Pathogenesis Of Brain Damage Research Articles

Сhanges of trace elements in the cerebellum and their influence on the rats behavior in elevated plus maze in the acute period of mild blast-induced brain injury

BackgroundIn connection with the widespread use of explosive devices in military conflicts, in particular in Ukraine, is relevant to detect the biometals changes in the cerebellum and determine the presence of their influence on the behavior changes of rats in the elevated plus maze in the acute period of a mild blast-traumatic brain injury (bTBI). MethodsThe selected rats were randomly divided into 3 groups: Group I - Experimental with bTBI (with an excess pressure of 26–36 kPa), Group II - Sham and Group III - Intact. Behavior studies was in the elevated plus maze. Brain spectral analysis was with using of energy dispersive X-ray fluorescence analysis, after obtaining the quantitative mass fractions of biometals, the ratios of Cu/Fe, Cu/Zn, Zn/Fe were calculated and the data between the three groups were compared. ResultsThe results showed an increase in mobility in the experimental rats, which indicates functional disorders of the cerebellum in the form of maladaptation in space. Changes in cognitive activity also is an evidence of cerebellum suppression, which is indicated by changes in vertical locomotor activity. Grooming time was shortened. We established a significant increase in Cu/Fe and Zn/Fe ratios in the cerebellum, a decrease in Cu/Zn. ConclusionsChanges in the Cu/Fe, Cu/Zn, and Zn/Fe ratios in the cerebellum correlate with impaired locomotor and cognitive activity in rats in the acute posttraumatic period. Accumulation of Fe on the 1st and 3rd day leads to disturbance of the Cu and Zn balance on the 7th day and starts a "vicious cycle" of neuronal damage. Cu/Fe, Cu/Zn, and Zn/Fe imbalances are secondary factors in the pathogenesis of brain damage as a result of primary bTBI.

Microwave Radiothermometry in Evaluating Brain Temperature Changes (Review)

Aim. This review aims to inform physicians of different specialties (anesthesiologists, intensivists, neurologists, neurosurgeons, oncologists) about the diagnostic capabilities of microwave radiothermometry, which enables to identify and analyze features of alterations of cerebral temperature in brain damage.The review displays a critical analysis of 80 recent Russian and foreign open access publications found by keywords.The review presents major clinical features and pathophysiological mechanisms of cerebral thermal balance disruptions in brain lesions. Slow responsiveness and vulnerability of cerebral thermal homeostasis regulation mechanisms that underlie development of different temperature heterogeneity levels in the cerebral cortex in healthy brain and brain lesions are highlighted. The authors postulate their concept about the critical role of hyperthermia in the pathogenesis of brain damage and disruption of interconnections in the global central regulation system. A body of evidence explaining direct association between the depth of consciousness impairment and degree of cerebral cortex temperature heterogeneity manifestation is presented. It is emphasized that a significant increase in temperature heterogeneity with areas of focal hyperthermia accompanies an acute period of ischemic stroke, while in post-comatose state usually associated with prolonged impairment of consciousness, the temperature heterogeneity significantly subsides. It has been suggested that lowering of an increased and rising of the reduced temperature heterogeneity, for example by using temperature exposure, can improve altered level of consciousness in patients with brain damage. The diagnostic capabilities of various technologies used for cerebral temperature measurement, including microwave radiothermometry (MWR), are evaluated. Data on high accuracy of MWR in measurement of the cerebral cortex temperature in comparison with invasive methods are presented.Conclusion. In healthy individuals MWR revealed a distinct daily rhythmic changes of the cerebral cortex temperature, and badly violated circadian rhythms in patients with brain lesions. Since MWR is an easy-toperform, non-invasive and objective diagnostic tool, it is feasible to use this technology to detect latent cerebral hyperthermia and assess the level of temperature heterogeneity disruption, as well as to study the circadian rhythm of temperature changes.

Molecular mechanisms of neuronal death in brain injury after subarachnoid hemorrhage.

