Superoxide dismutase,catalase, and U78517F attenuate neuronal damage in gerbils with repeated brief ischemic insults

Repeated ischemic insults at one hour intervals result in more severe neuronal damage than a single similar duration insult. The mechanism for the more severe damage with repetitive ischemia is not fully understood. We hypothesized that the prolonged reperfusion periods between the relatively short ischemic insults may result in a pronounced generation of oxygen free radicals (OFRs). In this study, we tested the protective effects of superoxide dismutase (SOD) and catalase (alone or in combination), and U78517F in a gerbil model of repetitive ischemia. Three episodes (two min each) of bilateral carotid occlusion were used at one hour intervals to produce repetitive ischemia. Superoxide dismutase and catalase were infused via osmotic pumps into the lateral ventricles. Two doses of U78517F were given three times per animal, one half hour prior to each occlusion. Neuronal damage was assessed 7 days later in several brain regions using the silver staining technique. The Mann-Whitney U test was used for statistical comparison. Superoxide dismutase showed significant protection in the hippocampus (CA4), striatum, thalamus and the medial geniculate nucleus (MGN). Catalase showed significant protection in the striatum, hippocampus, thalamus, and MGN and the substantia nigra reticulata. Combination of the two resulted in additional protection in the cerebral cortex. Compared to the controls, there was little protection with a dose of 3 mg/kg of U78517F. There was significant protection with a dose of 10 mg/kg in the hippocampus (CA4), striatum, thalamus, medial geniculate nucleus and the substantia nigra reticulata. The significant protection noted with SOD, catalase or U78517F with repeated ischemia supports, the hypothesis that OFRs may play a role in neuronal damage in repeated cerebral ischemia.     

Protective effect of hypothermia during ischemia in neural cell cultures

Hypothermia offers protection from the effects of ischemia in small animals. We have recently shown that similar to small animals, hypothermia may also be protective in an astrocytic model of simulated ischemia in cell culture. This study was designed to look at the protective effects of hypothermia in cultures of cerebellar granular (glutamatergic) and cortical (GABAergic) neurons. We used LDH release into the medium as an indicator for neuron damage. Experiments were all done in sister cultures, in groups of six cultures at two temperatures (37 and 32 degrees Celsius). The duration of ischemia was three hours in cerebellar granular neuronal cell cultures and six hours in cortical neurons. LDH release was measured immediately after the insult. Hypothermia protected both granular and cortical neurons. In granular cells, LDH release was 62+/–18 at 32 degrees and 212+/–15 at 37 degrees (p=0.02). Cortical neurons showed LDH release of 15+/–2 at 32 degrees and 32+/–2 at 37 degrees (p=0.005). Our study suggests that similar to astrocytes, the protective effects of hypothermia are evident in neuronal cell cultures from the cerebellum and the cerebral cortex. Cell culture systems should prove useful techniques in understanding mechanisms of hypothermic protection during simulated ischemia in neurons from different sites.     

Baclofen is cytoprotective to cerebral ischemia in gerbils

The release of the neurotransmitter, glutamate, and the activation of receptor operated calcium channels, may increase the degree of damage in ischemic brain tissue. Inhibition of excitatory neurotransmitters should therefore result in cytoprotection of ischemic brain tissue. In this study we evaluated the effect of baclofen, an inhibitor of presynaptic glutamate release, on ischemic gerbil cortex, hippocampus (CA 1 and CA4), striatum and thalamus. Histological evaluation was done in a blind manner in 4 groups (total 36 animals): a control group (9 animals) and three groups (27 animals) with varying doses of baclofen. For cerebral ischemia, we used single episode of five minutes of arterial occlusion of the carotid arteries. Baclofen in doses of 0, 25, 50, and 100 mg/kg were given to different groups five minutes prior to ischemic insult. This was followed by intraperitoneal injections given 24 and 48 hours after the initial insult. Statistically significant histological cytoprotection was demonstrated. Doses of 25 mg/kg appeared to demonstrate significant protection of the cortex (p=0.0002), the CA1 and CA4 regions of the hippocampus (p=0.0004 and 0.0001) respectively. At a dose of 50 mg/kg, significant cytoprotection was demonstrated at the hippocampus (CA1 and CA4 regions), in particular at the CA4 region (p=0.0029). The 100 mg/kg dose appeared to have most significant protection at the CA1 and CA4 regions of the hippocampus (both p=0.0001), striatum (p=0.0011), and the thalamus (p=0.0008). All statistical comparisons were done using non-parametric tests (Mann-Whitney U test). Our study demonstrates that baclofen is cytoprotective to ischemic neuronal cells, especially in the hippocampus. Clinically this may be beneficial to those patients with strokes or head injuries.     

GABA concentrations in the striatum following repetitive cerebral ischemia

GABAergic neurons in the striatum are very sensitive to the effects of ischemia. The progressive decline in striatal GABA following transient forebrain ischemia in gerbils may be secondary to either a decreased production or an increase in reuptake mechanisms or both. The current experiment was designed to evaluate release of GABA by stimulation with K+ or inhibition of its uptake with nipecotic acid or their combination (K+ nipecotic) after repetitive forebrain ischemia in gerbils by in-vivo microdialysis on Days 1, 3, 5, and 14 following the insult. Infusion of nipecotic acid or potassium chloride, resulted in a significant increase in extracellular GABA. This response was significantly decreased in the post-ischemic animals. The synergistic effect of increased GABA concentrations by the infusion of nipecotic acid+potassium chloride seen in the controls was not evident in the post-ischemic animals. In conclusion, though there is a reduction in the extracellular GABA concentrations in the first week following an ischemic insult, restorative mechanisms are operative in the second week as seen by the increasing GABA concentrations.     

