Degree Of Neuronal Damage Research Articles

Changes of Nuclear Factor Kappa-B Pathway Activity in Hippocampus After Acute Carbon Monoxide Poisoning and Its Role in Nerve Cell Injury.

Acute carbon monoxide poisoning (ACOP) causes tissue hypoxia and damage mainly by binding to hemoglobin (Hb). This article aimed to explore the changes in the activity of nuclear factor kappa-B (NF-κB) pathway in the hippocampus after ACOP and its role in nerve cell damage. This article used 30 Sprague-Dawley (SD) rats as the research object, which were randomly divided into two groups, ACOP group and controls. The model of carbon monoxide (CO) poisoning was established, and then the activity of NF-κB pathway in the hippocampus of the two groups of rats was detected, and the statistical analysis was performed. Compared with the controls, the activity of NF-κB pathway in the hippocampus of the ACOP group was significantly increased (P < 0.05). The degree of neuronal damage in the ACOP group was also significantly increased. ACOP increases the activity of the NF-κB pathway in the hippocampus and may cause neuronal damage through this pathway. This provides new ideas and methods for the treatment of ACOP, and also provides new evidence for the role of NF-κB pathway in neuronal injury.

Spatial amine metabolomics and histopathology reveal localized brain alterations in subacute traumatic brain injury and the underlying mechanism of herbal treatment.

Spatial changes of amine metabolites and histopathology of the whole brain help to reveal the mechanism of traumatic brain injury (TBI) and treatment. A newly developed liquid microjunction surface sampling-tandem mass tag-ultra performance liquid chromatography-mass spectrometry technique is applied to profile brain amine metabolites in five brain regions after impact-induced TBI at the subacute stage. H&E, Nissl, and immunofluorescence staining are performed to spatially correlate microscopical changes to metabolic alterations. Then, bioinformatics, molecular docking, ELISA, western blot, and immunofluorescence are integrated to uncover the mechanism of Xuefu Zhuyu decoction (XFZYD) against TBI. Besides the hippocampus and cortex, the thalamus, caudate-putamen, and fiber tracts also show differentiated metabolic changes between the Sham and TBI groups. Fourteen amine metabolites (including isomers such as L-leucine and L-isoleucine) are significantly altered in specific regions. The metabolic changes are well matched with the degree of neuronal damage, glia activation, and neurorestoration. XFZYD reverses the dysregulation of several amine metabolites, such as hippocampal Lys-Phe/Phe-Lys and dopamine. Also, XFZYD enhances post-TBI angiogenesis in the hippocampus and the thalamus. This study reveals the local amine-metabolite and histological changes in the subacute stage of TBI. XFZYD may promote TBI recovery by normalizing amine metabolites and spatially promoting dopamine production and angiogenesis.

Network pharmacology and the experimental findings of Bushenhuoxue formula for improving hippocampal neuron injury in vascular demented rats.

We used network pharmacology to predict the correlation between the pathway of Bushenhuoxue formula in the treatment of vascular dementia and carried out experiments to verify the correlation between drug composition and disease. By screening the active components and key targets through various databases and drawing the topological network diagram, we obtained 502 effective compound targets, 601 disease targets, 95 disease-related compound targets, and 162 pathways. The pathway related to vascular dementia may be neurodegeneration-multiple diseases, PI3K-Akt signaling pathway, Mitogen-activated protein kinase signaling pathway, or HIF-1 signaling pathway. By detecting the learning and memory ability of vascular dementia rats, the morphology of the hippocampus under the electron microscope, the degree of neuronal damage, and autophagy-related proteins, the results showed that the Bushenhuoxue formula could improve the neuronal injury induced by ischemia in the hippocampus, down-regulate the level of autophagy, and thereby improve learning and memory. Therefore, the Bushenhuoxue formula may improve the ischemic injury of neurons by regulating the mechanism of neuronal autophagy.

