Incomplete Cerebral Ischemia Research Articles

Long period changes of hippocampal diffusion kurtosis imaging and its correlation with cognitive dysfunction after incomplete cerebral ischemia-reperfusion in rats.

This study aims to summarize the changes of functional diffusion kurtosis imaging (DKI) parameters in the bilateral hippocampal CA1 region of the hemorrhagic shock reperfusion (HSR) model of rats and their correlation with cognitive dysfunction. Adult male Sprague-Dawley rats (9-10weeks of age, weighing 350-400g) were randomized into the HSR group (n = 30) and the sham-operated group (Sham) (n = 30). Rats in the HSR group and the Sham group were subdivided into five time points (1, 2, 4, 8, and 12weeks) for examination. Diffusion kurtosis imaging (DKI) was performed. Cognitive dysfunction was analyzed by the Morris Water Maze. The correlation between the DKI parameters and cognitive dysfunction was analyzed by the Spearman correlation. In the HSR group, the values of axial kurtosis (Ka), radial kurtosis (Kr), and mean kurtosis (MK) in the bilateral hippocampal CA1 of rats at 1, 2, 4, 8 and 12weeks after the surgery were significantly higher. The rats in the HSR group had significantly longer escape latency than in the Sham group. The rats in the HSR group had significantly shorter time and shorter distance in target quadrant than those in the Sham group. The escape latency had positive correlation with MK, Ka, and Kr. The distance and the time in target quadrant had negative correlation with MK, Ka, and Kr. The parameters get from the DKI could accurately evaluate the abnormal blood perfusion and microstructure changes in hippocampal CA1 area of the incomplete cerebral ischemia reperfusion rats induced by HSR. MK, Ka, and Kr values could reflect the decreased learning and memory ability in HSR rat model.

Long period changes of hippocampal cerebral blood flow and its correlation with anxiety-like behavior and inflammation after incomplete cerebral ischemia reperfusion in rats.

This study was designed to summarize the changes of cerebral blood flow (CBF) in the bilateral hippocampal CA1 region of the hemorrhagic shock reperfusion (HSR) model of rats and their correlation with anxiety-like behavior and inflammation. Rats were randomly divided into the HSR group and the Sham group. 30 rats in each group were subdivided into 5 time points (1 w, 2 w, 4 w, 8 w, and 12 w) for examination. 3D-arterial spin labeling (3D-ASL) was performed. Long period anxiety-like behaviors were analyzed through the open field test. Histopathology was used to detect astrocytic activation in bilateral hippocampus. The concentrations of pro-inflammatory cytokines were analyzed by ELISA. At 1, 2, 4, and 8 weeks, CBF in bilateral hippocampus CA1 area of the rats in the Sham group was significantly higher than the rats in the HSR group. The rats in the HSR group had significantly shorter total traveled distance, lower velocity, and less rearing counts than those in the Sham group at 1, 2, 4, 8, and 12 weeks after the surgery. The CBF at 1, 2, 4, 8, and 12 weeks after the surgery had positive correlation with the total traveled distance, velocity, and rearing counts in the open field test. The rats in the HSR group had significantly higher GFAP intensity and the concentrations of IL-6, IL-1β, and TNF-α than those in the Sham group at 1, 2, 4, 8, and 12 weeks after the surgery. The CBF at 1, 2, 4, 8 and 12 weeks after the surgery had significantly negative correlation with the GFAP intensity and the concentrations of IL-6, IL-1β, and TNF-α. In conclusion, CBF in bilateral hippocampus CA1 area, spatial exploration ability in rats with HSR were decreased while the astrocyte activation was enhanced. During the long period after the induction of HSR, the value of CBF in bilateral hippocampus CA1 area was proved to have significant correlation with anxiety-like behaviors and astrocyte activation.