Subarachnoid haemorrhage (SAH) is a common cerebrovascular disease with high disability and mortality rates worldwide. The pathophysiological mechanisms involved in an aneurysm rupture in SAH are complex and can be divided into early brain injury and delayed brain injury. The initial mechanical insult results in brain tissue and vascular disruption with hemorrhages and neuronal necrosis. Following this, the secondary injury results in diffused cerebral damage in the peri-core area. However, the molecular mechanisms of neuronal death following an aneurysmal SAH are complex and currently unclear. Furthermore, multiple cell death pathways are stimulated during the pathogenesis of brain damage. Notably, particular attention should be devoted to necrosis, apoptosis, autophagy, necroptosis, pyroptosis and ferroptosis. Thus, this review discussed the mechanism of neuronal death and its influence on brain injury after SAH.

Alteration of circulating unconventional T cells in cerebral ischemia: an observational study

Immune reactions provoked by cerebral ischemia play crucial roles in the pathogenesis of brain damage and contribute to tissue regeneration processes. While functions of many immune cell types in post-ischemic inflammation have been well studied in experimental stroke, the exact roles played by unconventional T cells in pathogenesis of the clinical stroke remain to be precisely determined. In the present study, we investigated the frequencies and absolute cell numbers of peripheral blood T lymphocyte subpopulations including those of invariant natural killer T (iNKT) cells, CD3+CD56+ NKT-like (NKTL) cells, and γδ T cells from patients with acute cerebral infarction (ACI), chronic cerebrovascular disease (CCD) or chronic cerebral circulation insufficiency (CCI) by flow cytometry, and analyzed their association with the disease severity and the clinical outcome. We observed significantly reduced cell numbers of circulating iNKT cells, NKTL cells and γδ T cells in cerebral ischemia patients as compared with the healthy controls. Of note, we also demonstrated that numbers of peripheral blood iNKT and γδ T cells are significantly reduced in patients with ACI when compared among different cerebral ischemia patient groups. Moreover, the reduced number of iNKT cells is significantly associated with the disease severity and recovery in cerebral ischemia patients. Our results demonstrate for the first time the reduction of peripheral blood NKTL, iNKT and γδ T cells in patients with the cerebral ischemia, and particularly reduced iNKT and γδ T cells in the acute phase. The reduction of iNKT cells seems to be significantly associated with the disease severity and recovery. We hope that our findings might lead to the identification of predictive and prognostic values of human peripheral unconventional T cell subsets in the cerebral ischemia.

Global DNA Methylation Of Brain Neurons In Acute Poisoning With Clozapine And Its Combination With Alcohol: An Experimental Study

Background — Acute poisoning with atypical neuroleptic clozapine is characterized by rapid progression, high risk of death and severe neurological manifestations. Neurotoxic effects of this pharmaceutical drug have also been reported at therapeutic doses. The pathogenesis of brain damage in acute clozapine poisoning is not fully understood. Changes in DNA methylation level may play an important role in the mechanisms of drug neurotoxicity. The available data on the effect of clozapine on brain cell DNA provide a rationale for studying the epigenetic aspects of the pathogenesis of acute poisoning with this neuroleptic agent. The objective of our study was to evaluate the global DNA methylation level in rat brain neurons in acute poisoning with clozapine and its combination with ethanol. Material and methods — Clozapine – 150 mg/kg in 2.0 ml of normal saline solution, or clozapine – 150 mg/kg in 2.0 ml of 40% ethanol were administered via a gastric tube to adult male Wistar rats (n=21) under anesthesia with sevoflurane. In the control group, saline was administered via a gastric tube. Animals were euthanized four hours after drug administration. Autopsy was performed with the collection of brain samples for histochemical examination and determination of the DNA methylation level using the fluorometric method. To detect DNA in sections of paraffin-embedded tissue, we used the Feulgen staining. The TUNEL method was employed to detect DNA fragmentation. Results — An increase in the level of global DNA methylation in brain neurons was found in the clozapine and clozapine+ethanol groups. The average level of methylated DNA in the clozapine+ethanol group was higher than in the control group or clozapine group (2.56±0.31 vs. 1.35±0.1, p=0.007 and 1.70±0.33, p=0.044, respectively). An increase in the mean optical density of the cortical neuron nuclei was observed in the clozapine+ethanol group compared with the control group and clozapine group. DNA fragmentation was not detected in any experimental group. Conclusion — Acute poisoning with clozapine in combination with alcohol caused an increase in the global DNA methylation level in brain neurons, which may have played a significant role in the pathogenesis of acute clozapine poisoning and could be an important factor in the neurotoxicity of this medication.