Ефективність, безпека та переносимість комбінації електролітів і цитиколіну (Нейроцитин®) у комплексному лікуванні пацієнтів із гострим ішемічним інсультом

Подані результати дослідження ефективності, безпеки та переносимості одного з найбільш відомих церебропротекторів (цитиколін) у комбінації з електролітами (Нейроцитин®) у комплексному лікуванні пацієнтів із гострим ішемічним інсультом. Матеріали та методи. Обстежено 55 пацієнтів з гострим ішемічним інсультом віком від 40 до 75 років. Хворі були рандомізовані на 2 групи: у контрольній групі (КГ) пацієнти отримували стандартну терапію, в основній групі (ОГ) окрім стандартної терапії отримували Нейроцитин. Усім пацієнтам проведено загальноклінічне та клініко-неврологічне обстеження. Ішемічний інсульт був верифікований за допомогою методів нейровізуалізації. Ступінь неврологічного дефіциту та функціональний стан хворих визначали за допомогою шкали NIHSS та модифікованої шкали Ренкіна (мШР) на 1-й та 14-й день ішемічного інсульту. Ступінь пошкодження нейронів оцінювали за рівнем нейронспецифічної єнолази (НСЄ). Біоелектричну активність кори головного мозку визначали за допомогою біспектрального індексу (BIS-індекс). Рівень оксигенації крові визначали за допомогою церебральної оксиметрії. Результати. На 14-й день лікування BIS-індекс на фоні терапії Нейроцитином (ОГ) зріс на 84,0 % від вихідного рівня (p &lt; 0,01) і був на 49,1 % вищим від показників КГ (p &lt; 0,05). Аналогічна тенденція спостерігалась за даними церебральної оксиметрії: в ОГ з 3-го дня лікування цей показник вірогідно перевищував вихідні показники на 31,1 % (p &lt; 0,05), з 5-го дня — на 57,8 % (p &lt; 0,01) і на 44,9 % перевищував аналогічний показник у КГ (p &lt; 0,05). В обох групах знизився рівень НСЄ в крові, проте вірогідно більш вираженими ці зміни були лише в пацієнтів ОГ на фоні терапії Нейроцитином. Неврологічний дефіцит у пацієнтів ОГ на 14-й день за NIHSS був на 59,7 % (p &lt; 0,01) нижчим за вихідний та на 36,6 % — за аналогічний показник КГ (p &lt; 0,05). При спостереженні в динаміці за функціональним станом хворих через 1,5 міс. після ішемічного інсульту бал за мШР у пацієнтів, які отримували стандартну терапію та Нейроцитин, вірогідно знизився порівняно з вихідним рівнем (p &lt; 0,05), тоді як у КГ такі зміни не досягли статистично вірогідних значень (p &gt; 0,05). Висновки. Нейроцитин® прискорює відновлення після гострого ішемічного інсульту за рахунок нейропротективного ефекту цитиколіну на тлі адекватної підтримки водно-електролітного балансу.

Trans-generational effects of copper on nerve damage in Caenorhabditis elegans

The potential toxicity of copper has received great attention for a long time, however, trans-generational effects of copper have not been extensively investigated. Caenorhabditis elegans (C. elegans) was used to evaluate the trans-generational toxicities of copper several physiological endpoints: growth, head thrashes and body bends and degree of neuronal damage. Copper significantly inhibited growth, body bends, head thrashes and caused degeneration of dopaminergic neurons in a concentration-dependent manner in parental worms. Further we found oxidative damage was to underlying the onset of neuron degeneration. In our study copper promoted ROS accumulation, and led to an increased expression of the oxidative stress response-related genes sod-3 and a decreased expression of metal detoxification genes mtl-1 and mtl-2. Moreover, copper increased the fluorescence intensity of the transgenic strain that encodes the antioxidant enzyme SOD-3. Gradually decline in copper-induced impairments were observed in the filial generations without exposure. No growth impairment was shown in F3, the trend of head thrashes recovery gradually appeared in F2 and no growth impairment was shown in F3, the body bends impairment caused by the parental copper exposure was recovery until F4 and no growth impairment was shown in F5. Besides, dopamine neurons revealed damage related to neurobehavioral endpoints, with hereditary effects in the progeny together. In addition, sequencing results suggested that copper exposure could cause epigenetic changes. QRT-PCR results showed that differentially expressed genes can also be passed on to offspring.

