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Introduction: Statins influence immune system activities through mechanisms independent of their lipid-lowering properties. T cells can be subdivided based on cytokine secretion patterns into two subsets: T-helper cells type 1 (Th1) and type 2 (Th2). Independent laboratory studies have shown statins to be potent inducers of a Th2 switch in immune cell response and be neuroprotective in several models of central nervous system (CNS) disease. This study was the first to evaluate the immune modulating effects of statins in subarachnoid hemorrhage (SAH)., Methods: Simvastatin was administered to rats intraperitoneally in two dosages (1 and 20 mg/kg) 30 min after the induction of SAH using endovascular perforation. Neurological scores were assessed 24 h later. Animals were then sacrificed, and samples of cortex and brain stem were tested for expression of the T-regulatory cell cytokine transforming growth factor (TGF) β1, as well as interleukin (IL) 1β, a proinflammatory cytokine associated with Th1 immune responses. The presence of TGF-β1 secreting T cells was evaluated with the use of brain slices., Results: SAH significantly impaired neurological function in all SAH groups (treated and untreated) versus sham. Animals treated with high-dose simvastatin had less neurological impairment than both untreated and low-dose groups. Cortical and brain-stem levels of TGF-β1 were significantly elevated following SAH in the high-dose group. IL-1β was significantly elevated following the induction of SAH but was inhibited by high-dose simvastatin. Double-labeled fluorescent immunohistochemical data demonstrated the presence of lymphocytes in the subarachnoid and perivascular spaces following SAH. Expression of TGF-β1 by lymphocytes was markedly increased following treatment with high-dose simvastatin., Conclusion: The present study elucidated the potential role of a Th2 immune switch in statin provided neuroprotection following SAH.

Background: Germinal matrix hemorrhage (GMH) is a potentially devastating neurological disease of very low birth weight premature infants. This leads to post-hemorrhagic hydrocephalus, cerebral palsy, and mental retardation. Hyperbaric oxygen (HBO) treatment is a broad neuroprotectant after brain injury. This study investigated the therapeutic effect of HBO after neonatal GMH., Methods: Neonatal rats underwent stereotaxic infusion of clostridial collagenase into the right germinal matrix (anterior caudate) brain region. Cognitive function was assessed at 3 weeks, and then sensorimotor, cerebral, cardiac, and splenic growths were measured 1 week thereafter., Results: Hyperbaric oxygen (HBO) treatment markedly improved upon the mental retardation and cerebral palsy outcome measurements in rats at the juvenile developmental stage. The administration of HBO early after neonatal GMH also normalized brain atrophy, splenomegaly, and cardiac hypertrophy 1 month after injury., Conclusion: This study supports the role of hyperbaric oxygen (HBO) treatment in the early period after neonatal GMH. HBO is an effective strategy to help protect the infant's brain from the post-hemorrhagic consequences of brain atrophy, mental retardation, and cerebral palsy. Further studies are necessary to determine the mechanistic basis of these neuroprotective effects.

Background: Intracerebral hemorrhage (ICH) is one of the most common causes of maternal deaths related to the postpartum period. This is a devastating form of stroke for which there is no available treatment. Although premenopausal females tend to have better outcomes after most forms of brain injury, the effects of pregnancy and child birth lead to wide maternal physiological changes that may predispose the mother to an increased risk for stroke and greater initial injury., Methods: Three different doses of collagenase were used to generate models of mild, moderate and severe cerebellar hemorrhage in postpartum female and male control rats. Brain water, blood-brain barrier rupture, hematoma size and neurological evaluations were performed 24 h later., Results: Postpartum female rats had worsened brain water, blood-brain barrier rupture, hematoma size and neurological evaluations compared to their male counterparts., Conclusion: The postpartum state reverses the cytoprotective effects commonly associated with the hormonal neuroprotection of (premenopausal) female gender, and leads to greater initial injury and worsened neurological function after cerebellar hemorrhage. This experimental model can be used for the study of future treatment strategies after postpartum brain hemorrhage, to gain a better understanding of the mechanistic basis for stroke in this important patient subpopulation.