Molecular Mechanisms of Proteins - Targets for SARS-CoV-2 (Review).

The rapidly accumulating information about the new coronavirus infection and the ambiguous results obtained by various authors necessitate further research aiming at prevention and treatment of this disease. At the moment, there is convincing evidence that the pathogen affects not only the respiratory but also the central nervous system (CNS).The aim of the study is to provide an insight into the molecular mechanisms underlying the damage to the CNS caused by the new coronavirus SARS-CoV-2.Results.By analyzing the literature, we provide evidence that the brain is targeted by this virus. SARS-CoV-2 enters the body with the help of the target proteins: angiotensin-converting enzyme 2 (ACE2) and associated serine protease TMPRSS2 of the nasal epithelium. Brain damage develops before the onset of pulmonary symptoms. The virus spreads through the brain tissue into the piriform cortex, basal ganglia, midbrain, and hypothalamus. Later, the substantia nigra of the midbrain, amygdala, hippocampus, and cerebellum become affected. Massive death of neurons, astrogliosis and activation of microglia develop at the next stage of the disease. By day 4, an excessive production of proinflammatory cytokines in the brain, local neuroinflammation, breakdown of the blood-brain barrier, and impaired neuroplasticity are detected. These changes imply the involvement of a vascular component driven by excessive activity of matrix metalloproteinases, mediated by CD147. The main players in the pathogenesis of COVID-19 in the brain are products of angiotensin II (AT II) metabolism, largely angiotensin 1-7 (AT 1-7) and angiotensin IV (AT IV). There are conflicting data regarding their role in damage to the CNS in various diseases, including the coronavirus infection.The second participant in the pathogenesis of brain damage in COVID-19 is CD147 — the inducer of extracellular matrix metalloproteinases. This molecule is expressed on the endothelial cells of cerebral microvessels, as well as on leukocytes present in the brain during neuroinflammation. The CD147 molecule plays a significant role in maintaining the structural and functional integrity of the blood-brain barrier by controlling the basal membrane permeability and by mediating the astrocyte-endothelial interactions. Via the above mechanisms, an exposure to SARS-CoV-2 leads to direct damage to the neurovascular unit of the brain.

Lupus serum IgG induces microglia activation through Fc fragment dependent way and modulated by B-cell activating factor

BackgroundNeuropsychiatric manifestations are frequent in patients with systemic lupus erythematosus (SLE), yet the etiology and pathogenesis of brain damage in SLE remains unclear. Because the production of autoantibodies, formation and deposition of immunocomplexes are major serological characteristics of SLE, the elevated level of serum immunoglobulin may contribute to brain tissue injury of SLE. To testify this, in this study, we examined whether immunoglobulin G (IgG) in the serum of SLE patients affects the cellular functions in central nervous system and the potential mechanism.MethodsIn vivo intracerebral injection of SLE-serum in mouse was used to activate microglia and the production of pro-inflammatory cytokine was assessed by ELISA. Sera was divided into IgG and IgG depleted fractions, while IgG was further divided into Fc and Fab fragments to examine which part has an effect on microglia. Flow cytometry, immunofluorescence and quantitative PCR (qPCR) were used to verify the synergistic effect of B-cell activating factor (BAFF) on IgG stimulation of microglia.ResultsWe found that IgG in lupus sera can induce M1 activation of brain microglia following intraventricular injection into normal mice, and BAFF facilitates this process. In vitro, we identified that IgG bound to microglia through Fc rather than Fab fragments, and BAFF up-regulated the expression of Fc receptors (FcγR) on the surface of microglia, consequently, promote IgG binding to microglia.ConclusionOur results suggest that lupus serum IgG causes inflammatory responses of microglia by involving the Fc signaling pathway and the activity could be up-regulated by BAFF. Accordingly, disruption of the FcγR-mediated signaling pathway and blockade of microglia activation may be a therapeutic target in patients with neuropsychiatric lupus erythematosus.