Changes in the amino acid pool in the rat parietal lobe and hippocampus with incomplete cerebral ischemia

Introduction. Amino acids and their derivatives are involved in synaptic transmission as neurotransmitters and neuromodulators, and some of them are involved in the formation of neurotransmitters of the nervous system. Therefore, the study of the state of the amino acid pool in incomplete cerebral ischemia plays a significant role.The objective was to assess the nature of changes in amino acid pool and evaluate their participation in oxidative processes in rats with incomplete cerebral ischemia.Methods and materials. The experiments were carried out on 16 male outbred white rats weighing 260±20 g in compliance with the requirements of the Directive of the European Parliament and of the Council No. 2010/63/EU of September 22, 2010 on the protection of animals used for scientific purposes.Results. Compared with the indicators in the control group, rats with an ischemic period of 1 hour in the parietal lobe had a decrease in the content of sulfur-containing amino acids: methionine by 12 % and cysteate by 28 %. In addition, there was an increase of L-arginine in the parietal lobe by 39 %, and in the hippocampus – by 56 %.Conclusions. The following changes are characteristic for one-hour incomplete cerebral ischemia: a decrease in the content of sulfur-containing amino acids, with a decrease in both methionine and an increase in the content of L-arginine. Changes in the parietal lobe and hippocampus had a similar nature, except for the absence of a drop in the level of cysteate in the hippocampus, as a reflection of the higher sensitivity of the parietal lobe to oxygen deficiency, compared with the hippocampus.

Changes in the parameters of pro-oxidant–antioxidant balance in the brain of rats with stepwise incomplete cerebral ischemia

Objective: to evaluate the activity of oxidative stress in rats with stepwise incomplete cerebral ischemia (SICI). Material and methods. Experiments were performed on 24 male outbred rats weighing 260±20 g, allocated into 3 subgroups (6 animals in each) based on time of ligation of both common carotid arteries (CCA). The control group comprised of sham-operated rats of the same sex and similar weights (n=6). To identify the pro-oxidant–antioxidant state of the brain based on its homogenates, the activity of lipid peroxidation processes, the content of thiobarbituric acid reactive substances (TBARS), the concentration of reduced glutathione (GSH), total thiol groups (TSH), and the activity of glutathione peroxidase were determined. Results. SICI with ligation interval of both CCAs of 1 day and 3 days led to a significant decrease in the total SH groups of proteins and glutathione by 30% (p=0.038) and 46% (p=0.044), respectively, TBARS concentration by 29% (p=0.038) and 31% (p=0.043), respectively. SICI with the maximum interval between CCA ligations was manifested by less pronounced changes in the pro-oxidant–antioxidant state of the brain. Conclusion. In SICI with ligation of both CCAs 7 days apart, at which histological changes were the least pronounced, changes in the pro-oxidant–antioxidant balance were insignificant. The most pronounced disorders of the pro-oxidant–antioxidant balance in the brain were observed in the subgroup with the minimum interval between CCA ligations, which implied the highest activity of oxidative stress.

Changes of the genome-wide DNA methylation level in various regions of the rat brain with incomplete cerebral ischemia

To quantify genome-wide DNA methylation in the olfactory bulbs, fronto-parietal and occipital regions, and cerebellum in normal male Wistar rats and in modeling incomplete cerebral ischemia caused by permanent bilateral occlusion of the common carotid arteries. The study was performed on 23 male Wistar rats divided into groups: «Sham operation» and «Cerebral ischemia». The level of genome-wide methylation of CCGG sites was determined by methyl-sensitive restriction using MspI/HpaII endonucleases followed by densitometric analysis of electrophoregrams by ImageJ software. Incomplete cerebral ischemia on the 7th day leads to 56.3% (95% CI: 33.2-76.90) mortality. In the surviving rats of the «Cerebral ischemia» group, compared with the animals of the «Sham operation» group, a pronounced neurological deficit was observed, which was accompanied by changes in the level of whole-genome DNA methylation in the nervous tissue of brain structures (p<0.05). Incomplete cerebral ischemia in male Wistar rats was characterized by interhemispheric asymmetry in the severity and direction of the epigenomic reaction of the nervous tissue in both ischemic and non-ischemic areas of the brain. It is likely that it is precisely this dynamics of changes in the status of genome-wide DNA methylation in the nervous tissue that imparts plasticity to neuronal function during ischemic damage.