The impact of interventions in the global land and agri‐food sectors on Nature’s Contributions to People and the UN Sustainable Development Goals

Interlocked challenges of climate change, biodiversity loss, and land degradation require transformative interventions in the land management and food production sectors to reduce carbon emissions, strengthen adaptive capacity, and increase food security. However, deciding which interventions to pursue and understanding their relative co‐benefits with and trade‐offs against different social and environmental goals have been difficult without comparisons across a range of possible actions. This study examined 40 different options, implemented through land management, value chains, or risk management, for their relative impacts across 18 Nature's Contributions to People (NCPs) and the 17 Sustainable Development Goals (SDGs). We find that a relatively small number of interventions show positive synergies with both SDGs and NCPs with no significant adverse trade‐offs; these include improved cropland management, improved grazing land management, improved livestock management, agroforestry, integrated water management, increased soil organic carbon content, reduced soil erosion, salinization, and compaction, fire management, reduced landslides and hazards, reduced pollution, reduced post‐harvest losses, improved energy use in food systems, and disaster risk management. Several interventions show potentially significant negative impacts on both SDGs and NCPs; these include bioenergy and bioenergy with carbon capture and storage, afforestation, and some risk sharing measures, like commercial crop insurance. Our results demonstrate that a better understanding of co‐benefits and trade‐offs of different policy approaches can help decision‐makers choose the more effective, or at the very minimum, more benign interventions for implementation.     

Intracerebral microdialysis and its clinical application: a review

In vivo intracerebral microdialysis is an important neurochemical technique that has been used extensively in the experimental setting. Relatively recently, techniques have been developed to utilize this method in human subjects. The past decade has seen the advent of clinical investigations utilizing in vivo microdialysis in a number of neuropathological states. This review summarizes the principles of in vivo microdialysis techniques, as applied to humans, while discussing the significance of recent investigations for future clinical development.     

Innovative Technological Approach to Ebola Virus Disease Outbreak Response in Nigeria Using the Open Data Kit and Form Hub Technology

The recent outbreak of Ebola Virus Disease (EVD) in West Africa has ravaged many lives. Effective containment of this outbreak relies on prompt and effective coordination and communication across various interventions; early detection and response being critical to successful control. The use of information and communications technology (ICT) in active surveillance has proved to be effective but its use in Ebola outbreak response has been limited. Due to the need for timeliness in reporting and communication for early discovery of new EVD cases and promptness in response; it became imperative to empower the response team members with technologies and solutions which would enable smooth and rapid data flow. The Open Data Kit and Form Hub technology were used in combination with the Dashboard technology and ArcGIS mapping for follow up of contacts, identification of cases, case investigation and management and also for strategic planning during the response. A remarkable improvement was recorded in the reporting of daily follow-up of contacts after the deployment of the integrated real time technology. The turnaround time between identification of symptomatic contacts and evacuation to the isolation facility and also for receipt of laboratory results was reduced and informed decisions could be taken by all concerned. Accountability in contact tracing was ensured by the use of a GPS enabled device. The use of innovative technologies in the response of the EVD outbreak in Nigeria contributed significantly to the prompt control of the outbreak and containment of the disease by providing a valuable platform for early warning and guiding early actions.     

Cyclin-dependent kinase-5 prevents neuronal apoptosis through ERK-mediated upregulation of Bcl-2

Cyclin-dependent kinase-5 (Cdk5) is required for neuronal survival, but its targets in the apoptotic pathways remain unknown. Here, we show that Cdk5 kinase activity prevents neuronal apoptosis through the upregulation of Bcl-2. Treatment of SH-SY5Y cells with retinoid acid (RA) and brain-derived neurotrophic factor (BDNF) generates differentiated neuron-like cells. DNA damage triggers apoptosis in the undifferentiated cells through mitochondrial pathway; however, RA/BDNF treatment results in Bcl-2 upregulation and inhibition of the mitochondrial pathway in the differentiated cells. RA/BDNF treatment activates Cdk5-mediated PI3K/Akt and ERK pathways. Inhibition of Cdk5 inhibits PI3K/Akt and ERK phosphorylation and Bcl-2 expression, and thus sensitizes the differentiated cells to DNA-damage. Inhibition of ERK, but not PI3K/Akt, abrogates Cdk5-medidated Bcl-2 upregulation and the protection of the differentiated cells. This study suggests that ERK-mediated Bcl-2 upregulation contributes to BDNF-induced Cdk5-mediated neuronal survival.     

Delayed minocycline but not delayed mild hypothermia protects against embolic stroke

Background  

Inflammatory reactions occurring in the brain after ischemia may contribute to secondary damage. In the present study, effects of minocycline, an anti-inflammatory agent, alone or in combination with mild hypothermia on focal embolic cerebral ischemia have been examined.