Hypoxic-ischemic brain injury remains a leading cause of mortality and morbidity in neonates. The inflammatory response, which is characterized in part by activation of local immune cells, has been implicated as a core component for the progression of damage to the immature brain following hypoxia-ischemia (HI). However, mounting evidence implicates circulating immune cells recruited to the site of damage as orchestrators of neuron-glial interactions and perpetuators of secondary brain injury. This suggests that re-directing our attention from the local inflammatory response toward the molecular mediators believed to link brain-immune cell interactions may be a more effective approach to mitigating the inflammatory sequelae of perinatal HI. In this review, we focus our attention on cyclooxygenase-2, a mediator by which peripheral immune cells may modulate signaling pathways in the brain that lead to a worsened outcome. Additionally, we present an overview of emerging therapeutic modalities that target mechanisms of neuroinflammation in the hypoxic-ischemic neonate.

Objective: Oxidative stress contributes significantly to the development of secondary brain injury after intracerebral hemorrhage (ICH). It has been previously demonstrated that hydrogen gas can decrease oxidative stress by scavenging reactive oxygen species. We hypothesized that hydrogen therapy will reduce brain oxidative stress in mice after ICH and thereby will lead to reduced brain edema and improved neurological outcomes., Materials and Methods: CD1 male mice (weight 30-35 g) were divided into the following groups: sham, ICH+vehicle (room air), ICH+1-h hydrogen treatment, and ICH+2-h hydrogen treatment. ICH was induced by injection of bacterial collagenase into the right basal ganglia. The evaluation of outcomes was done at two time points: 24 and 72 h post-ICH. Brain water content was measured for assessment of brain edema (wet/dry weight method), and three neurological tests were performed pre- and postoperatively., Results: Collagenase injection was found to induce brain edema and impair functional performance of rats. The hydrogen inhalation reduced these effects acutely (24 h); however it exhibited only a tendency to improvement in the delayed study (72 h)., Conclusions: Our results suggest that hydrogen inhalation exerts an acute brain-protective effect in the mouse ICH model. However, the acute hydrogen therapy alone is not sufficient to improve delayed ICH outcomes in this model.

The present study was designed to examine if hyperbaric oxygen preconditioning (HBO-PC) is neuroprotective in a mouse model of surgical brain injury (SBI). C57BL mice were administered 100% oxygen for 1 h at 2.5 ATA for 5 consecutive days and subjected to SBI on the following day. The HBO-PC + SBI animals were compared to sham and normoxia + SBI groups for brain water content in different brain regions at 24 and 72 h after surgery. Blood-brain barrier (BBB) permeability was evaluated using Evan's blue dye extravasation at 24 h. Neurological assessment of the animals was done by a blinded observer at 24 and 72 h. The results showed that brain water content was significantly increased in the right (ipsilateral) frontal lobe surrounding the site of resection. This was attenuated by HBO-PC at 24 and 72 h. However, HBO-PC did not have any effect on the increased BBB permeability observed after SBI. Significant neurological deficits were observed after SBI. HBO-PC improved neurological deficits at 72 h on the 21-point sensorimotor scale and at 24 and 72 h on the wire hang and beam balance scoring. In conclusion, HBO-PC attenuates post-operative brain edema and improves neurological outcomes following SBI.

Matrix metalloproteinase-9 (MMP-9) plays a deleterious role in cell death after global cerebral ischemia. Preconditioning with hyperbaric oxygen (HBO-PC) reduces neuronal damage in the post-ischemic brain; however, its effect on ischemia-induced increase in MMP-9 activity and expression remains unexplored.We investigated effects of HBO-PC on alterations in MMP-9 activity/tissue expression accompanying neuronal death after transient global cerebral ischemia.Male SD rats (300-350 g), were allocated either to non-ischemic (naive control or sham-operated) or ischemic (four-vessel occlusion, 4VO; 10 min) groups that were HBO-preconditioned (2.5 ATA, 1 h daily for 5 days; the last session 24 h before ischemia) or not. Neurobehavioral deficits were assessed prior to collection of brain tissue for gel zymography (MMP-9) and histology (MMP-9 immunofluorescence, TUNEL) at 0 (without ischemia), 6, 24, 72 h and 7 days after 4VO.Both, MMP-9 levels and cell death increased in the hippocampus at 72 h after 4VO. HBO-PC suppressed postischemic MMP-9 activity and CA1 cell damage, and improved functional performance. The increase in MMP-9 immunoreactivity in the brain was also detected after HBO-PC alone. HBO-PC suppresses MMP-9 activity and expression in the postischemic hippocampus. The mechanism of HBO preconditioning may depend on the induction of MMP-9 in the preischemic phase and may be in part mediated by exhaustion of MMP-9 stores in cerebral tissues.