Structural and Functional Reorganization of the Sensorimotor Cortex During Ligation of the Common Carotid Arteries (Experimental Study)

Aim of the study. To explore the structural and functional changes of neurons, glial cells, and synaptic terminals in layers I, III, and V of the sensorimotor cortex (SMC) of the rat brain after bilateral common carotid artery ligation (CCAL).Material and methods. Incomplete cerebral ischemia was simulated by irreversible bilateral CCAL (2-vessel model of global ischemia without hypotension) on white rats (n=36). Comparative evaluation of the studied SMC structures was performed in the control group (intact rats, n=6) on days 1, 3, 7, 14, and 30 (n=30) after CCAL. Nissl, hematoxylin-eosin staining, and immunohistochemical reactions for NSE, MAP-2, p38, GFAP, and IBA1 were used. Numerical density of pyramidal neurons, astrocytes, oligodendrocytes, microglial cells, and relative area of p38-positive material (synaptic terminals) were determined. Statistical hypotheses were tested using nonparametric methods with Statistica 8.0 software.Results. After CCAL, the number of degenerative neurons in rat brain SMCs increased. The peak of numerical density of unshrunken neurons was detected after day 1. Later, the numerical density of hyperchromic unshrunken neurons decreased, while that of shrunken neurons increased. These parameters did not reach the control values. The changes in SMC neurons were accompanied by an increase in the numerical density of microglial cells after day 1 and its subsequent decrease. Immunohistochemistry for IBA1 revealed signs of microglial cell activation such as change in shape and loss of processes. Maximum increase in the SMC density of oligodendrocytes was observed on day 7, and that of astrocytes on day 14 after CCAL. The maximum number of NSE-positive neurons occurred on day 1 after CCAL. There was a significant decrease in the number of NSEpositive neurons in SMC layer III on days 3, 7, and 14, and an increase in the number of NSE-positive neurons on day 30. The number of NSE-positive neurons in layer V of the SMC progressively decreased throughout the whole study period. The evolution of changes in the proportion of p38-positive material (synaptic terminal area) differed significantly between the layers of SMC. In the layers I and III, this parameter first decreased (days 1 and 3) and then increased (days 7, 14, and 30). In layer V of SMC, the activation of the protein expression was observed in the acute phase (days 1 and 3), then it decreased on days 7 and 14, and increased again on day 30. The changes found in the numerical density of neurons, glial cells and synaptic terminals were associated with dehydration and overhydration of SMC. We found strong to medium significant associations between the relative area of terminals and neuropil swelling and edema zones.Conclusion. After CCAL, layers I, III, and V of the SMC of white rats revealed destructive and compensatory changes in neurons, glial cells, and inter-neuronal communication structures. Taken together, all these changes indicate a significant layer-by-layer variability of the neural tissue response to CCAL. Layer III (secondary projection complex) of the SMC was affected to a greater extent. Reorganization of neuronal-glial and interneuronal interrelations occurred along with a prominent neuropil overhydration.

Comparison of the immunohistochemical and ultrastructural studies of the white rats sensorimotor cortex synaptic terminals reaction to common carotid arteries ligation

The aim of the research was to study the structural and functional changes in axonal terminals in layers I, III, and V of the sensorimotor cortex (SMC) of the brain of Wistar rats after the common carotid artery (CCA) bilateral ligation using immunohistochemical and apparatus-microscopic methods. Material and methods. Incomplete cerebral ischemia was modeled by bilateral ligation of the common carotid arteries (CCA - 2-vessel model of global ischemia without hypotension) in white Wistar rats (n=36). SMC was studied in the control (intact rats, n=6), 1, 3, 7, 14 and 30 days (n=30) after POCA. Nissl, hematoxylin-eosin, immunohistochemical reactions for p38, and electron microscopy were used. The total number density and relative area of axonal terminals were determined. Statistical hypotheses were tested using nonparametric methods for pairwise and multiple comparisons using the Statistica 8.0 program. Results. After CCA bilateral ligation, the content of degeneratively altered neurons in the rat brain SMC increased. Changes in the SMC neurons were accompanied by neuropil hyperhydration and reactive astrogliosis. The total number density of terminals in all SMC layers decreased statistically significantly after 1 day (by 28.6% in layer I, 46.9% in layer III, and 46.4% in layer V) and remained approximately at this level throughout the entire observation period. . The relative area of synaptic terminals differed in the compared SMC layers. In layers I and III of the SMC, the values of this indicator first (days 1 and 3) decreased, and then (days 7, 14, and 30) they increased. In layer V of the SMC, activation of the expression of this protein occurred already in the acute period (days 1 and 3), decreased after 7 and 14 days, and increased again after 30 days. Ultrastructural examination revealed more small terminal axonal branches. However, the general trend of changes in the number of terminals was similar. Conclusion. After CCA bilateral ligation, destructive and compensatory-restorative changes in axonal terminals were revealed in layers I, III, and V of the rat MMC. The reorganization of interneuronal relationships occurred against the background of pronounced manifestations of neuropil hyperhydration. The maximum destruction of synaptic terminals was noted in layer III of the SMC, and their adaptive changes were observed in layer V. The results of immunohistochemical and ultrastructural studies are comparable and complement each other. All this can probably be considered as a structural basis for changes in the integrative-starting activity of the brain after CCA bilateral ligation.

