Models Of Cerebral Ischemic Injury Research Articles

A new cerebral ischemic injury model in rats, preventive effect of gallic acid and in silico approaches.

Current study was designed multiple occlusions and reperfusion of bilateral carotid arteries induced cerebral injury model and evaluated the protective effect of gallic acid on it. In silico study was involved to study gallic acid binding affinity on cerebrotonic proteins compared with standard drugs using Autodoc vina tool. Cerebral ischemia was induced by occlusion of bilateral common carotid arteries for 10 mins followed by 10 reperfusions (1 cycle), cycle was continued to 3 cycles (MO/RCA), then pathological changes were observed by estimation of brain antioxidants as superoxide dismutase, glutathione, catalase, oxidants like malonaldehyde, cerebral infarction area, histopathology, and study gallic acid treatment against cerebral injury. Gallic acid exhibited a strong binding affinity on targeted cerebrotoxic proteins. MO/RCA rat brain antioxidant levels were significantly decreased and increased MDA levels (p<0.0001), Infarction size compared to sham rats. Gallic acid treatment rat brain MDA levels significantly decreased (p<0.4476) and increased SOD (p<0.0001), CAT (p<0.0001), GSH (p<0.0001), cerebral infarction area when compared to MO/RCA group. Developed model showed significant cerebral ischemic injury in rats, injury was ameliorated by Gallic acid treatment and in silico approaches also inhibit the cerebrotoxic protein function by targeting on active sites.

Study on the Pharmacodynamic Material Basis of Naomaitong for Cerebral Ischemia Based on vitro Cell Model

Background: Based on the theoretical basis of the pathological mechanism of cerebral ischemic injury, from the molecular level, using PC12 cells in vitro cell model pharmacodynamics and PK-PD correlation model research, to explain NaomaitongNMTpharmacodynamic material basis for the treatment of cerebral ischemic injury. Methods: Four in vitro cell models of cerebral ischemic injury were established. The side-leakage of lactate dehydrogenase (LDH) and NO content were used as pharmacodynamic indicators to establish the corresponding drug-time curves of NMT and each single-drug; Based on the SVM algorithm, a PK-PD correlation mathematical model was established. Results: The cerebral ischemia model caused by NMT has obvious protective effects compared with each single herb. Each single herb has different protective effects on the four damage mechanisms. The protective effect of Radix Pueraria(RP) was stronger in cerebral ischemic injury induced by Glu, In the cerebral ischemic injury caused by calcium overload mechanism, the protective effect of Ligusticum chuanxiongLCwas greater than that of Panax Ginseng(PG) and RP. The 15 components in NMT contained drug serum had a certain correlation with the cell injury model caused by the four mechanisms. It may be a medicinal material for NMT, and the different components have different correlations for cerebral ischemia damage caused by different mechanisms, and each component also has different efficacy. Conclusions: It reveals the medicinal substance basis of NMT in treating cerebral ischemia,and provides reference for the clinical rational use of NMT for the treatment of cerebral ischemic injury, and provides guidance for the basic research on the substance of traditional Chinese medicine.

Preclinical Development of a Prophylactic Neuroprotective Therapy for the Preventive Treatment of Anticipated Ischemia-Reperfusion Injury.

Ischemia-reperfusion brain injury can be iatrogenically induced secondary to life-saving procedures. Prophylactic treatment of these patients offers a promising prevention for lifelong complications. We postulate that a cytosine-guanine (CpG) oligodeoxynucleotide (ODN) can provide robust antecedent protection against cerebral ischemic injury with minimal release of pro-inflammatory cytokines, making it an ideal candidate for further clinical development. Mouse and nonhuman primate (NHP) models of cerebral ischemic injury were used to test whether an A-type CpG ODN, which induces minimal systemic inflammatory cytokine responses, can provide prophylactic protection. Extent of injury in the mouse was measured by histological staining of live tissue. In the NHP, injury was assessed 2 and 7days post-occlusion from T2-weighted magnetic resonance images and neurological and motor deficits were cataloged daily. Plasma cytokine levels were measured using species-specific Luminex assays. Prophylactic administration of an A-type CpG ODN provided robust protection against cerebral ischemic injury in the mouse with minimal systemic inflammation. Rhesus macaques treated with D192935, a mixture of human optimized A-type CpG ODNs, had smaller infarcts and demonstrated significantly less neurological and motor deficits following ischemic injury. Our findings demonstrate the translational potential of D192935 as a prophylactic treatment for patients at risk of cerebral ischemic injury.

