Recently it was demonstrated that exposure of the developing brain during the period of synaptogenesis to drugs that block NMDA glutamate receptors or drugs that potentiate GABA(A) receptors can trigger widespread apoptotic neurodegeneration. All currently used general anesthetic agents have either NMDA receptor-blocking or GABA(A) receptor-enhancing properties. To induce or maintain a surgical plane of anesthesia, it is common practice in pediatric or obstetrical medicine to use agents from these two classes in combination. Therefore, the question arises whether this practice entails significant risk of inducing apoptotic neurodegeneration in the developing human brain. To begin to address this problem, we have administered to 7-d-old infant rats a combination of drugs commonly used in pediatric anesthesia (midazolam, nitrous oxide, and isoflurane) in doses sufficient to maintain a surgical plane of anesthesia for 6 hr, and have observed that this causes widespread apoptotic neurodegeneration in the developing brain, deficits in hippocampal synaptic function, and persistent memory/learning impairments.

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Apolipoprotein E (apoE) genotype has a major influence on the risk for Alzheimer disease (AD). Different apoE isoforms may alter AD pathogenesis via their interactions with the amyloid ␤-peptide (A␤).Amyloid precursor protein (APP) C-terminal fragments were not different between Abca1 genotypes prior to plaque deposition in 3-month-old PDAPP mice, suggesting that deletion of Abca1 did not affect APP processing or A␤ production. As expected, 3-monthold PDAPP Abca1 ؊/؊ mice had decreased apoE levels, but they also had a higher percentage of carbonate-insoluble apoE, suggesting that poorly lipidated apoE is less soluble in vivo. We also found that 12-month-old PDAPP Abca1 ؊/؊ mice had a higher percentage of carbonate-insoluble apoE and that apoE deposits co-localize with amyloid plaques, demonstrating that poorly lipidated apoE co-deposits with insoluble A␤. Together, these data suggest that despite substantially lower apoE levels, poorly lipidated apoE produced in the absence of ABCA1 is strongly amyloidogenic in vivo.Apolipoprotein E (apoE) 2 genotype is a strong determinant of risk for Alzheimer disease (AD) and cerebral amyloid angiopathy (CAA) (1-3). Relative to subjects with the more common ⑀3 allele of apoE, subjects with one or more ⑀4 alleles have a higher risk for AD and CAA, whereas subjects with one or more ⑀2 alleles have a decreased risk for AD (2, 4). Evidence suggests that the mechanism by which different apoE alleles affect the pathogenesis of AD and CAA is by modifying interactions between apoE and the amyloid ␤-peptide (A␤), which aggregates and deposits into the amyloid plaques that are thought to initiate AD and CAA pathogenesis (5, 6). ApoE may act as a chaperone for A␤ by binding the peptide and altering its conformation, thereby influencing its clearance and ability to aggregate (7). Evidence supporting the role of apoE as an A␤ chaperone comes from a wide range of experiments. ApoE isoforms and levels affect the aggregation, fibrillogenesis, clearance, and degradation of A␤ in cell-free, cell-based, and tissue-based experiments (6, 8 -11).Studies have also shown a profound effect of apoE on A␤ deposition and conformation in vivo. The PDAPP and Tg2576 transgenic mouse models of AD, which overexpress the human amyloid precursor protein (APP) containing AD-causing mutations, develop several aspects of AD-like pathology beginning at 6 -9 months of age, including diffuse and fibrillar A␤ deposits, neuritic plaques, gliosis, and CAA (12, 13). When Tg2576 and PDAPP mice were bred to animals lacking murine apoE, the Tg2576 Apoe Ϫ/Ϫ , and PDAPP Apoe Ϫ/Ϫ mice developed much less A␤ deposition, almost no fibrillar A␤ deposits or neuritic plaques, and no CAA (14 -17). These effects were dose-dependent such that Apoe ϩ/Ϫ mice had less than 50% as much A␤-related pathology as Apoe ϩ/ϩ mice (14, 17). These findings demonstrate that murine apoE strongly promotes A␤-related pathology in vivo. The influence of apoE type and the levels on A␤ behavior in many different systems supports the hypothesis that apoE...