Neuroglial relationships and structures of interneuronal communication of the white rat sensorimotor cortex layer v after the common carotid artery ligation

The aim of research was to study changes in neurons, gliocytes and structures of the interneuronal communication system (dendrites, terminals) of the mature white rat sensorimotor cortex (SMC) layer V after the common carotid artery (CCA) bilateral ligation.Material and methods. Acute/chronic incomplete cerebral ischemia was simulated in white Wistar rats by the CCA bilateral ligation. The brain was fixed by perfusion. A comparative histological, immunohistochemical and morphometric evaluation of the related structures in the norm (n=6), and in 1, 3, 7, 14 and 30 days after the common carotid artery bilateral ligation (n=30) was carried out. Nissl and hematoxylin-eosin stains, immunohistochemical reactions for NSE, MAP-2, p38, GFAP and IBA1 were used. The numerical density of pyramidal neurons, astrocytes, oligodendrocytes, microgliocytes and the relative area of p38-positive material (synapse terminals) were determined. Statistical hypotheses were tested by nonparametric methods using Statistica 8.0 program.Results. CCA bilateral ligation led to the appearance of destructively altered dark, hypochromic, vacuolated neurons and shadow cells in layer V of the SMC. These changes were accompanied by a decreased overall numerical density of pyramidal neurons, hyperhydration of the neuropil (processes of dendrites, astrocytes, and synapses), and a pronounced reaction (hypertrophy, proliferation) of all neuroglial cell types. One day after the CCA bilateral ligation, the appearance of neurons with both reversible and irreversible changes was accompanied by an increase in the layer V relative area of edema-swelling zones in the neuropil of the rat SMC up to 14.5 (10.6– 16.4) %, in control – 7.2 (6.9–7.5) %. The maximum content of destructively altered neurons (25%) was found in the rat SMC layer V one day after ischemia. The total number density of neurons in layer V of the SMC decreased by 27.9% after 30 days (Mann–Whitney U Test; p=0.0001). In the areas of damaged neuron accumulation, the content of astrocytes, microgliocytes, and oligodendrocytes increased. The neuroglial index in the control group was 1.30; it was 1.37 in 3 days, it was 1.50 in 7 days, it was 1.63 in 14 days, and it was 1.30 in 30 days. The maximum increase in the number density of microgliocytes was noted after 1 day (Mann–Whitney U Test; p=0.001), oligodendrocytes – 7 days after CCA ligation (Mann–Whitney U Test; p=0.02). According to the data of immunohistochemical typing of p38, two peaks of the relative area of the terminals were revealed: in the acute period (days 1 and 3) and after 30 days. These quantitative changes were first associated with an increase (on the 1st and 3rd day) and then a decrease in the degree of the neuropil hydration. Negative statistically significant strong correlations were detected in 3 days (R=-0.90) and 7 days (R=-0.70) after CCA ligation. This can be explained by hydropic changes in the terminals (destruction of synapses according to the light type). The total numerical density of neuropil terminals decreased to 102300±19400 (by 35.0%) in 3 days after CCA ligation in layer V of white rats and partially recovered to 135000±27100 (24.4%) after 30 days, compared to the animals of the control (157500±20500 per 1 mm2).Conclusion. Thus, the CCA ligation resulted in destructive and compensatory-restorative changes in the structures of interneuronal communication associated with preservation of a significant part of pyramidal neurons and compensatory reorganization of neuroglial relationships in layer V of white rats.