Ferulic acid prevents the cerebral ischemic injury-induced decreases of astrocytic phosphoprotein PEA-15 and its two phosphorylated forms

Ferulic acid protects neuronal cells against focal cerebral ischemic injury through its anti-oxidative and anti-inflammatory effects. Phosphoprotein enriched in astrocytes 15 (PEA-15) is known to modulate various cellular processes including cell proliferation, apoptosis, and survival. This study was investigated whether ferulic acid can regulate the levels of PEA-15 and its two phosphorylated forms (Ser 104 and Ser 116) in a cerebral ischemic injury model and in neuronal cells exposed to glutamate. A middle cerebral artery occlusion (MCAO) was performed to induce focal cerebral ischemic injury. Adult male rats were immediately treated with vehicle or ferulic acid (100mg/kg) at the beginning of the MCAO, and then cerebral cortices were collected 24h after MCAO. The decrease in PEA-15 level after ischemic injury was detected using a proteomic approach. Ferulic acid administration prevented the ischemic injury-induced decrease of PEA-15 level. Moreover, Western blot analysis clearly confirmed that ferulic acid attenuates the ischemic injury-induced decreases in PEA-15, phospho-PEA-15 (Ser 104), and phospho-PEA-15 (Ser 116) levels. Glutamate exposure induced significant reductions in the levels of PEA-15 and the two phospho-PEA-15 (Ser 104 and Ser 116) in cultured hippocampal neuron, while pretreatment with ferulic acid prevented the glutamate toxicity-induced decreases in these proteins levels. The decrease of phospho-PEA-15 protein level indicates that the anti-apoptotic function of PEA-15 was being inhibited. Thus, these results suggest that ferulic acid protects neuronal cells against ischemic injury by maintenance of phospho-PEA-15 protein levels.

Purification and neuroprotective effects of polysaccharides from Opuntia Milpa Alta in cultured cortical neurons

Opuntia is a traditional plant from China with medicinal applications. In this experiment, polysaccharides from Opuntia Milpa Alta (MAPs) were analyzed using gas chromatograph–mass spectrometer (GC–MS) method and result showed that MAPs contained mannose (6.37%), rhamnose (14.94%), xylose (1.99%), arabinose (24.07%), galactose (38.25%), ribose (2.63%) and glucose (11.48%). The neuroprotective effects of MAPs were evaluated at the mechanistic level in vitro models of cerebral ischemic injury. In vitro oxygen/glucose deprivation (OGD) model, MAPs (0.5μg/ml, 5μg/ml, 50μg/ml) effectively increased cell viability by methyl thiazolyl tetrazolium (MTT) assay, inhibited cell cytotoxicity by lactate dehydrogenase (LDH) assay, reduced neuronal cell death, suppressed the production of intracellular reactive oxygen species (ROS), decreased of intracellular free Ca2+ concentrations ([Ca2+]i), and reduced extracellular glutamate level. Therefore, MAPs might prevent intracellular calcium overload and decreased glutamate excitotoxicity, both of which can cause neuronal injury and death in vitro models of cerebral ischemic injury.