Magnetic resonance imaging and magnetic resonance venography features in heat stroke: a case report

BackgroundHeat stroke (HS) is a critical illness that can cause multiple organ dysfunction, including damage to the central nervous system (CNS), which can be life-threatening in severe cases. Brain lesions in patients with HS who present with CNS damage have been rarely reported before, and they usually vary in different cases, hence, patients with such lesions may present a clinical challenge in terms of diagnosis and management. Cerebral venous thrombosis (CVT) is a rare cause of stroke that mostly affects young individuals and children. The pathogenesis of brain damage caused by HS is complex, and CVT may be involved in the pathogenesis of HS with CNS damage. In this manuscript, we have reported a case of a patient with HS having CVT with symmetrical lesions in the bilateral putamen, posterior limb of the internal capsule, external capsule, insular lobe, and subcortical white matter in the brain.Case presentationWe encountered a 48-year-old man who presented with HS in the summer season. During admission, he had a high body temperature and was in coma and shock. Then, he developed rhabdomyolysis syndrome, acute kidney and liver damage, electrolyte imbalance, and acid–base balance disorders, and his D-dimer level was elevated. After several days of anti-shock treatment, the patient’s level of consciousness improved. However, he experienced a decline in vision. Cerebral magnetic resonance imaging (MRI) showed symmetrical lesions in the bilateral posterior limb of the internal capsule, putamen, external capsule, insula, and subcortical white matter, and cerebral magnetic resonance venography (MRV) showed the development of CVT. Therefore, anti-coagulation treatment was provided. After timely clinical intervention, the symptoms of the patient gradually improved.ConclusionsThis case showed that HS can cause CVT. Therefore, cerebral MRI findings in HS must be assessed; in addition, early MRV can help in the diagnosis of the disease, which can effectively improve prognosis.

Brain Perfusion Imaging in Neonates: An Overview.

The development of cognitive function in children has been related to a regional metabolic increase and an increase in regional brain perfusion. Moreover, brain perfusion plays an important role in the pathogenesis of brain damage in high-risk neonates, both preterm and full-term asphyxiated infants. In this article, we will review and discuss several existing imaging techniques for assessing neonatal brain perfusion.

Сучасні аспекти патогенезу ураження головного мозку в дітей, котрі народилися з екстремально низькою масою тіла

Сучасні аспекти патогенезу ураження головного мозку в дітей, котрі народилися з екстремально низькою масою тіла

Platelet-mediated changes to neuronal glutamate receptor expression at sites of microthrombosis following experimental subarachnoid hemorrhage.

Glutamate is important in the pathogenesis of brain damage after cerebral ischemia and traumatic brain injury. Notably, brain extracellular and cerebrospinal fluid as well as blood glutamate concentrations increase after experimental and clinical trauma. While neurons are one potential source of glutamate, platelets also release glutamate as part of their recruitment and might mediate neuronal damage. This study investigates the hypothesis that platelet microthrombi release glutamate that mediates excitotoxic brain injury and neuron dysfunction after subarachnoid hemorrhage (SAH). The authors used two models, primary neuronal cultures exposed to activated platelets, as well as a whole-animal SAH preparation. Propidium iodide was used to evaluate neuronal viability, and surface glutamate receptor staining was used to evaluate the phenotype of platelet-exposed neurons. The authors demonstrate that thrombin-activated platelet-rich plasma releases glutamate, at concentrations that can exceed 300 μM. When applied to neuronal cultures, this activated plasma is neurotoxic, and the toxicity is attenuated in part by glutamate receptor antagonists. The authors also demonstrate that exposure to thrombin-activated platelets induces marked downregulation of the surface glutamate receptor glutamate receptor 2, a marker of excitotoxicity exposure and a possible mechanism of neuronal dysfunction. Linear regression demonstrated that 7 days after SAH in rats there was a strong correlation between proximity to microthrombi and reduction of surface glutamate receptors. The authors conclude that platelet-mediated microthrombosis contributes to neuronal glutamate receptor dysfunction and might mediate brain injury after SAH.