Changes in respiration of the mitochondrial fraction of brain homogenates in rats with stepwise incomplete cerebral ischemia

Objective: to conduct a comparative analysis of mitochondrial respiration in brain homogenates of rats with stepwise incomplete cerebral ischemia (SICI) with varying duration between ligations of both common carotid arteries (CCA). Material and methods. The experiments were performed on 24 male mongrel white rats weighing 260±20 g. All rats were distributed among three subgroups. Cerebral ischemia was simulated under intravenous thiopental anesthesia (40-50 mg/kg). The control group (n=6) comprised sham-operated rats of similar gender and weight. To study mitochondrial respiration, the brain was extracted in the cold environment (0-4 °C), dried with filter paper, weighed and homogenized sensu the modified technique in an isolation medium containing 0.32 M sucrose, 10 mM Tris-HCl, 1 mM EDTA, pH of 7.4 (in a ratio of 1:10), using Potter – Elvehjem homogenizer with Teflon pestle. Results. SICI with an interval of 1 and 3 days between ligation of both CCA led to neuronal damage in the parietal cortex and hippocampus of rats, which manifested itself in a reduction of the neuron size, deformation of the perikaryons, an increase in the number of shrunken neurons and shadow cells. The most pronounced changes were observed in the subgroup with one-day interval between ligations. These changes were similar to the changes in incomplete cerebral ischemia (ICI) (p=0.07), except for the absence of cells with pericellular edema in the hippocampus and a smaller number of those in the parietal cortex. ICI with seven-day interval between ССА ligations, on the contrary, was manifested by less pronounced histological changes, especially in the hippocampus. Conclusion. Comparative analysis of mitochondrial respiration in brain homogenates revealed that the severity of brain damage in SSIC depended on the interval between blood flow arrest in both CCA. At the same time, the highest level of energy metabolism disorder was observed during CCA ligation with an interval of one day, which implied insufficient implementation of compensatory mechanisms.

METHODS FOR ESTIMATING NEUROLOGICAL DISTURBANCES IN EXPERIMENTAL CEREBRAL ISCHEMIA

Investigation of the brain pathology in experimental ischemia requires adequate methods for assessing the neurological deficit that occurs in laboratory animals, including sensory-based and behavioural disorders. In this research, we aimed to compare motor and behavioural disorders in rats with partial and subtotal experimental cerebral ischemia. The rats modelled with cerebral ischemia are found to exhibit a decrease in muscle strength, resistance to hypoxia, motor and emotional activity. The animals with incomplete cerebral ischemia demonstrated more pronounced sensory-based motor and behavioural disorders compared both with those modelled with partial cerebral ischemia and, in particular, with the control group.

Investigation of Linarinic acid and one of its derivatives against cerebral ischemia in mice

The study aims to investigate the effects of (-)-Linarinic acid (LA) and one of its derivatives (LAd) on brain injury induced by ischemia. Malonaldehyde (MDA) is determined as an index for lipid peroxidation both in vitro and vivo. Mice were pre-treated with LA and LAd for 3 d. Thereafter, they were induced to have incomplete cerebral ischemia with both bilateral carotid artery occlusion and hypotension (BCAOH). In the first part of the in vivo experiment, mice were divided into four groups: sham (control), ischemia, ischemia + LA (200 mg/kg, i.g.) and ischemia + LAd (200 mg/kg, i.g.). In the second part, the dose-response of LAd was investigated at 100, 200 and 400 mg/kg i.g., respectively. A modified neurological severity score was developed for evaluating behavioral deficits of the mice with ischemia. Brains of the mice were excised in order to determinate MDA after ischemia for 6 h. Survival time, survival rate, neurological injury score and MDA level in brains were observed. Results were: 1) The data in vitro showed that both LA and LAd could inhibit the generation of MDA. IC50 values obtained by Probit analysis were 2.9 mM for LAd and 4.88 mM for LA; 2) BCAOH could significantly shorten the survival span, reduce the survival rate and cause neurological deficits, which were associated with high level of lipid hydroperoxide production in cerebral tissues; 3) LAd decreased lipid peroxidation and improved the neurological outcome more than LA. It is concluded that LAd offers a better neuroprotection than LA against brain damage caused by cerebral ischemia.

