Percentage Of Damaged Neurons Research Articles

Power suppression in EEG after the onset of SAH is a significant marker of early brain injury in rat models

We analyzed the correlation between the duration of electroencephalogram (EEG) recovery and histological outcome in rats in the acute stage of subarachnoid hemorrhage (SAH) to find a new predictor of the subsequent outcome. SAH was induced in eight rats by cisternal blood injection, and the duration of cortical depolarization was measured. EEG power spectrums were given by time frequency analysis, and histology was evaluated. The appropriate frequency band and recovery percentage of EEG (defined as EEG recovery time) to predict the neuronal damage were determined from 25 patterns (5 bands × 5 recovery rates) of receiver operating characteristic (ROC) curves. Probit regression curves were depicted to evaluate the relationships between neuronal injury and duration of depolarization and EEG recovery. The optimal values of the EEG band and the EEG recovery time to predict neuronal damage were 10–15 Hz and 40%, respectively (area under the curve [AUC]: 0.97). There was a close relationship between the percentage of damaged neurons and the duration of depolarization or EEG recovery time. These results suggest that EEG recovery time, under the above frequency band and recovery rate, may be a novel marker to predict the outcome after SAH.

Changes in the number of macrophages, T-lymphocytes, activity of antioxidant enzymes in the brain, behavior and structure of the central nervous system neurons in adult and aging mice of different strains with the MPTP-induced model of parkinsonism

Background. Oxidative stress and immune cell (T-lymphocytes, macrophages) products are important for the development of morpho-functional disorders of the nervous system in Parkinson’s disease. Connection of Parkinson’s disease with age and functioning of the major histocompatibility complex genes are also shown. The purpose was to assess changes in the brain of T-lymphocytes, macrophages, malondialdehyde (MDA) contents, the activity of antioxidant enzymes, the structure of brain and spinal cord neurons, as well as behavior in adult and aging mice with different H-2 haplotypes and toxic model of parkinsonism. Materials and methods. Adult and aging female mice of FVB/N (genotype H-2q) and 129/Sv (genotype H-2b) strains were once injected with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at the dose of 30 mg/kg. Contents of CD3+, CD3–CD11b+, CD3+CD11b+ cells, MDA and the activity of antioxidant enzymes in the brain were evaluated. The structure of neurons of the substantia nigra, lumbar spine, behavior in the open field test, as well as in rigidity and rotarod performance tests were studied. Results. In adult mice of both strains, motor and non-motor (spatial-exploratory, emotional) activity is impaired under the influence of MPTP. At the same time, linear differences in behavior changes were revealed in their directions and expressiveness. In aging FVB/N experimental mice, motor behavior disorders prevailed and were combined with non-motor changes in 129/Sv mice. Violations in the structure of substantia nigra neurons after MPTP administration were more severe in FVB/N mice while those in the lumbar spinal cord neurons were more pronounced in the 129/Sv mice. In aging experimental mice of both strains, the percentage of damaged neurons in the brain and spinal cord was significantly lower than in adult animals. After MPTP administration to adult mice, the direction of changes in the brain T-lymphocytes and macrophages (increase or decrease) depended on their strains. In aging experimental mice, the linear heterogeneity of changes was preserved for the T-lymphocyte content, while the macrophage level was increased regardless of the animal strains. Under MPTP influence, the MDA content increased in the brain of mice of all experimental groups. The direction of changes in superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase activities (decrease or increase) depended on the strains of animals and their age. Conclusions. MPTP-induced changes (directions, expressiveness) in T-lymphocyte, macrophage contents, antioxidant enzymes activity, the structure of neurons of the substantia nigra and lumbar spine, as well as behavioral reactions largely depended on the adult mice H-2 haplotype. There were age-related effects of the neurotoxin on changes in the studied indicators in mice of different strains. At the same time, dependence of changes in most above indicators on the H-2 haplotype preserved.

Omecamtiv mecarbil treatment improves post-resuscitation cardiac function and neurological outcome in a rat model.