Foetal alcohol spectrum disorder

Since the first description of the foetal damage of alcohol in 1967, numerous studies have outlined different aspects of neurodevelopmental dysfunction, adversely affecting the lives of children worldwide. Although the cause of the syndrome is sorted out, the pathogenesis of brain damage is far from being clear. In contrast to children exhibiting the full facial dysmorphology, who are relatively easy to diagnose, in those presenting only with alcohol-related neurodevelopmental damage diagnosis is much more challenging due to poor specificity of the brain dysfunction. Hence, identifying the neurodevelopmental phenotype of foetal alcohol spectrum disorder (FASD) is a major challenge. Recently, a behavioural phenotype of FASD has been described and validated using items from the Child Behaviour Checklist. This tool has high sensitivity and specificity in separating children with FASD from those with ADHD and from healthy controls. In parallel, a number of intervention studies show promise in improving the abilities of children and adolescents with the syndrome to cope with daily tasks and improve their quality of life. The neurobehavioural screening test can facilitate screening for FASD and is an official screening tool in the FASD toolkit of the Public Health Agency of Canada. Promising new interventions may attenuate the long-term outcome of these children.

Abstract TP266: Platelet-Derived Glutamate Contributes to Neuronal Injury after Experimental Subarachnoid Hemorrhage

Background: Glutamate toxicity (excitotoxicity) is well-studied in the pathogenesis of brain damage after cerebral ischemia and traumatic brain injury. Patients with subarachnoid hemorrhage (SAH) also have increased intracerebral glutamate as detected by microdialysis. While neurons and glia are potential sources of glutamate, platelets also release glutamate as part of their recruitment and might mediate neuronal damage. Studies have shown that intraluminal platelets escape into brain parenchyma after SAH. Therefore, we studied the hypothesis that formation of platelet microthrombi after SAH, and their subsequent extravasation releases glutamate that mediates excitotoxic brain injury and neuron dysfunction after SAH. Methods: We used two models, primary neuronal cultures exposed to activated platelets, and a model of SAH created by injection of 300 μl of fresh, unheparinized arterial blood into the prechiasmatic cistern of Sprague-Dawley rats (300-350 g). Glutamate was measured using amperometric microelectrode arrays. Propidium iodide was used to evaluate neuronal viability in neuronal cultures, and surface glutamate receptor immunohistochemical staining was used to evaluate the phenotype of platelet-exposed cultured neurons and brain after SAH. Microthrombi were stained with anti-fibrinogen antibodies. Results: We first demonstrated that thrombin-activated platelet-rich plasma releases glutamate in concentrations that exceed 300 μmol/l. When applied to neuronal cultures, this activated plasma was neurotoxic, and neurotoxicity was attenuated by glutamate receptor antagonism. Exposure of cultured neurons to thrombin-activated platelets induced a marked downregulation of the surface glutamate receptor GluR2, a marker of excitotoxicity and a possible mechanism of neuron dysfunction. Microthrombi were detected in rat cerebral cortex 7 days after SAH and linear regression demonstrated a strong correlation between proximity to microthrombi and reduction of surface glutamate GluR2 receptors. Conclusions: These correlative data support the novel hypothesis that platelet-mediated microthrombosis contributes to neuronal glutamate receptor dysfunction and might therefore influence clinical outcome following SAH.

Posterior Circulation Stroke: Animal Models and Mechanism of Disease

Posterior circulation stroke refers to the vascular occlusion or bleeding, arising from the vertebrobasilar vasculature of the brain. Clinical studies show that individuals who experience posterior circulation stroke will develop significant brain injury, neurologic dysfunction, or death. Yet the therapeutic needs of this patient subpopulation remain largely unknown. Thus understanding the causative factors and the pathogenesis of brain damage is important, if posterior circulation stroke is to be prevented or treated. Appropriate animal models are necessary to achieve this understanding. This paper critically integrates the neurovascular and pathophysiological features gleaned from posterior circulation stroke animal models into clinical correlations.

