The current study examined efficacy of a small Tat (trans-activator of transcription)-conjugated peptide activator of the Nrf2 (nuclear factor-E2-related factor-2) antioxidant/cell-defense pathway as a potential injury-specific, novel neuroprotectant against global cerebral ischemia (GCI). A competitive peptide, DEETGE-CAL-Tat, was designed to facilitate Nrf2 activation by disrupting interaction of Nrf2 with Keap1 (kelch-like ECH-associated protein 1), a protein that sequesters Nrf2 in the cytoplasm and thereby inactivates it. The DEETGE-CAL-Tat peptide contained the critical sequence DEETGE for the Nrf2-Keap1 interaction, the cell transduction domain of the HIV-Tat protein, and the cleavage sequence of calpain, which is sensitive to Ca 2ϩ increase and allows injury-specific activation of Nrf2. Using an animal model of GCI, we demonstrated that pretreatment with the DEETGE-CAL-Tat peptide markedly decreased Nrf2 interaction with Keap1 in the rat hippocampal CA1 region after GCI, and enhanced Nrf2 nuclear translocation and DNA binding. The DEETGE-CAL-Tat peptide also induced Nrf2 antioxidant/cytoprotective target genes, reduced oxidative stress, and induced strong neuroprotection and marked preservation of hippocampal-dependent cognitive function after GCI. These effects were specific as control peptides lacked neuroprotective ability. Intriguingly, the DEETGE-CAL-Tat peptide effects were also injury specific, as it had no effect upon neuronal survival or cognitive performance in sham nonischemic animals. Of significant interest, peripheral, postischemia administration of the DEETGE-CAL-Tat peptide from days 1-9 after GCI also induced robust neuroprotection and strongly preserved hippocampal-dependent cognitive function. Based on its robust neuroprotective and cognitive-preserving effects, and its unique injury-specific activation properties, the DEETGE-CAL-Tat peptide represents a novel, and potentially promising new therapeutic modality for the treatment of GCI.

Global cerebral ischemia, such as occurs following cardiac arrest, can lead to oxidative stress, hippocampal neuronal cell death, and cognitive defects. The current study examined the potential beneficial effect and underlying mechanisms of post-treatment with the naturally occurring isoflavonic phytoestrogen, genistein, which has been implicated to attenuate oxidative stress. Genistein (1 mg kg(-1)) was administered i.v. 5 min after reperfusion in rats subjected to four-vessel global cerebral ischemia (GCI). The results revealed that genistein exerted significant neuroprotection of hippocampal CA1 neurons following GCI, as evidenced by an increase in NeuN-positive neurons and the decrease in TUNEL-positive neurons. Furthermore, genistein treatment also resulted in significantly improved spatial learning and memory as compared to vehicle control animals. The beneficial effects of genistein appear to be mediated by an increase of phosphorylation/activation of eNOS, with subsequent activation of the antioxidant/detoxification Nrf2/Keap1 transcription system. Along these lines, genistein increased keap1 S-nitrosylation, with a corresponding nuclear accumulation and enhanced DNA binding activity of Nrf2. Genistein also enhanced levels of the Nrf2 downstream antioxidant protein, heme oxygenase (HO)-1, as compared to vehicle control groups. In accordance with its induction of Nrf2 activation, genistein exerted a robust attenuation of oxidative DNA damage and lipid peroxidative damage in hippocampal CA1 neurons after GCI, as measured by immunofluorescence staining of the oxidative stress markers, 8-hydroxy-2-deoxyguanosine (8-OHdG) and 4-Hydroxynonenal (4-HNE). Interestingly, the aforementioned effects of genistein were abolished by pretreatment with L-NAME, an inhibitor of eNOS activation. In conclusion, the results of the study demonstrate that low dose genistein can exert significant antioxidant, neuroprotective, and cognitive-enhancing effects in the hippocampal CA1 region following GCI. Mechanistically, the beneficial effects of genistein appear to be mediated by enhanced eNOS phosphorylation/activation and nitric oxide (NO)-mediated thiol modification of Keap1, with subsequent upregulation of the Nrf2/HO-1 antioxidative signaling pathway and a resultant attenuation of oxidative stress.