BackgroundMyocardial dysfunction is a major cause of poor outcomes in the post-cardiac arrest period. Omecamtiv mecarbil (OM) is a selective small molecule activator of cardiac myosin that prolongs myocardial systole and increases stroke volume without apparent effects on myocardial oxygen demand. OM administration is safe and improves cardiac function in patients with acute heart failure. Whether OM improves post-resuscitation myocardial dysfunction remains unclear. This study investigated the effect of OM treatment on post-resuscitation myocardial dysfunction and outcomes.Methods and resultsAdult male rats were resuscitated after 9.5 min of asphyxia-induced cardiac arrest. OM and normal saline was continuously intravenously infused after return of spontaneous circulation (ROSC) at 0.25 mg/kg/h for 4 h in the experimental group and control group, respectively (n = 20 in each group). Hemodynamic parameters were measured hourly and monitored for 4 h after cardiac arrest. Recovery of neurological function was evaluated by neurological functioning scores (0–12; favorable: 11–12) for rats 72 h after cardiac arrest. OM treatment prolonged left ventricular ejection time and improved post-resuscitation cardiac output. Post-resuscitation heart rate and left ventricular systolic function (dp/dt40) were not different between groups. Kaplan-Meier analysis showed non-statistically higher 72-h survival in the OM group (72.2% [13/18] and 58.8% [10/17], p = 0.386). The OM group had a higher chance of having favorable neurological outcomes in surviving rats 72 h after cardiac arrest (84.6% [11/13] vs. 40% [4/10], p = 0.026). The percentage of damaged neurons was lower in the OM group in a histology study at 72 h after cardiac arrest (55.5±2.3% vs. 76.2±10.2%, p = 0.004).ConclusionsOM treatment improved post-resuscitation myocardial dysfunction and neurological outcome in an animal model. These findings support further pre-clinical studies to improve outcomes in post-cardiac arrest care.

Dental Pulp Stem Cells Transplantation Improves Passive Avoidance Memory and Neuroinflammation in Trimethyltin-Induced Alzheimer’s Disease Rat Model

Background: According to the increasing incidence of Alzheimer’s disease (AD), this study aimed to investigate the effect of dental pulp stem cells (DPSCs) transplantation on passive avoidance memory and neuroinflammation in trimethyltin (TMT)-induced AD rat model. Materials and Methods: In this experimental study, 18 male Wistar rats were randomly divided into three groups: the control that rats received 8 mg/kg TMT plus 0.5 ml phosphate buffered saline (PBS) and TMT+DPSCs (TMT + 1×106 cells/ml DPSC in 0.5 ml PBS) groups. Then, after one month, passive avoidance test was performed. Also measured the Nuclear Factor Kappa-β (NF-Kβ) serum level and the percentage of damaged neurons in the hippocampus were determined. Results: DPSCs transplantation showed significantly increased step-through latency to the dark compartment in comparison with control and TMT+PBS groups in 24 hours after shock. Also, time spent in the dark compartment of TMT+DPSCs significantly decreased compared to control and TMT+PBS groups in 24 and 48 hours after shock (P<0.05). Furthermore, DPSCs transplantation significantly decreased the NF-Kβ serum level and percentage of damaged pyramidal neurons of CA1 compared with TMT+PBS (P<0.05). Conclusion: DPSCs transplantation improved memory and learning, regulated NF-Kβ serum level, and decreased damage neurons of CA1 hippocampus in TMT-induced AD rat model.

Dental Pulp Stem Cells Transplantation Improves Passive Avoidance Memory and Neuroinflammation in Trimethyltin-Induced Alzheimer's Disease Rat Model