Matrix metalloproteinases in intracerebral hemorrhage

Purpose: The objective of this study is to review the role of matrix metalloproteinases in intracerebral hemorrhage, which is associated with hypertension, head trauma and premature birth.Materials and methods: A PubMed search of literature pertaining to this study was conducted in April 2008 using specific keyword search terms pertaining to intracerebral hemorrhage and matrix metalloproteinases. Some papers are not cited here as it is not possible to be all inclusive or due to the space limit from the journal.Discussion: The prognosis following ICH is more detrimental than that of ischemic strokes. Matrix metalloproteases have been implicated in the pathogenesis of brain damage following ICH. The goal of this review is to bring together recent diverse data concerning the roles of matrix metalloproteinases after intracerebral hemorrhage, which includes the role of matrix metalloproteinases in central nervous system, matrix metalloproteinases in animal models and humans of intracerebral hemorrhage, the relationship between matrix metalloproteinases and neuroinflammation, neuronal death, blood–brain barrier disruption and interaction with other molecules, as well as treatment of intracerebral hemorrhage with anti-matrix metalloproteinases agents. Besides deleterious roles in the acute period of intracerebral hemorrhage, some matrix metalloproteinases function in the later stages following intracerebral hemorrhage may have beneficial remodeling activity.Conclusion: At present, the experimental data support the use of pharmacologic anti-matrix metalloproteinases strategies in the acute periods following intracerebral hemorrhage to alleviate injury.

Relationships between free radical levels during carotid endarterectomy and markers of arteriosclerotic disease

Free radical production is elevated in jugular venous blood emerging from the brain in conjunction with carotid endarterectomy. This study explores the relationships between markers for lesion progression in arteriosclerosis, production of radicals and clinical characteristics. The radical production during carotid endarterectomy was studied in 13 patients with an ex vivo spin trap method using OXANOH as a spin trap. MCP-1, ICAM-1, MMP-9 and oxLDL were determined in venous blood samples before, during and after clamping of the carotid artery. Principal component analysis (PCA) as well as partial least square regression analysis (PLS) was applied to interpret the data. PCA and PLS analysis revealed that high values of MMP-9 and low values of ICAM-1 were associated with high radical production whereas MCP-1 and oxLDL were not correlated to radical production. MMP-9 was elevated at diabetes, high haemoglobin, high leucocyte counts and thrombocyte counts as well as at contralateral stenosis, whereas ICAM-1 showed reversed relationships to these clinical variables. MCP-1 increased during surgery. The main finding in our study is that MMP-9 in plasma is asscociated with radical production during carotid endarterectomy, suggesting that this enzyme might be involved in the pathogenesis of brain damage in conjunction with ischaemia-reperfusion.

Chronic administration of ethyl docosahexaenoate decreases mortality and cerebral edema in ischemic gerbils

Dietary docosahexaenoic acid (DHA) intake can decrease the level of membrane arachidonic acid (AA), which is liberated during cerebral ischemia and implicated in the pathogenesis of brain damage. Therefore, in the present study, we investigated the effects of chronic ethyl docosahexaenoate (E-DHA) administration on mortality and cerebral edema induced by transient forebrain ischemia in gerbils. Male Mongolian gerbils were orally pretreated with either E-DHA (100, 150 mg/kg) or vehicle, once a day, for 4 weeks and were subjected to transient forebrain ischemia by bilateral common carotid occlusion for 30 min. The content of brain lipid AA at the termination of treatment, the survival ratio, change of regional cerebral blood flow (rCBF), brain free AA level, thromboxane B 2 (TXB 2) production and cerebral edema formation following ischemia and reperfusion were evaluated. E-DHA (150 mg/kg) pretreatment significantly increased survival ratio, prevented post-ischemic hypoperfusion and attenuated cerebral edema after reperfusion compared with vehicle, which was well associated with the reduced levels of AA and TXB 2 in the E-DHA treated brain. These data suggest that the effects of E-DHA pretreatment on ischemic mortality and cerebral edema could be due to reduction of free AA liberation and accumulation, and its metabolite synthesis after ischemia and reperfusion by decreasing the content of membrane AA.

Does Thrombin Play a Role in the Pathogenesis of Brain Damage After Periventricular Hemorrhage?