Cerebroprotective activity of 3-benzylxanthine derivative - compound Ale-15, in conditions of bilateral common carotid arteries ligation (ischemic stroke)

Background: Acute ischemic stroke is a leading cause of mortality, morbidity, long-term disability in industrialized countries. One of main parts of it pathogenesis is production of reactive oxygen species. The accumulation of them in neurons results in lipid peroxidation, protein oxidation, DNA damage, and finally cell death. Thereby the search of novel drugs, that have antioxidant action and can be used to complex treatment of cerebral strokes is reasonable. It is known, that xanthine derivatives exhibit a broad spectrum of biological activity, including antioxidant. So that, the goal of this research was to study in vivo neuroprotective action of water-soluble derivative of 3-benzylxanthine – morpholin-4-ium 3-benzylxanthinyl-8-methylthioacetate (Ale-15 compound) in comparison with neuroprotector-antioxidant – Mexidol. Methods: Experimental part was done on white Wistar rats of both sexes of 220-260 g weight. For assessment of neuroprotective action of compound we used a model of global incomplete cerebral ischemia, that was reproduced by bilateral common carotid arteries ligation. Results: It was studied an acute toxicity of Ale-15 compound, it influence on survival of laboratory animals, on progression of neuralgic deficit, on the content of adenylic nucleotides, on criteria of energy metabolism, on the activity of antioxidant enzymes and on oxidative modification of protein. Results of study showed, that injection of Ale-15 compound to animals with ischemic stroke intragastrically during 4 days positively reduced death rate and quantity of animals with serious neurologic symptoms. The main parts of Ale-15 cerebroprotective mechanism are antioxidant and anti-ischemic actions. Conclusions: The performed study revealed significant cerebroprotective features of Ale-15 compound in conditions of experimental cerebrovascular accident.

Effect of Streptozotocin-Induced Diabetes and Incomplete Global Cerebral Ischemia on Apoptosis in the Rat Thymus

Effect of Streptozotocin-Induced Diabetes and Incomplete Global Cerebral Ischemia on Apoptosis in the Rat Thymus

Volatile anesthetics as a neuroprotective agent

Pharmacologic protection of brain from ischemic insult has been intensively investigated since the early 1960s [1] and a considerable amount of work has been performed to show the effectiveness of various drugs. Among these studies, anesthetic agents, including intravenous and volatile drugs, were shown to be promising agents. In an article published in this issue of the Korean Journal of Anesthesiology, Park et al. [2] present the neuroprotective effect of sevoflurane on forebrain ischemic injury in a rat model. They show the protective effect of sevoflurane in near-complete brain ischemia and the influence of time on the ischemia in the rat brain. In previous studies, the effects of anesthetic agents on ischemic insults were shown to vary depending on the ischemic intensity. Among these studies, Miura et al. [3] demonstrated that isoflurane, ketamine or nitrous oxide and fentanyl had neuroprotective effects against incomplete brain ischemic, but in near-complete global ischemic, only isoflurane was effective. In addition, Park et al. confirmed that in near-complete ischemia, sevoflurane also displayed neuroprotective properties in rats. Volatile anesthetics were shown to be neuroprotective in an acute ischemic rat model. Park et al. performed TUNEL staining, which measures apoptosis of neurons, on the 7th day after ischemic insult and did not observe any differences between the control and sevoflurane group. However, when using an incomplete brain ischemia model, Pape et al. [4] found that sevoflurane had long-term effects on neuronal cell damage and expression of apoptotic factors. Engelhard et al. [5] also investigated the effect of propofol on neuronal ischemia after incomplete cerebral ischemia. They found reduced neuronal cell damage and favorable modulation of apoptosis-regulating proteins over long-term period. But Bayona et al. [6] showed that propofol infusion was protective until 3 days after ischemic insult; however, after 3 weeks there were no differences compared to the control group. Kawaguchi et al. [7] concluded that isoflurane delays but does not prevent cerebral infarction in rats subjected to focal ischemia. In this regard, it seems that the long-term neuroprotective action of anesthetic agents is only effective when the ischemic insult is mild and the neuroprotective effect is not sustained for near-complete ischemic. But these shortterm effects in near-complete ischemia can still save time to allow for the use of other agents directed against apoptosis. Park et al. also demonstrate the effect of ischemic duration on the severity of ischemia. It is reasonable to conclude that shorter duration produces less damage than longer duration. These combined finding indicate that volatile anesthetics are promising agents to prevent neuronal injury during the early ischemic period and provide additional time for the administration of other neuroprotective agents.