Background: According to the increasing incidence of Alzheimer's disease (AD), this study aimed to investigate the effect of dental pulp stem cells (DPSCs) transplantation on passive avoidance memory and neuroinflammation in trimethyltin (TMT)-induced AD rat model. Materials and Methods: In this experimental study, 18 male Wistar rats were randomly divided into three groups: the control rats, TMT+phosphate-buffered saline (PBS) group that received 8 mg/kg TMT plus 0.5 ml PBS, and TMT+DPSCs (TMT+1×106 cells/ml DPSC in 0.5 ml PBS). Then, after one month, a passive avoidance test was performed. Also, nuclear factor kappa-β (NF-Kβ) serum level and the percentage of damaged neurons in the hippocampus were determined. Results: DPSCs transplantation showed significantly increased step-through latency to the dark compartment compared to control and TMT+PBS groups 24 hours aftershock. Also, time spent in the dark compartment of the TMT+DPSCs group significantly decreased compared to control and TMT+PBS groups in 24 and 48 hours after shock (P<0.05). Furthermore, DPSCs transplantation significantly decreased the NF-Kβ serum level and percentage of damaged pyramidal neurons of CA1 compared to the TMT+PBS group (P<0.05). Conclusion: DPSCs transplantation improved memory and learning, regulated NF-Kβ serum level, and decreased damaged neurons of CA1 hippocampus in the TMT-induced AD rat model.

Effects of Monosodium Glutamate (MSG) on Neuron Damages in Hippocampus in Sprague-Dawley rats

Introduction: Monosodium glutamate (MSG) is a flavor enhancer commonly used worldwide. Studies haveshown that high dose of MSG could act as neurotoxic or excitotoxic agent for neurons in the central nervoussystem. The aim of this study was to determine the effect of MSG on neuron changes of hippocampusanimalmodel.Materials and Methods: A total of 25 white male Sprague-Dawleyrats, aged 8-10 weeks,were dividedinto5 groups (2 control groups (i.e., none and solvent group) and3 treatment groups that received2, 4and 6 mg/gram MSG orallyfor 30 days). Afterfour weeks on treatment, all animals were sacrificed and the entire braintissueswere removed and immediately fixed in formalin for hematoxylin and eosin (H&E) staining.Results:The percentage of damaged neurons in three Cornuammonisareas of hippocampus was higher inanimal supplemented with MSG compared to controls. At the highest MSG concentration (6 mg/gram),52.1%, 55.2% and 66.0% of neurons from Cornuammonis 1, 2, and 3, respectively were damaged. Thepercentage of neuron damages in hippocampus was in dose-dependent manner.Conclusion: Our data suggested that high dose of MSG increased thehippocampus neuron damages in dosedependenteffect. This suggests the neurotoxicity effect of high dose of MSG.

Neuropathological Correlates of Hyperglycemia During Prolonged Polymicrobial Sepsis in Mice.

Glucose toxicity may play a crucial role in evoking neurologic complications of critical illness. We studied whether the neuropathological alterations in fatal human critical illness observed under hyperglycemia are present and can be attenuated by maintaining normoglycemia in a mouse model of prolonged sepsis induced by cecal ligation and puncture. Mice were randomized to moderate hyperglycemia (>8.3 mmol/L, n = 8) or normoglycemia (4.4-6.7 mmol/L, n = 8). After 5 days, hippocampus and frontal cortex from septic mice were compared with those from healthy controls (n = 8). Blood glucose was 7.8 ± 1.3 mmol/L in hyperglycemic and 6.1 ± 0.7 mmol/L in normoglycemic critically ill mice (P = 0.007). The percentage of damaged neurons was twofold higher in frontal cortex (P = 0.01) and hippocampus (P = 0.06) of hyperglycemic ill mice than that of healthy mice. In frontal cortex, neuronal damage was attenuated under normoglycemia (P = 0.04). Critical illness reduced astrocyte density and activation status fourfold in hippocampus (P ≤ 0.02), but not in frontal cortex, irrespective of glycemic control. Microglia were twofold to fourfold more abundant in both brain areas of hyperglycemic critically ill mice (P ≤ 0.002), but only in frontal cortex were they reduced in number with normoglycemia (P = 0.0008). The density of apoptotic cells and abundance of carbonylated proteins were significantly higher than normal in frontal cortex of hyperglycemic ill mice only (P = 0.05). In a mouse model of prolonged polymicrobial sepsis, remarkable neuropathological changes develop with neuronal damage, impaired astrocyte activation, increased microglia, apoptosis, and accumulation of carbonylated proteins. These changes were partially prevented or attenuated when hyperglycemia was prevented with insulin. Frontal cortex appeared more vulnerable to hyperglycemic insults than hippocampus.