Neonatal periventricular hemorrhage (PVH) is a devastating complication of prematurity in the human infant. Based upon observations made primarily in adult rodents and the fact that the immature brain uses proteolytic systems for cell migration and growth, we hypothesized that thrombin and plasmin enzyme activities contribute to the brain damage after PVH. The viability of mixed brain cells derived from newborn rat periventricular region was suppressed by whole blood and thrombin, but not plasmin. Following injection of autologous blood into the periventricular region of newborn rat brain, proteolytic activity was detected in a halo around the hematoma using membrane overlays impregnated with thrombin and plasmin fluorogenic substrates. Two-day old rats received periventricular injection of blood, thrombin, and plasminogen. After 2 days, thrombin and blood were associated with significantly greater damage than saline or plasminogen. Two-day old mice received intracerebral injections of blood in combination with saline or the proteolytic inhibitors hirudin, alpha2macroglobulin, or plasminogen activator inhibitor-1. After 2 days, hirudin significantly reduced brain cell death and inflammation. Two-day-old mice then received low and high doses of hirudin mixed with blood after which behavioral testing was conducted repeatedly. At 10 weeks there was no statistically significant evidence for behavioral or structural brain protection. These results indicate that thrombin likely plays a role in neonatal periventricular brain damage following PVH. However, additional factors are likely important in the recovery from this result.

Blockade of NMDA receptor subtype NR2B prevents seizures but not apoptosis of dentate gyrus neurons in bacterial meningitis in infant rats

BackgroundExcitotoxic neuronal injury by action of the glutamate receptors of the N-methyl-d-aspartate (NMDA) subtype have been implicated in the pathogenesis of brain damage as a consequence of bacterial meningitis. The most potent and selective blocker of NMDA receptors containing the NR2B subunit is (R,S)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperid inepropanol (RO 25-6981). Here we evaluated the effect of RO 25-6981 on hippocampal neuronal apoptosis in an infant rat model of meningitis due to Streptococcus pneumoniae. Animals were randomized for treatment with RO 25-6981 at a dosage of either 0.375 mg (15 mg/kg; n = 28) or 3.75 mg (150 mg/kg; n = 15) every 3 h or an equal volume of sterile saline (250 μl; n = 40) starting at 12 h after infection. Eighteen hours after infection, animals were assessed clinically and seizures were observed for a period of 2 h. At 24 h after infection animals were sacrificed and brains were examined for apoptotic injury to the dentate granule cell layer of the hippocampus.ResultsTreatment with RO 25-6981 had no effect on clinical scores, but the incidence of seizures was reduced (P < 0.05 for all RO 25-6981 treated animals combined). The extent of apoptosis was not affected by low or high doses of RO 25-6981. Number of apoptotic cells (median [range]) was 12.76 [3.16–25.3] in animals treated with low dose RO 25-6981 (control animals 13.8 [2.60–31.8]; (P = NS) and 9.8 [1.7–27.3] (controls: 10.5 [2.4–21.75]) in animals treated with high dose RO 25-6981 (P = NS).ConclusionsTreatment with a highly selective blocker of NMDA receptors containing the NR2B subunit failed to protect hippocampal neurons from injury in this model of pneumococcal meningitis, while it had some beneficial effect on the incidence of seizures.

Heat shock proteins expression in brain stem after subarachnoid hemorrhage in rats.

The pathogenesis of brain damage after subarachnoid hemorrhage (SAH) especially at molecular or gene level remains unclear. We used complimentary deoxyribonucleic acid (cDNA) macroarray technique and compared gene expression in brain stem after experimental SAH in rats. The upregulation of several heat shock proteins (HSPs) demonstrated by cDNA array was further confirmed by Western blotting. The expressions of 9 genes were upregulated 30 minutes or 2 days after SAH. They included four upregulated HSPs: HSP90alpha, HSP60, HSP27, and HSP10. Western blotting demonstrated increases in the HSP27 and HSP10 proteins on Day 2. SAH enhanced the induction of several HSP mRNAs in the brainstems, even though the functions of these HSPs after SAH remain unclear.