IL-33 modulates inflammatory brain injury but exacerbates systemic immunosuppression following ischemic stroke.

Stroke triggers a complex inflammatory process in which the balance between pro- and antiinflammatory mediators is critical for the development of the brain infarct. However, systemic changes may also occur in parallel with brain inflammation. Here we demonstrate that administration of recombinant IL-33, a recently described member of the IL-1 superfamily of cytokines, promotes Th2-type effects following focal ischemic stroke, resulting in increased plasma levels of Th2-type cytokines and fewer proinflammatory (3-nitrotyrosine+F4/80+) microglia/macrophages in the brain. These effects of IL-33 were associated with reduced infarct size, fewer activated microglia and infiltrating cytotoxic (natural killer-like) T cells, and more IL-10-expressing regulatory T cells. Despite these neuroprotective effects, mice treated with IL-33 displayed exacerbated post-stroke lung bacterial infection in association with greater functional deficits and mortality at 24 hours. Supplementary antibiotics (gentamicin and ampicillin) mitigated these systemic effects of IL-33 after stroke. Our findings highlight the complex nature of the inflammatory mechanisms differentially activated in the brain and periphery during the acute phase after ischemic stroke. The data indicate that a Th2-promoting agent can provide neuroprotection without adverse systemic effects when given in combination with antibiotics.

Vitamin D3 Supplementation Reduces Subsequent Brain Injury and Inflammation Associated with Ischemic Stroke.

Acute inflammation can exacerbate brain injury after ischemic stroke. Beyond its well-characterized role in calcium metabolism, it is becoming increasingly appreciated that the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25-VitD3), has potent immunomodulatory properties. Here, we aimed to determine whether 1,25-VitD3 supplementation could reduce subsequent brain injury and associated inflammation after ischemic stroke. Male C57Bl6 mice were randomly assigned to be administered either 1,25-VitD3 (100 ng/kg/day) or vehicle i.p. for 5 day prior to stroke. Stroke was induced via middle cerebral artery occlusion for 1 h followed by 23 h reperfusion. At 24 h post-stroke, we assessed infarct volume, functional deficit, expression of inflammatory mediators and numbers of infiltrating immune cells. Supplementation with 1,25-VitD3 reduced infarct volume by 50% compared to vehicle. Expression of pro-inflammatory mediators IL-6, IL-1ß, IL-23a, TGF-ß and NADPH oxidase-2 was reduced in brains of mice that received 1,25-VitD3 versus vehicle. Brain expression of the T regulatory cell marker, Foxp3, was higher in mice supplemented with 1,25-VitD3 versus vehicle, while expression of the transcription factor, ROR-γ, was decreased, suggestive of a reduced Th17/γδ T cell response. Immunohistochemistry indicated that similar numbers of neutrophils and T cells were present in the ischemic hemispheres of 1,25-VitD3- and vehicle-supplemented mice. At this early time point, there were also no differences in the impairment of motor function. These data indicate that prior administration of exogenous vitamin D, even to vitamin D-replete mice, can attenuate infarct development and exert acute anti-inflammatory actions in the ischemic and reperfused brain.

Combination Therapy with Low-Dose IVIG and a C1-esterase Inhibitor Ameliorates Brain Damage and Functional Deficits in Experimental Ischemic Stroke.

Acute ischemic stroke causes a high rate of deaths and permanent neurological deficits in survivors. Current interventional treatment, in the form of enzymatic thrombolysis, benefits only a small percentage of patients. Brain ischemia triggers mobilization of innate immunity, specifically the complement system and Toll-like receptors (TLRs), ultimately leading to an exaggerated inflammatory response. Here we demonstrate that intravenous immunoglobulin (IVIG), a scavenger of potentially harmful complement fragments, and C1-esterase inhibitor (C1-INH), an inhibitor of complement activation, exert a beneficial effect on the outcome of experimental brain ischemia (I) and reperfusion (R) injury induced by transient occlusion of middle cerebral artery in mice. Both IVIG and C1-INH significantly and in a dose-responsive manner reduced brain infarction size, neurological deficit and mortality when administered to male mice 30 min before ischemia or up to 6 h after the onset of reperfusion. When combined, suboptimal doses of IVIG and C1-INH potentiated each other's neuroprotective therapeutic effects. Complement C3 and TLR2 signals were colocalized and significantly greater in brain cells adjacent to infracted brain lesions when compared to the corresponding regions of the contralateral hemisphere and to control (sham) mice. Treatment with IVIG and C1-INH effectively reduced deposition of C3b and downregulated excessive TLR2 and p-JNK1 expression at the site of I/R injury. Taken together, these results provide a rationale for potential use of IVIG and C1-INH, alone or in combination with ischemic stroke and other neurological conditions that involve inappropriately activated components of the innate immune system.

Phytochemicals in Ischemic Stroke.

Stroke is the second foremost cause of mortality worldwide and a major cause of long-term disability. Due to changes in lifestyle and an aging population, the incidence of stroke continues to increase and stroke mortality predicted to exceed 12 % by the year 2030. However, the development of pharmacological treatments for stroke has failed to progress much in over 20 years since the introduction of the thrombolytic drug, recombinant tissue plasminogen activator. These alarming circumstances caused many research groups to search for alternative treatments in the form of neuroprotectants. Here, we consider the potential use of phytochemicals in the treatment of stroke. Their historical use in traditional medicine and their excellent safety profile make phytochemicals attractive for the development of therapeutics in human diseases. Emerging findings suggest that some phytochemicals have the ability to target multiple pathophysiological processes involved in stroke including oxidative stress, inflammation and apoptotic cell death. Furthermore, epidemiological studies suggest that the consumption of plant sources rich in phytochemicals may reduce stroke risk, and so reinforce the possibility of developing preventative or neuroprotectant therapies for stroke. In this review, we describe results of preclinical studies that demonstrate beneficial effects of phytochemicals in experimental models relevant to stroke pathogenesis, and we consider their possible mechanisms of action.

Lowering corticosterone levels reinstates hippocampal brain-derived neurotropic factor and Trkb expression without influencing deficits in hypothalamic brain-derived neurotropic factor expression in leptin receptor-deficient mice.

BACKGROUND/AIMS: Changes in the glucocorticoid milieu contribute to alterations in neurotropic factor expression across multiple brain regions. Insulin-resistant diabetes is often accompanied by dysregulation of adrenal steroid production in humans and animal models. Leptin receptor-deficient mice (db/db) show reduced expression of brain-derived neurotropic factor (BDNF) in the hippocampus and increases in circulating corticosterone levels, but the extent to which elevated corticosterone levels mediate deficits in BDNF expression has not been determined. METHODS: Using in situ hybridization, we measured the expression of BDNF, its receptor TrkB, and neurotropin-3 (NT-3) in the hippocampus and hypothalamus of db/db mice and wild-type controls following adrenalectomy and low-dose corticosterone replacement (ADX+CORT) or sham operation. RESULTS: Lowering corticosterone levels restored BDNF and TrkB expression in the hippocampus of db/db mice. However, deficits in hypothalamic BDNF expression were not reversed following ADX+CORT. There was no effect of genotype or adrenalectomy on NT-3 expression in any brain region examined. CONCLUSION: Leptin receptor-deficient mice exhibit reduced BDNF expression in the hippocampus and hypothalamus. In the db/db mouse hippocampus, suppression of BDNF occurs in a glucocorticoid-dependent fashion, while hypothalamic BDNF expression is reduced via glucocorticoid-independent mechanisms. Region-specific signals therefore play a role in the interaction between corticosteroids and neurotropic factor expression.