Increasing glucose load while maintaining normoglycemia does not evoke neuronal damage in prolonged critically ill rabbits

Preventing severe hyperglycemia with insulin reduced the neuropathological alterations in frontal cortex during critical illness. We investigated the impact of increasing glucose load under normoglycemia on neurons and glial cells. Hyperinflammatory critically ill rabbits were randomized to fasting or combined parenteral nutrition containing progressively increasing amounts of glucose (low, intermediate, high) within the physiological range but with a similar amount of amino acids and lipids. In all groups, normoglycemia was maintained with insulin. On day 7, we studied the neuropathological alterations in frontal cortex neurons, astrocytes and microglia, and MnSOD as marker of oxidative stress. The percentage of damaged neurons was comparable among all critically ill and healthy rabbits. Critical illness induced an overall 1.8-fold increase in astrocyte density and activation status, largely irrespective of the nutritional intake. The percentage of microglia activation in critically ill rabbits was comparable with that in healthy rabbits, irrespective of glucose load. Likewise, MnSOD expression was comparable in critically ill and healthy rabbits without any clear impact of the nutritional interventions. During prolonged critical illness, increasing intravenous glucose infusion while strictly maintaining normoglycemia appeared safe for neuronal integrity and did not substantially affect glial cells in frontal cortex.

Cerebral protection with trimetazidine in transient brain ischemia in rats

The neuroprotective effect of trimetazidine (TMZ) on ischemic-reperfusion injury was tested by randomized, controlled, prospective study in a rat model of transient global cerebral ischemia. Thirty wistar albino rats were used for study. Animals in TMZ group (n=10) received trimetazidine (3 mg/kg IV bolus) before the occlusion of carotid arteries. A similar volume of saline solution was used in the control group (n=10). The sham group (n=10) were anaesthetized and subjected to operative dissections without vascular occlusion. Physiological parameters, somatosensory evoked potentials (SEP's) were monitored. The neurological outcomes had been clinically evaluated and scored up to 4 days post ischemia. The intergroup differences were compared. Histological observations were clearly correlated with the neurological findings. The percentage of damaged neurons in CA1 and CA3 in subfield of hypochampus 34±6% and 16±6% in the TMZ group, whereas it was 44±5% and 24±5% in the control group (p<0.05). The average neurologic score was significantly better in animals which received TMZ than in the controls at postoperative 24 hours (17.9±1.4 in the TMZ group and 14.9±1.6 in the control group, p<0.05). The results suggest that trimetazidine reduces cerebral injury and preserves neurological function in transient global ischemia in rats.

Cerebral Protection with Trimetazidine in Transient Brain Ischemia in Rats

The neuroprotective effect of trimetazidine (TMZ) on ischemic-reperfusion injury was tested by randomized, controlled, prospective study in a rat model of transient global cerebral ischemia. Thirty wistar albino rats were used for study. Animals in TMZ group (n = 10) received trimetazidine (3 mg/kg IV bolus) before the occlusion of carotid arteries. A similar volume of saline solution was used in the control group (n = 10). The sham group (n = 10) were anaesthetized and subjected to operative dissections without vascular occlusion. Physiological parameters, somatosensory evoked potentials (SEP's) were monitored. The neurological outcomes had been clinically evaluated and scored up to 4 days post ischemia. The intergroup differences were compared. Histological observations were clearly correlated with the neurological findings. The percentage of damaged neurons in CA1 and CA3 in subfield of hypochampus 34 ± 6% and 16 ± 6% in the TMZ group, whereas it was 44 ± 5% and 24 ± 5% in the control group (p < 0.05). The average neurologic score was significantly better in animals which received TMZ than in the controls at postoperative 24 hours (17.9 ± 1.4 in the TMZ group and 14.9 ± 1.6 in the control group, p < 0.05). The results suggest that trimetazidine reduces cerebral injury and preserves neurological function in transient global ischemia in rats.

Threshold of ischemic depolarization for neuronal injury following four-vessel occlusion in the rat cortex.

