DHEA, together with DHEAS, is the most abundant steroid in the blood of young adult humans. Levels in humans decline with age and during certain types of illness or stress. We have found that DHEA(S) can prevent or reduce the neurotoxic actions in the hippocampus of the glutamate agonists N-methyl-D-aspartic acid (NMDA) both in vitro and in vivo or ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainic acid in vitro. Pre-treatment with DHEA (10-100 nM for 6-8 h) protected primary hippocampal cultures from embryonic day 18 (E18) embryos against NMDA-induced toxicity (0.1, 1, 10, and 50 mM). DHEA added either with NMDA (1 mM) or 1 h later had lesser, but still significant, protective actions. DHEAS also reduced NMDAinduced toxicity (1 mM), although the lowest effective dose of DHEAS (100 nM) was higher than that of DHEA (10 nM). DHEA (100 nM) protected cultured neurons against the neurotoxic actions of either AMPA (25 M) or kainic acid (1 mM) as well. In vivo, s.c. pellets of DHEA, which resulted in plasma levels that resembled those in young adult humans, protected hippocampal CA1͞2 neurons against unilateral infusions of 5 or 10 nmol of NMDA. Because the release of glutamate has been implicated in the neural damage after cerebral ischemia and other neural insults, these results suggest that decreased DHEA levels may contribute significantly to the increased vulnerability of the aging or stressed human brain to such damage. Levels of DHEA, together with DHEAS, peak at Ϸ20 years of age in humans and then decline ineluctably to reach values of 20-30% at Ϸ70-80 years of age (1). DHEA(S) levels also are reduced by intercurrent stressful events such as an episode of major depressive disorder (2, 3) or systemic disease (4, 5). Recent evidence shows that DHEA and DHEAS have direct actions on the brain, acting as allosteric modulators of ␥-aminobutyric acid type A receptors (6), interacting with voltagegated Ca 2ϩ channels in CA1 hippocampal neurons (7), reducing aggression, and improving memory in mice (8, 9). The functional and clinical significance of age-related or stressinduced declines in DHEA or DHEAS for neural function is not understood. Both age and stress are associated with neuronal vulnerability to degeneration (10). We have found that DHEA or DHEAS can prevent or reduce the neurotoxic actions of the glutamate agonist N-methyl-D-aspartic acid (NMDA) in the hippocampus both in vitro and in vivo, as well as that of two other glutamate receptor agonists, ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainic acid in vitro. Because the release of glutamate has been implicated in the neural damage after cerebral ischemia and other neural insults (11-13), these results suggest that decreased DHEA(S) levels may contribute significantly to the increased vulnerability of the aging or stressed human brain to such damage.

Objective Perihematomal edema results from disruption of the blood-brain barrier (BBB) by key mediators, such as thrombin, following intracerebral hemorrhage (ICH). Platelet derived growth factor receptor alpha (PDGFR-α), a tyrosine kinase receptor, was found in previous studies to play a role in orchestrating BBB impairment. In the present study, we investigated the role of PDGFR-α following ICH-induced brain injury in mice, specifically investigating its effect on BBB disruption. Methods Brain injury was induced by autologous arterial blood (30 μl) or thrombin (5 U)-injection into mice brains. A PDGFR antagonist (Gleevec) or agonist (PDGF-AA) was administered following ICH. PDGF-AA was injected with a thrombin inhibitor, hirudin in ICH mice. Thrombin-injected mice were given Gleevec or PDGF-AA neutralizing antibody. A p38 MAPK inhibitor, SB203580 was delivered with PDGF-AA in naïve animals. Post-assessment included neurological function tests, brain edema measurement, Evans blue extravasation, immunoprecipitation, western blot and immunohistology assay. Results PDGFR-α suppression prevented neurological deficits, brain edema and Evans blue extravasation at 24–72 hours following ICH. PDGFR-α activation led to BBB impairment and this was reversed by SB203580 in naïve mice. Thrombin inhibition suppressed PDGFR-α activation and exogenous PDGF-AA increased PDGFR-α activation, regardless of thrombin inhibition. Animals receiving a PDGF-AA neutralizing antibody or Gleevec showed minimized thrombin injection-induced BBB impairment. Interpretation PDGFR-α signaling may contribute to BBB impairment via p38 MAPK mediated MMP activation/expression following ICH and thrombin may be the key upstream orchestrator. The therapeutic interventions targeting the PDGFR-α signaling may be a novel strategy to prevent thrombin-induced BBB impairment following ICH.