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T-lymphocytes promote cerebral inflammation, thus aggravating neuronal injury after stroke. Fingolimod, a sphingosine 1-phosphate receptor analog, prevents the egress of lymphocytes from primary and secondary lymphoid organs. Based on these findings, we hypothesized fingolimod treatment would reduce the number of T-lymphocytes migrating into the brain, thereby ameliorating cerebral inflammation following experimental intracerebral hemorrhage (ICH). We investigated the effects of fingolimod in two well-established murine models of ICH, implementing intrastriatal infusions of either bacterial collagenase (cICH) or autologous blood (bICH). Furthermore, we tested the long term neurological improvements by Fingolimod in a collagenase-induced rat model of ICH. Fingolimod, in contrast to vehicle administration alone, improved neurological functions and reduced brain edema at 24 and 72 hours following experimental ICH in CD-1 mice (n=103; p<0.05). Significantly fewer lymphocytes were found in blood and brain samples of treated animals when compared to the vehicle group (p<0.05). Moreover, fingolimod treatment significantly reduced the expression of intercellular adhesion molecule-1 (ICAM-1), interferon-γ (INF-γ), and interleukin-17 (IL-17) in the mouse brain at 72 hours post-cICH (p<0.05 compared to vehicle). Long-term neurocognitive performance and histopathological analysis were evaluated in Sprague-Dawley rats between 8 and 10 weeks post-cICH (n=28). Treated rats showed reduced spatial and motor learning deficits, along with significantly reduced brain atrophy and neuronal cell loss within the basal ganglia (p<0.05 compared to vehicle). We conclude that fingolimod treatment ameliorated cerebral inflammation, at least to some extent, by reducing the availability and subsequent brain infiltration of T-lymphocytes, which improved the short and long-term sequelae after experimental ICH in rodents.

The concept of the neurovascular unit as the key brain component affected by stroke is controversial, because current definitions of this entity neglect mechanisms that control perfusion and reperfusion of arteries and arterioles upstream of the cerebral microcirculation. Indeed, although definitions vary, many researchers consider the neurovascular unit to be restricted to endothelial cells, neurons and glia within millimetres of the cerebral capillary microcirculation. This Perspectives article highlights the roles of vascular smooth muscle, endothelial cells and perivascular innervation of cerebral arteries in the initiation and progression of, and recovery from, ischaemic stroke. The concept of the vascular neural network—which includes cerebral arteries, arterioles, and downstream neuronal and glial cell types and structures—is introduced as the fundamental component affected by stroke pathophysiology. The authors also propose that the vascular neural network should be considered the main target for future therapeutic intervention after cerebrovascular insult.

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Perinatal hypoxic-ischemic encephalopathy (HIE) is associated with high neonatal mortality and severe long-term neurologic morbidity. Yet the mechanisms of brain injury in infants with HIE remain largely elusive. The present study determined a novel mechanism of microRNA-210 (miR-210) in silencing endogenous neuroprotection and increasing hypoxicischemic brain injury in neonatal rats. The study further revealed a potential therapeutic effect of miR-210 inhibition using complementary locked nucleic acid oligonucleotides (miR-210-LNA) in 10-day-old neonatal rats in the Rice-Vannucci model. The underlying mechanisms were investigated with intracerebroventricular injection (i.c.v) of miR-210 mimic, miR-210-LNA, glucocorticoid receptor (GR) agonist and antagonist. Luciferase reporter gene assay was conducted for identification of miR-210 targeting GR 3’untranslated region. The results showed that the HI treatment significantly increased miR-210 levels in the brain, and miR-210 mimic significantly decreased GR protein abundance and exacerbated HI brain injury in the pups. MiR-210-LNA administration via i.c.v. 4 hours after the HI insult significantly decreased brain miR-210 levels, increased GR protein abundance, reduced HI-induced neuronal death and brain infarct size, and improved long-term neurological function recovery. Of importance, the intranasal delivery of miR-210-LNA 4 hours after the HI insult produced similar effects in decreasing HI-induced neonatal brain injury and improving neurological function later in life. Altogether, the present study provides evidence of a novel mechanism of miR-210 in a neonatal HI brain injury model, and suggests a potential therapeutic approach of miR-210 inhibition in the treatment of neonatal HIE.