis. The inflammatory response to brain injury involves early accumulation of neutrophils, which adhere to the endothelium and migrate into the tissue. Inflammation contributes to lipid-membrane peroxidation, exacerbates tissue injury, and causes cytotoxic products from activated leukocytes. The signaling mechanisms in brain inflammation involve TNF-α, IL-1β, chemotactic cytokines, and adhesion molecules. These mechanisms are crucial for leukocyte adherence and infiltration, and for enhancing endothelial permeability. TNF-α and IL-