The systemic immune response has a vital role in propagating the damage of an intracerebral hemorrhage (ICH). Vascular adhesion protein-1 (VAP-1), a semicarbazide (SCZ)-sensitive-amine-oxidase, was found in previous studies to have a role in migration of immune cells. In this study, we hypothesize that VAP-1 inhibition may decrease brain injury by attenuating the transmigration of immune cells to the injury site, and by doing so, reduce cerebral edema and improve neurobehavioral function in mice. Two VAP-1 inhibitors, LJP1586 and SCZ were given 1 hour after ICH induction by either collagenase or autologous blood injection. The VAP-1 siRNA, a VAP-1 gene silencer, and human recombinant AOC3 protein, a VAP-1 analogue, were delivered by intracerebroventricular injection. Postassessment included neurobehavioral testing, brain edema measurement, quantification of neutrophil infiltration and microglia/macrophage activation, and measurement of intercellular adhesion molecule-1 (ICAM-1), P-selectin, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-α (TNF-α) expression 24 hours after ICH. We found that LJP1586 and SCZ reduced brain edema and neurobehavioral deficits 24 hours after ICH induction. These two drugs were also found to decrease levels of ICAM-1, MCP-1, TNF-α, and inhibit neutrophilic infiltration and microglia/macrophage activation. We conclude that VAP-1 inhibition provided antiinflammation effect by reducing adhesion molecule expression and immune cell infiltration after ICH.

AMD retinas exhibited increased mtDNA control region SNPs compared to normal retinas. This correlated with an increased frequency of mtDNA SNPs associated with haplogroups J, T and U in patients with AMD. These results implicate mitochondrial alterations in the etiology of AMD.

Objective Isoflurane, a volatile anesthetic agent, has been recognized for its potential neuroprotective properties and has antiapoptotic effects. We examined whether isoflurane posttreatment is protective against early brain injury (EBI) after subarachnoid hemorrhage (SAH) and determined whether this effect needs sphingosine-related pathway activation. Design Controlled in vivo laboratory study. Setting Animal research laboratory. Subjects 179 eight-week-old male CD-1 mice weighing 30 to 38 g. Interventions SAH was induced in mice by endovascular perforation. Animals were randomly assigned to sham-operated, SAH-vehicle, and SAH+2% isoflurane. Neurobehavioral function and brain edema were evaluated at 24 and 72 hours. The expression of sphingosine kinase (SphK), phosphorylated Akt (p-Akt) and cleaved caspase-3 was determined by Western blotting and immunofluorescence. Neuronal cell death was examined by terminal deoxynucleotidyl transferase-mediated uridine 5′-triphosphate-biotin nick end-labeling staining. Effects of a SphK inhibitor DMS, or a sphingosine 1 phosphate receptor inhibitor VPC23019 on isoflurane’s protective action against post-SAH EBI were also examined. Measurements and Main Results Isoflurane significantly improved neurobehavioral function and brain edema at 24 hours but not 72 hours after SAH. At 24 hours, isoflurane attenuated neuronal cell death in the cortex, associated with an increase in SphK1 and p-Akt, and a decrease in cleaved caspase-3. The beneficial effects of isoflurane were abolished by DMS and VPC23019. Conclusions Isoflurane posttreatment delays the development of post-SAH EBI through antiapoptotic mechanisms including sphingosine-related pathway activation, implying its use for anesthesia during acute aneurysm surgery or intervention.