Synthesis and antioxidant activity of 3,5-dimethyl-4-hydroxybenzylthiododecane

The new multifunctional antioxidant 3,5-dimethyl-4-hydroxybenzylthiododecane (DHBD) demonstrated high activity both in vitro and in vivo. Experiments in vitro showed that the antioxidant activity of DHBD significantly exceeded that of the well-known reference drug ionol. A course of DHBD administration (100 mg/kg, p.o.) significantly decreased the content of lipid peroxidation products in rat brain on the model of long-term incomplete cerebral ischemia.

Sevoflurane‐induced post‐conditioning has no beneficial effects on neuroprotection after incomplete cerebral ischemia in rats

The aim of this study was to investigate whether sevoflurane-induced post-conditioning has a neuroprotective effect against incomplete cerebral ischemia in rats. After cerebral ischemia by right common carotid artery occlusion in combination with hemorrhagic hypotension (35 mmHg) for 30 min, 1.0 minimum alveolar concentration of sevoflurane was administered for 15 min (Post-C 15, n=8), 30 min (Post-C 30, n=8), or 60 min (Post-C 60, n=8) in rats. Sevoflurane was not administered in control (n=8) and sham control rats (n=8). Neurologic evaluations were performed at 24, 48, and 72 h after ischemia. Degrees of neuronal damage in ischemic hippocampal CA1 and the cortex were assessed by counting eosinophilic neurons, and detection of DNA fragmentation was performed by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining. Neurologic deficit scores in the Post-C 60 group were higher than in the control group at 48 and 72 h post-ischemia (P<0.05). No differences were observed in the percentages of eosinophilic neurons among the control (CA1: 37.3 +/- 25.4, cortex: 26.0 +/- 8.9), Post-C 15 (CA1: 54.0 +/- 21.4, cortex: 30.8 +/- 19.9), or Post-C 30 (CA1: 68.4 +/- 17.5, cortex: 38.0 +/- 11.0) groups in ischemic CA1 and cortices. However, in the Post-C 60 group, the percentages of eosinophilic neurons were higher than in the control group in CA1 and cortices (P<0.05). The percentages of TUNEL-positive cell were similar in the control group and the post-conditioned groups. These findings show that sevoflurane administration after ischemia does not provide neuroprotection in rats subjected to incomplete cerebral ischemia.

Neuroprotective effects of a combination of dexmedetomidine and hypothermia after incomplete cerebral ischemia in rats

Dexmedetomidine and hypothermia are known to reduce neuronal injury following cerebral ischemia. We examined whether a combination of dexmedetomidine and hypothermia reduces brain injury after transient forebrain ischemia in rats to a greater extent than either treatment alone. Thirty-eight male Sprague-Dawley rats were anesthetized with fentanyl and nitrous oxide in oxygen. Four groups were tested: group C (saline 1 ml/kg, temporal muscle temperature 37.5 degrees C); group H (saline 1 ml/kg, 35.0 degrees C); group D (dexmedetomidine 100 microg/kg, 37.5 degrees C); and group DH (dexmedetomidine 100 microg/kg, 35.0 degrees C). Dexmedetomidine or saline was administered intraperitoneally 30 min before ischemia. Cerebral ischemia was produced by right carotid artery ligation with hemorrhagic hypotension (mean arterial pressure 40 mmHg) for 20 min. Neurologic outcome was evaluated at 24, 48, and 72 h after ischemia. Histopathology was evaluated in the caudate and hippocampus at 72 h after ischemia. Neurologic outcome was significantly better in the group DH than the group C (P<0.05), whereas it was similar between the group DH and the groups D or H. Survival rate of the hippocampal CA1 neurons was significantly greater in groups D, H, and DH than group C (P<0.05). Histopathologic injury in the caudate section was significantly less in groups H and DH than group C (P<0.05). The combination of dexmedetomidine and hypothermia improved short-term neurologic outcome compared with the control group, whereas the combination therapy provided comparable neuroprotection with either of the two therapies alone.

