al deficits in experimental global cerebral ischemia in rats

This study was aimed to assess the effect of a new pyrimidine derivative (PIR-12 50 mg/kg) on survival and neurological deficits in rat global brain ischemia. It has been confirmed that the investigated compound PIR-12 contributes to an increase in survival up to 80% and a decrease in neurological status by 73,3% compared to the control group of animals and exceeds the strength of the effect of the reference drug Cavinton by 30% and 22,48%, respectively.

Effect of Methionine Diet on Time-Related Metabolic and Histopathological Changes of Rat Hippocampus in the Model of Global Brain Ischemia

Hyperhomocysteinemia (hHcy) represents a strong risk factor for atherosclerosis-associated diseases, like stroke, dementia or Alzheimer’s disease. A methionine (Met)-rich diet leads to an elevated level of homocysteine in plasma and might cause pathological alterations across the brain. The hippocampus is being constantly studied for its selective vulnerability linked with neurodegeneration. This study explores metabolic and histo-morphological changes in the rat hippocampus after global ischemia in the hHcy conditions using a combination of proton magnetic resonance spectroscopy and magnetic resonance-volumetry as well as immunohistochemical analysis. After 4 weeks of a Met-enriched diet at a dose of 2 g/kg of animal weight/day, adult male Wistar rats underwent 4-vessel occlusion lasting for 15 min, followed by a reperfusion period varying from 3 to 7 days. Histo-morphological analyses showed that the subsequent ischemia-reperfusion insult (IRI) aggravates the extent of the sole hHcy-induced degeneration of the hippocampal neurons. Decreased volume in the grey matter, extensive changes in the metabolic ratio, deeper alterations in the number and morphology of neurons, astrocytes and their processes were demonstrated in the hippocampus 7 days post-ischemia in the hHcy animals. Our results suggest that the combination of the two risk factors (hHcy and IRI) endorses and exacerbates the rat hippocampal neurodegenerative processes.

Effect of ischemic postconditioining on reaction of neocortex microglia after global brain ischemia in rats

Introduction. Ischemic postconditioning (IPostC) is a new concept in the brain protection strategy. Almost all researches in this area focus on the functioning and survival of neurons, while non-neuronal cells affected by IPostC remain unexplored. The aim is to study the IPostC effect on changes in microglia in the neocortex of Wistar rats after global brain ischemia during various periods of reperfusion. Materials and methods. Male Wistar rats were used as a model of a 10-minute global brain ischemia with a subsequent IPostC; the reperfusion-ischemia cycle was 15 s/15 s. In the early (2 days) and late (7 days) reperfusion periods, the number of morphologically unchanged neurons and Iba-1-positive nucleated microglyocytes in the occipital cortex was estimated. Results. It has been shown that global brain ischemia in rats leads to 25.9% (P<0.05) neuron death and an increase of 30.9% (P<0.05) in the number of Iba-1-positive microglia cells by the 2nd day of the reperfusion period in the occipital neocortex; by the 7th day of reperfusion, there was observed a neuron death significant increasing by 34.5% (P<0.05) and the number of Iba-1-positive microglia cells increasing of 65.2% (P<0.05) compared to similar indicators in sham-operated groups. The IPostC by 2 days of reperfusion was found to increase the number of unchanged neurons in the occipital region of the cerebral cortex by 18.3% (P<0.05), which is not accompanied by a significant change in the number of Iba-1-positive microglial cells; by 7 days of reperfusion the increase number of unchanged neurons was found to be 23.5% (P<0.05) in the analysed brain region , which is accompanied by a decrease in the number of Iba-1-positive microgliosis by 32.5% (P<0.05) comparing with similar indicators in groups without IPostC. Conlusions. The results of this work suggest that the cytoprotective effect of IPostC for neurons of the occipital neocortex of Wistar rats in the long-term reperfusion period is caused by blocking the infiltration of the ischemic brain region by both resident and recruited cells of the immune system.

Meta-analysis of targeted temperature management in animal models of cardiac arrest

Background Targeted temperature management (TTM) of 32 to 34 °C has been the standard treatment for out-of-hospital cardiac arrest since clinical trials in 2002 indicated benefit on survival and neurological outcome. In 2013, a clinical trial showed no difference in outcome between TTM of 33 °C and TTM of 36 °C. In this meta-analysis, we investigate the evidence for TTM in animal models of cardiac arrest. Methods We searched PubMed and EMBASE for adult animal studies using TTM as a treatment in different models of cardiac arrest or global brain ischemia which reported neurobehavioural outcome, brain histology or mortality. We used a random effects model to calculate estimates of efficacy and assessed risk of bias using an adapted eight-item version of the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADES) quality checklist. We also used a scoring system based on the recommendations of the Stroke Treatment Academic Industry Roundtable (STAIR), to assess the scope of testing in the field. Included studies which investigated a post-ischemic induction of TTM had their treatment regimens characterized with regard to depth, duration and time to treatment and scored against the modified STAIR criteria. Results The initial and updated search generated 17809 studies after duplicate removal. One hundred eighty-one studies met the inclusion criteria, including data from 1,787, 6,495 and 2,945 animals for neurobehavioural, histological and mortality outcomes, respectively. TTM was favoured compared to control for all outcomes. TTM was beneficial using short and prolonged cooling, deep and moderate temperature reduction, and early and delayed time to treatment. Median [IQR] study quality was 4 [3 to 6]. Eighteen studies checked seven or more of the eight CAMARADES quality items. There was no clear correlation between study quality and efficacy for any outcome. STAIR analysis identified 102 studies investigating post-ischemic induction of TTM, comprising 147 different treatment regimens of TTM. Only 2 and 8 out of 147 regimens investigated comorbid and gyrencephalic animals, respectively. Conclusions TTM is beneficial under most experimental conditions in animal models of cardiac arrest or global brain ischemia. However, research on gyrencephalic species and especially comorbid animals is uncommon and a possible translational gap. Also, low study quality suggests risk of bias within studies. Future animal research should focus on mimicking the clinical scenario and employ similar rigour in trial design to that of modern clinical trials.

Nanotherapeutic modulation of excitotoxicity and oxidative stress in acute brain injury

Excitotoxicity is a primary pathological process that occurs during stroke, traumatic brain injury (TBI), and global brain ischemia such as perinatal asphyxia. Excitotoxicity is triggered by an overabundance of excitatory neurotransmitters within the synapse, causing a detrimental cascade of excessive sodium and calcium influx, generation of reactive oxygen species, mitochondrial damage, and ultimately cell death. There are multiple potential points of intervention to combat excitotoxicity and downstream oxidative stress, yet there are currently no therapeutics clinically approved for this specific purpose. For a therapeutic to be effective against excitotoxicity, the therapeutic must accumulate at the disease site at the appropriate concentration at the right time. Nanotechnology can provide benefits for therapeutic delivery, including overcoming physiological obstacles such as the blood–brain barrier, protect cargo from degradation, and provide controlled release of a drug. This review evaluates the use of nano-based therapeutics to combat excitotoxicity in stroke, TBI, and hypoxia–ischemia with an emphasis on mitigating oxidative stress, and consideration of the path forward toward clinical translation.