Interest in excitotoxicity expanded following its implication in the pathogenesis of ischemic brain injury in the 1980s, but waned subsequent to the failure of N-methyl-D-aspartate (NMDA) antagonists ...in high profile clinical stroke trials. Nonetheless there has been steady progress in elucidating underlying mechanisms. This review will outline the historical path to current understandings of excitotoxicity in the ischemic brain, and suggest that this knowledge should be leveraged now to develop neuroprotective treatments for stroke.
Several large pharmaceutical companies have selectively downsized their neuroscience research divisions, reflecting a growing view that developing drugs to treat brain diseases is more difficult and ...often more time-consuming and expensive than developing drugs for other therapeutic areas, and thus represents a weak area for investment. These withdrawals reduce global neuroscience translational capabilities and pose a serious challenge to society’s interests in ameliorating the impact of nervous system diseases. While the path forward ultimately lies in improving understandings of disease mechanisms, many promising therapeutic approaches have already been identified, and rebalancing the underlying risk/reward calculus could help keep companies engaged in making CNS drugs. One way to do this that would not require upfront funding is to change the policies that regulate market returns for the most-needed breakthrough drugs. The broader neuroscience community including clinicians and patients should convene to develop and advocate for such policy changes.
Choi et al. discuss stemming the withdrawal of large pharmaceutical companies from CNS drug development through policy changes affecting market rewards (“pull incentives”). They suggest that the neuroscience community organize to lead the crafting and implementation of these policy changes.
We examined the relationship between parent-child nativity, race/ethnicity, and adverse childhood experiences (ACEs) among US children. We found that a high proportion of Black/Hispanic children ...experienced ACEs, with variation by generation for Hispanic but not Black children, and a lower but increasing proportion of White children experienced ACEs by generation.
Glycosylation with O-linked β-N-acetylglucosamine (O-GlcNAc) is one of the protein glycosylations affecting various intracellular events. However, the role of O-GlcNAcylation in neurodegenerative ...diseases such as Alzheimer's disease (AD) is poorly understood. Mitochondrial adenosine 5'-triphosphate (ATP) synthase is a multiprotein complex that synthesizes ATP from ADP and Pi. Here, we found that ATP synthase subunit α (ATP5A) was O-GlcNAcylated at Thr432 and ATP5A O-GlcNAcylation was decreased in the brains of AD patients and transgenic mouse model, as well as Aβ-treated cells. Indeed, Aβ bound to ATP synthase directly and reduced the O-GlcNAcylation of ATP5A by inhibition of direct interaction between ATP5A and mitochondrial O-GlcNAc transferase, resulting in decreased ATP production and ATPase activity. Furthermore, treatment of O-GlcNAcase inhibitor rescued the Aβ-induced impairment in ATP production and ATPase activity. These results indicate that Aβ-mediated reduction of ATP synthase activity in AD pathology results from direct binding between Aβ and ATP synthase and inhibition of O-GlcNAcylation of Thr432 residue on ATP5A.
Abstract
Background
The blood-brain barrier has been a hindrance to developing blood-based diagnostic tests for dementias, as it limits the appearance of brain biomarkers in the blood. Our aim was to ...see if the natural opening of the blood-brain barrier induced by ischemic stroke would increase serum levels of inflammatory biomarkers known to be elevated in the brains of patients with Alzheimer’s disease and other neurodegenerative dementias.
Methods
Forty-three patients with acute ischemic stroke presenting to Stony Brook University Hospital were prospectively enrolled in the study. Eight of these patients were clinically diagnosed as having an underlying neurodegenerative dementia. Blood was drawn acutely within 72 h of stroke symptom onset, and serum levels of the classic inflammatory biomarkers, interleukin-6 (IL-6) and C-reactive protein (CRP) were measured, along with levels of S100B protein (S100B) and complement C3 (CC3).
Results
Serum levels of IL-6 and CRP in patients with acute ischemic stroke and underlying dementia (AIS + D) were significantly higher (
p
= 0.002 and 0.003, respectively) than in patients with acute ischemic stroke alone (AIS). Serum levels of S100B and CC3 did not differ significantly between the groups.
Conclusions
This study supports the possibility that opening of the blood-brain barrier may enhance the blood appearance of brain tissue markers of inflammation associated with neurodegenerative dementia. Further study is warranted to test this possibility, given the recent emergence of methods to open the blood-brain barrier for diagnostic or therapeutic purposes.
To examine associations between race, ethnicity, and parent-child nativity, and common mental health conditions among U.S. children and adolescents.
Data were from 2016 to 2019 National Survey of ...Children's Health, a US population-based, serial cross-sectional survey, and restricted to children who had access to health care. We used weighted multivariable logistic regression to examine the associations between race and ethnicity (Asian, Black, Hispanic, White, Other-race); mental health outcomes (depression, anxiety, and behavior/conduct problems) stratified by household generation; and between household generation and outcomes stratified by race and ethnicity, adjusting for demographics (age, sex, family income to poverty ratio, parental education), and an adverse childhood experience (ACE) score.