Protective effects of l-pGlu-(2-propyl)- l-His- l-ProNH 2, a newer thyrotropin releasing hormone analog in in vitro and in vivo models of cerebral ischemia

In the present study, the newly synthesized TRH analog ( l-pGlu-(2-propyl)- l-His- l-ProNH 2; NP-647) was evaluated for its effects in in vitro (oxygen glucose deprivation (OGD)-, glutamate- and H 2O 2-induced injury in PC-12 cells) and in vivo (transient global ischemia) models of cerebral ischemic injury. PC-12 cells were subjected to oxygen and glucose deprivation for 6 h. Exposure of NP-647 was given before and during OGD. In glutamate and H 2O 2 induced injury, exposure of NP-647 was given 1, 6 and 24 h prior to exposure of glutamate and H 2O 2 exposure. NP-647, per se found to be non-toxic in 1–100 μM concentrations. NP-647 showed protection against OGD at the 1 and 10 μM. The concentration-dependent protection was observed in H 2O 2- and glutamate-induced cellular injury. In in vivo studies, NP-647 treatment showed protection of hippocampal (CA1) neuronal damage in transient global ischemia in mice and subsequent improvement in memory retention was observed using passive avoidance retention test. Moreover, administration of NP-647 resulted in decrease in inflammatory cytokines TNF-α and IL-6 as well as lipid peroxidation. These results suggest potential of NP-647 in the treatment of cerebral ischemia and its neuroprotective effect may be attributed to reduction of excitotoxicity, oxidative stress and inflammation.

¿Cómo reparar el daño cerebral isquémico? Utilidad de los modelos experimentales en la búsqueda de respuestas

The major aim of experimental models of cerebral ischemia is to study the cerebral ischemic damage under controlled and reproducible conditions. Experimental studies have been fundamental in the establishment of new concepts regarding the mechanisms underlying the ischemic brain injury, such as the ischemic penumbra, the reperfusion injury, the cell death or the importance of the damage induced on mitochondria, glial cells and white matter. Disagreement between experimental and clinical studies regarding the benefit of drugs to reduce or restore the cerebral ischemic damage has created a growing controversy about the clinical value of the experimental models of cerebral ischemia. One of the major explanations for the failure of the clinical trials is the reductionist approach of most therapies, which are focused on the known effect of a single molecule within a specific pathway of ischemic damage. This philosophy contrasts to the complex morphological design of the cerebral tissue and the complex cellular and molecular physiopathology underlying the ischemic brain injury. We believe that the main objective of studies carried out in experimental models of cerebral ischemic injury must be a better understanding of the fundamental mechanisms underlying progression of the ischemic injury. Clinical trials should not be considered if the benefit obtained in experimental studies is limited or weak.

Leptin as a neuroprotective agent

Leptin is a hormone produced by adipocytes that regulates satiety (food uptake) and energy homeostasis by activating receptors expressed in neurons of the hypothalamus. Leptin receptors are also found in other brain regions such as the hippocampus and cerebral cortex, and have known roles in regulating neural development and neuroendocrine functions. Recent evidence indicates that leptin could be neuroprotective, enhancing neuronal survival both in vitro and in vivo. Intriguingly, administration of leptin protects against neuronal death in animal models of cerebral ischemic injury and hemiparkisonism. Activation of the Janus kinase (JAK)-signal transducers and activator of transcription (STAT), phosphatidylinositol (PI) 3-kinase and the extracellular signal regulated kinase (ERK) pathways are known downstream events of leptin receptor signaling, all of which are pro-survival and anti-apoptotic. The relative ease of leptin’s accessibility to the brain by peripheral administration makes it a potential drug candidate in the development of therapeutics for brain injuries and neurodegeneration.