Previous studies have indicated that prolonging the onset of ischemic depolarization reduces neuronal damage. However, the relationship between the duration of ischemic depolarization and its histological outcome has not been quantitatively evaluated. Rats were anesthetized (with 1% halothane), intubated, and placed in a stereotaxic frame. Direct current (DC)-potential in the 5th layer of the parietal cortex was measured. Changes in cerebral blood flow (CBF) were monitored by a laser-Doppler flow probe placed adjacent to the DC-electrode. Animals were subjected to four-vessel occlusion for 5 minutes, 10 minutes, or 20 minutes. The histological outcome was evaluated at the DC-recorded site 7 days after the insult. Initiation of ischemia reduced CBF to 9%-28% of the preischemic value. Initial DC-deflection (14+/-3 mV), indicating ischemic depolarization, was observed at 172+/-112 seconds after the onset of ischemia. Total durations of ischemic depolarization were 6.4+/-1.5 minutes, 10.6+/-3.5 minutes and 19.8+/-4.6 minutes in rats in which ischemia was induced for 5 minutes, 10 minutes, and 20 minutes, respectively. The regression curve showed that there was a close relationship between percentage of damaged neurons and duration of ischemic depolarization (r2 = 0.80, P = .001). The durations of ischemic depolarization for neuronal injury in 30%, 50%, and 70% of pyramidal neurons in the parietal cortex were 15.6 minutes (95% confidence interval, 14.2-17.0 minutes), 20.3 minutes (18.5-22.7 minutes) and 25.0 minutes (22.7-28.5 minutes), respectively. It is thought that shortening the duration of ischemic depolarization is a rational approach for reducing the severity of ischemic injury.

Neuroprotection by the novel calcium antagonist PCA50938, nimodipine and flunarizine, in gerbil global brain ischemia

Calcium is involved in the physiopathology of cerebral ischemia. Calcium antagonists might prevent the calcium overload and death of cells from ischemically compromised tissue. We compare the neuroprotective effect of various doses (0.2, 0.5 and 1 mg/kg) of two dihydropyridines, nimodipine and the novel 1,4-dihydropyridine derivative PCA50938, and flunarizine in the gerbil model of global ischemia. Improvements in morbidity were observed 2 h after the end of carotid occlusion (McGraw's scale) with 0.5 mg/kg of flunarizine, all doses of PCA50938 and 0.2 mg/kg nimodipine. Neuronal loss in the CA1 sector of the hippocampus was examined. The animals treated with 0.5 mg/kg flunarizine and those treated with 1 mg/kg PCA50938 showed a significant reduction in the percentage of damaged neurons in the hippocampal CA1 area, 72 h after transient ischemia. None of the animals treated with 0.5 mg/kg flunarizine had more than 80% of the evaluated neurons altered. We conclude that PCA50938 and flunarizine may act as neuroprotective drugs with different patterns of dose–response and neuroprotective-morbidity-mortality relationships, in the model of global cerebral ischemia in the gerbil. Flunarizine has a narrow therapeutic range.

Calcium antagonists

Calcium is involved in the physiopathology of cerebral ischemia. Calcium antagonists might prevent the calcium overload and death of cells from ischemically compromised tissue. We compare the neuroprotective effect of various doses (0.2, 0.5 and 1 mg/kg) of two dihydropyridines, nimodipine and the novel 1,4-dihydropyridine derivative PCA50938, and flunarizine in the gerbil model of global ischemia. Improvements in morbidity were observed 2 h after the end of carotid occlusion (McGraw's scale) with 0.5 mg/kg of flunarizine, all doses of PCA50938 and 0.2 mg/kg nimodipine. Neuronal loss in the CA1 sector of the hippocampus was examined. The animals treated with 0.5 mg/kg flunarizine and those treated with 1 mg/kg PCA50938 showed a significant reduction in the percentage of damaged neurons in the hippocampal CA1 area, 72 h after transient ischemia. None of the animals treated with 0.5 mg/kg flunarizine had more than 80% of the evaluated neurons altered. We conclude that PCA50938 and flunarizine may act as neuroprotective drugs with different patterns of dose–response and neuroprotective-morbidity-mortality relationships, in the model of global cerebral ischemia in the gerbil. Flunarizine has a narrow therapeutic range.