Acute Functional Recovery of Cerebral Blood Flow after Forebrain Ischemia in Rat

After complete cerebral ischemia, the postischemic blood flow response to functional activation is severely attenuated for several hours. However, little is known about the spatial and temporal extent of the blood flow response in the acute postischemic period after incomplete cerebral ischemia. To investigate the relative cerebral blood flow (rCBF) response in the somatosensory cortex of rat to controlled vibrissae stimulation after transient incomplete ischemia (15-min bilateral common carotid artery occlusion+hypotension), we employed laser speckle imaging combined with statistical parametric mapping. We found that the ischemic insult had a significant impact on the baseline blood flow (P<0.005) and the activation area in response to functional stimulation was significantly reduced after ischemia (P<0.005). The maximum rCBF response in the activation area determined from the statistical analysis did not change significantly up to 3 h after ischemia (P>0.1). However, the time when rCBF response reached its maximum was significantly delayed (P<0.0001) from 2.4+/-0.2 secs before ischemia to 3.6+/-0.1 secs at 20 mins into reperfusion (P<0.001); the delay was reduced gradually to 2.9+/-0.2 secs after 3 h, which was still significantly greater than that observed before the insult (P=0.04).

Effects of propofol and halothane on long-term potentiation in the rat hippocampus after transient cerebral ischaemia

Propofol is reported to have protective effects on cerebral ischaemia-induced neuronal death. The aim of this study was to explore whether propofol and halothane can protect hippocampal neuronal function from ischaemic injury during general anaesthesia in rats. Rats were divided into 2-vessel occlusion (incomplete cerebral ischaemia) and 4-vessel occlusion (complete cerebral ischaemia) groups consisting of three subgroups each (sham-operated, propofol and halothane groups). One hour after starting propofol 1 mg kg(-1) min(-1) with 30% O2 and N2 or halothane 0.8% in 30% O2 and N2 rats with or without bilateral vertebral artery occlusion had bilateral common carotid arteries occluded by vessel clips for 10 min. Anaesthesia was maintained for another 1 h. Seven days after ischaemia-reperfusion, hippocampal long-term potentiation in the perforant path-dentate gyrus synapse was determined as an index of cerebral outcome. In the propofol groups, the formation of long-term potentiation was significantly impaired in the 2-vessel and 4-vessel occlusion groups compared to the respective sham-operated groups (P < 0.01 and P < 0.05, respectively). Impaired formation of long-term potentiation in propofol groups was comparable to that in halothane groups. The formation of long-team potentiation in the propofol and halothane 2-vessel group was not significantly different from that in the awake 2-vessel group. Propofol and halothane administered during ischaemia do not possess protective effects against hippocampal neuronal dysfunction induced by cerebral ischaemia-reperfusion as evaluated by our transient ischaemic rat models.

Hemodilution with liposome-encapsulated low-oxygen-affinity hemoglobin does not attenuate hypothermic cerebral ischemia in rats

Hypothermia decreases cerebral metabolism and increases hemoglobin oxygen affinity. A hypothesis that the reversal of increased oxygen affinity would further attenuate hypothermic cerebral ischemia was tested by evaluating the effects of liposome-encapsulated hemoglobin (LipoHb) with low oxygen affinity (P50 = 40-50 mmHg) on hypothermic incomplete cerebral ischemia. Wistar rats were randomly assigned to one of the following two groups: (A) exchange transfusion with LipoHb solution (Hb = 6 g/dl) (LipoHb, n = 5), (B) no exchange transfusion (control, n = 5). After surface cooling to 22 degrees C, forebrain ischemia was induced for 15 min by bilateral carotid artery occlusion combined with a decrease in the mean arterial pressure (MAP) to 40 mmHg. (31)P-magnetic resonance spectroscopy was performed during ischemia and 45 min of reperfusion. After reperfusion, MAP was significantly higher in the control group than in the LipoHb group (P < 0.01), although there were no significant differences during ischemia. Intracellular pH and phosphocreatine (PCr) levels decreased during ischemia and returned to the preischemic level in both groups following reperfusion. The LipoHb group had a significantly larger decrease and smaller recovery in PCr than the control group (P < 0.0001). Althouth beta-adenosine triphosphate decreased during ischemia in the LipoHb group, it increased in the control group (P < 0.0001). Inorganic phosphate (Pi) increased during ischemia and decreased to the normal value after reperfusion. The LipoHb group experienced a significantly larger production of Pi than the control group (P = 0.02). Hemodilution with high-P50 LipoHb does not reduce ischemic energy depletion induced by hypothermic incomplete forebrain ischemia in rats.