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The current study examined whether the steroid hormone, 17β-estradiol (E2) can exert long-lasting beneficial effects upon axonal health, synaptic plasticity, dementia-related amyloid-beta (Aβ) protein expression, and hippocampal-dependent cognitive function in an animal model of chronic cerebral hypoperfusion and vascular dementia (VaD). Chronic cerebral hypoperfusion and VaD was induced by bilateral common carotid artery occlusion (BCCAO) in adult male Sprague Dawley rats. Low dose E2 administered for the first 3-months after BCCAO exerted long-lasting beneficial effects, including significant neuroprotection of hippocampal CA1 neurons and preservation of hippocampal-dependent cognitive function when examined at 6-months after BCCAO. E2 treatment also prevented BCCAO-induced damage to hippocampal myelin sheaths and oligodendrocytes, enhanced expression of the synaptic proteins synaptophysin and PSD95 in the hippocampus, and prevented BCCAO-induced loss of total and mushroom dendritic spines in the hippocampal CA1 region. Furthermore, E2-treatment also reduced BCCAO induction of dementia-related proteins expression such as p-tau (PHF1), total ubiquitin, and Aβ1-42, when examined at 6 m after BCCAO. Taken as a whole, the results suggest that low-dose E2 replacement might be a potentially promising therapeutic modality to attenuate or block negative neurological consequences of chronic cerebral hypoperfusion and VaD.

The propellers and turbines used in aeroplanes are typically powered by fossil-fuel combustion. Recently, Xu et al (2018 Nature 563 532–5) demonstrated a successful flight of an aeroplane using ionic-wind propulsion, which does not require combustion or moving parts. The ionic wind phenomenon induced by electrical discharges has been revealed since 17th century, but it was the first practical example of the so called solid-state propulsion. The detailed capabilities of such ionic wind based or electroaerodynamic driven aeroplanes have aroused the interest of both researchers and industries, detailed modeling works are required for deeper insights. In this paper, a 2D unipolar ion drift model coupled with Navier–Stokes equations is developed and validated by experiments. The electric field, space charge distribution, ionic wind velocity and body force are obtained. The flight velocity, the lift and distance of the ionic wind based aeroplane in the experiment and in an extreme case are analyzed theoretically based on the modeling results. The results show that the performance of an ionic wind based aeroplane depends on the matching between electrical parameters (discharge geometry, voltage, etc), flight parameters (initial velocity, weight control, airfoil, wingspan, etc) and power storage (battery storage, battery weight, etc).

Ischemic postconditioning (Post C), which involves administration of a brief ischemia after the initial ischemic event, has been demonstrated to be strongly neuroprotective against global cerebral ischemia (GCI) and to improve cognitive outcome. To enhance understanding of the underlying mechanisms, the current study examined the role of NMDA receptors in mediating the beneficial effects of Post C (3 min ischemia) administered 2 days after GCI in adult male rats. The results revealed that Post C was strongly neuroprotective against GCI, and that this effect was blocked by administration of the NMDA receptor antagonist MK-801. Further work revealed that the NR2A-type NMDA receptors mediate the Post C beneficial effects as administration of a NR2A-preferring antagonist (NVP-A) blocked Post C neuroprotection and cognitive enhancement, while administration of a NR2B-preferring antagonist (Ro25) was without effect. Post C significantly up-regulated NR2A levels and phosphorylation of NR2A in the hippocampal CA1 region after Post C. Post C also increased Ca(2+) influx and activation/phosphorylation of CamKIIα at Thr(286), effects that were NR2A mediated as they were blocked by NVP-A. Phosphorylation of ERK and CREB was also increased by Post C, as were two downstream CREB-dependent prosurvival factors, brain derived neurotropic factor (BDNF) and Bcl2, effects that were blocked by the NR2A antagonist, NVP-A. Taken as a whole, the current study provides evidence that NR2A-activation and downstream prosurvival signaling is a critical mediator of Post C-induced neuroprotection and cognitive enhancement following GCI.

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