Modelos experimentales de isquemia cerebral

To provide a summary of the different experimental models of cerebral ischemia designed both under in vivo and in vitro conditions. A clear and concise description of the specific types of brain lesion reproduced by each model is given together with the most frequent technical troubles associated. Experimental models of cerebral ischemia have contributed substantially to the understanding of the physiopathology of the ischemic brain injury and to test the beneficial effects of new therapies. Outcome of patients suffering from an ischemic stroke has improved considerably with the use of these models, particularly after the introduction of thrombolytic and neuroprotective drugs. Experimental models allow the study of the evolving ischemic brain injury under strict and controlled conditions. Usefulness of experimental models is limited by their reliability, simplicity and reproducibility among different researchers. Small rodents, especially rats, have been the preferred animals used to develop models of cerebral ischemic injury, due to their cerebral physiology and vascularisation which is closer to the human. The use of experimental models of cerebral ischemia constitutes the most suitable tool to investigate the physiopathology of this type of injury. However their simplicity prevents an exact reproduction of the cerebral damage observed in clinical settings. This could be the main reason for the discrepancies observed between the therapeutic effect in the experimental and clinical studies.

The effect of voluntary exercise exposure on histological and neurobehavioral outcomes after ischemic brain injury in the rat

Physical activity can induce neuroplastic adaptations and improve outcomes after cerebral injury. To determine if these outcomes are dependent on the type and timing of physical rehabilitation and the particular outcome/endpoint being tested, we evaluated the effect of voluntary exercise exposure beginning 24 h after cerebral ischemic injury on behavioral, physiological, and histological outcomes. In an observer-blinded fashion, Sprague–Dawley (300 g) male rats were allocated to three groups [sham–exercise (SHAM), stroke–exercise (SE), stroke–no exercise (SNE)] before a 1-h right middle cerebral artery occlusion (MCAo). Running wheels were used for voluntary exercise. A significant difference was found at 1 week post-infarction between the SNE and SE, with SNE showing worst neurological scores and higher number of foot faults. In addition, nearly 20% more of the SE animals regained their pre-MCAo weight by 7 days. These differences were not as evident at 2 weeks. No differences were found between the three groups in the paw preference test, wheel activity, and body temperature, as well as between SNE and SE with regards to infarct or hemispheric volumes, body weight, synaptophysin staining, and electroencephalography (EEG) testing. Within-group comparisons showed no relationships between infarct volume and foot faults, neurological scores, or exercise level. We conclude that (1) unlike behavioral outcomes, physiological and histological outcomes may not be influenced by the introduction of voluntary exercise once lesion maturation has occurred at 24 h, and (2) repetitive outcomes testing can obscure findings in rat models of cerebral ischemic injury.

Energy utilization in the ischemic/reperfused brain

Publisher Summary Stroke and cardiac arrest are among the leading contributors to mortality and morbidity. Elevated blood glucose levels, as in diabetes, are associated with an increase in ischemic brain injuries and a reduction in the likelihood of functional recovery. Pre-, but not post-, ischemic hyperglycemia exaggerates brain damage in the animal models of cerebral ischemic injury. This outcome has been widely attributed to a rise in lactate production from anaerobic glycolysis, with a concomitant tissue acidosis. It has been assumed that acidosis is toxic to neurons, initiating the dying process. It was therefore disturbing to observe that hyperglycemia reduced the ischemia-evoked release of the excitotoxic amino acids, glutamate and aspartate, which is considered to be among the primary causes of cerebral ischemic injury. This result suggested that hyperglycemia might actually have a cerebroprotective action during the ischemic episode, possibly due to lactate formation in astrocytes, with lactate serving as a source of metabolic energy for neurons, and that the damaging effects of hyperglycemia occur during reperfusion, as the intracellular pH reverts to normal levels. The evidence in support of this suggestion came from the observation that there was a marked increase in brain extracellular free fatty acid levels during the initial minutes of reperfusion, indicative of a sudden increase in phospholipase activation and cell membrane degradation. Future directions for research will involve a detailed examination of mitochondrial function in ischemia/reperfusion brains. This chapter reviews the recent findings on cerebral metabolism in normoxic and ischemic brains exposed to the physiologic and elevated levels of glucose. The role of insulin, plasma levels of which are depleted in many diabetics, in brain metabolism is also discussed.