When stratifying by household generation, racial and ethnic minority children generally had similar to lower odds of outcomes compared with White children, with the exception of higher odds of behavior/conduct problems among third + -generation Black children. When stratifying by race and ethnicity, third + generation children had increased odds of depression compared to their first-generation counterparts. Third + generation, racial and ethnic minority children had increased odds of anxiety and behavior/conduct problems compared with their first-generation counterparts. The associations generally remained significant after adjusting for the ACE score.
Lower odds of common mental health conditions in racial and ethnic minority children could be due to factors such as differential reporting, and higher estimates, including those in third + generation children, could be due to factors including discrimination; systemic racism; and other factors that vary by generation and need further investigation to advance health equity.
Roughness contrast patterns were generated on copper surfaces by a simple one-step site-selective oxidation process using a felt-tipped ink pen masking method. The patterned surface exhibited strong ...underwater oil wettability contrast which allows oil droplet confinement. Oil droplets placed on two patterned smooth dots (reservoirs) connected by a patterned smooth channel will spontaneously exchange liquid as a result of Laplace pressure differences until their shapes have reached equilibrium. In our experiments, residual solubility of the oil in water was overcome by using saturated oil-in-water solutions as the aqueous medium. In the saturated solution, the dependence of pattern geometry and oil viscosity on transported volume and the flow rate in the underwater oil transport process was investigated for dichloromethane and hexadecane. Experimental results were in good agreement with a simple model for Laplace pressure-driven flow. Depending on droplet curvatures, oil can be transported from large to small reservoirs or vice versa. The model predictions enable the design of reservoir and channel dimensions to control liquid transport in the water–solid surface–oil system. The patterning technique was extended to more complex patterns with multiple reservoirs for smart oil separation and mixing processes. The concepts demonstrated in this study can be employed to seed droplet arrays with specific initial drop volumes and achieve subsequent droplet mixing at controlled flow rates for potential lab-on-a-chip applications ranging from oil-droplet-based miniature reactors and sensors to high-throughput assays.
Bacterial adhesion to stainless steel 316L (SS316L), which is an alloy typically used in many medical devices and food processing equipment, can cause serious infections along with substantial ...healthcare costs. This work demonstrates that nanotextured SS316L surfaces produced by electrochemical etching effectively inhibit bacterial adhesion of both Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus, but exhibit cytocompatibility and no toxicity toward mammalian cells in vitro. Additionally, the electrochemical surface modification on SS316L results in formation of superior passive layer at the surface, improving corrosion resistance. The nanotextured SS316L offers significant potential for medical applications based on the surface structure-induced reduction of bacterial adhesion without use of antibiotic or chemical modifications while providing cytocompatibility and corrosion resistance in physiological conditions.
Transplantation approaches using cellular bridges, fetal central nervous system cells, fibroblasts expressing neurotrophin-3 (ref. 6), hybridoma cells expressing inhibitory protein-blocking ...antibodies, or olfactory nerves ensheathing glial cells transplanted into the acutely injured spinal cord have produced axonal regrowth or functional benefits. Transplants of rat or cat fetal spinal cord tissue into the chronically injured cord survive and integrate with the host cord, and may be associated with some functional improvements. In addition, rats transplanted with fetal spinal cord cells have shown improvements in some gait parameters, and the delayed transplantation of fetal raphe cells can enhance reflexes. We transplanted neural differentiated mouse embryonic stem cells into a rat spinal cord 9 days after traumatic injury. Histological analysis 2-5 weeks later showed that transplant-derived cells survived and differentiated into astrocytes, oligodendrocytes and neurons, and migrated as far as 8 mm away from the lesion edge. Furthermore, gait analysis demonstrated that transplanted rats showed hindlimb weight support and partial hindlimb coordination not found in 'sham-operated' controls or control rats transplanted with adult mouse neocortical cells.
•H2 therapy reduced infarct volume in both H2 and H2M groups compared to controls at 1 and 7 days after stroke.•Both H2 and H2M improved neurologic functional recovery on day 7 after stroke.•H2M ...treatment attenuated post-stroke hyperperfusion in hyperacute phase.•H2 minimized and H2M markedly minimized white matter injury after stroke.
Free radicals are downstream mediators of several cytotoxic cascades contributing to ischemic brain injury. Molecular hydrogen (H2) is an antioxidant potentially useful in the treatment of stroke. Hydrogen is easy to deliver, biologically non-toxic and diffuses freely through all biological structures including the blood-brain barrier and cellular membranes. This study evaluated the efficacy of hydrogen treatments in a rat stroke model compared to vehicle-treated controls using multiparametric MRI and neurological tests. Additionally, comparison of H2 treatment alone was made with H2 combined with minocycline (H2M) treatment (12 rats per group). The primary findings were: i) H2 therapy reduced infarct volume in both H2 and H2M groups compared to controls at 1 and 7 days after stroke, and ii) both H2 and H2M improved neurologic functional recovery on day 7. The secondary outcomes were: iii) H2M treatment attenuated post-stroke hyperperfusion in the hyperacute phase, and iv) H2M markedly minimized white matter injury. In conclusion, this is the first study to use MRI to longitudinally study H2 and H2M treatment on ischemic stroke and the first study to compare H2 treatment combined with another potential stroke therapeutic (H2M).
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