Morphofunctional changes and expression of LAMP2 in the rat hippocampus in chronic cerebral ischemia

AbstractBackgroundThe hippocampus, part of the limbic system, is involved in the formation of the cognitive sphere and is one of the most vulnerable structures in chronic cerebral ischemia.MethodChronic cerebrovascular disorders modeled in rats by limiting blood flow with applying ligatures to the carotid arteries. Behavioral status, cognitive and mnemonic functions, the degree of neuronal damage, and the level of LAMP2 expression in the pyramidal layer of the hippocampus were investigated.ResultAfter a 20‐day subtotal cerebral ischemia, we revealed a change in the functional state of the nervous system, expressed in a decrease of the main reflexes, tentative‐research activity, as well as a decrease in memory. Dystrophic changes in pyramidal neurons were of different severity, determined by a significant increase in the number of hyperchromic neurons, and in most of them total nuclear and cytoplasmic hyperchromia was observed, combined with a picture of spongiosis due to pericellular edema. A significant increase in LAMP2 expression compared to the control in both the relative area by 0.8% (p &lt;0.05) and the intensity of the expression was detected in the CA1 zone.ConclusionThe amplification of LAMP‐2 expression is a marker for the inclusion of autophagy mechanisms aimed at implementing compensatory processes in many disorders of the central nervous system, including chronic cerebral ischemia. The observed increase in the specific number of pyramidal neurons with signs of damage, sharp pericellular and perivascular edema in combination with increased expression of LAMP‐2 in the CA1 zone of the hippocampus indicates the important role of autophagy for the survival of neurons in chronic cerebral ischemia.

Dynamic Changes of Beclin-1 in the Hippocampus of Male Mice with Vascular Dementia at Different Time Points.

This study tried to investigate the dynamic changes of Beclin-1 in the hippocampus of male mice with vascular dementia (VD) at different time points. The mouse model of VD was established by the four-vessel blocking method. Then, the VD mice were randomly divided into five groups (n = 12) according to the disease duration: the 0.1-day model group, 0.5-day model group, 1-day model group, 3-day model group, 5-day model group and 14-day model group. In addition, all surgical procedures were the same in the sham group as those in the model groups, except the mice in the sham group were not subjected to clipping. The expression of Beclin-1, LC3B, p62, Bcl-2, Bax, BACE1, GFAP, MBP and ET-1 mRNA were determined by RT-PCR; the expression of Beclin-1 was detected by Western blot and immunofluorescence; the pathological characteristics of the hippocampus were observed by haematoxylin-eosin (HE) staining; and the correlation of Beclin-1 with other VD-related proteins was analysed by Pearson's correlation. Compared with that in the sham group, the expression of Beclin-1, LC3B, Bax, BACE1, GFAP, MBP and ET-1 mRNA was increased in the VD mice at different time points (0.1day, 0.5day, 1day, 3days, 5days and 14days) (P < 0.05) and then remained relatively stable in the 0.5-day VD mice, whereas the p62 and Bcl-2 mRNA levels decreased (P < 0.05). Beclin-1 protein expression was significantly increased in the VD mice at different time points (P < 0.05). The hippocampus showed a certain degree of neuronal damage in the VD mice at different time points (P < 0.05). Additionally, certain correlations among LC3B, p62, Bcl-2, Bax, BACE1, GFAP, MBP, ET-1 and Beclin-1 were observed in this study. In conclusion, the results described above demonstrated that neuronal damage and dynamic stability of Beclin-1 expression were established in the VD male mice after 0.5day by the four-vessel blocking method.

Pathoanatomical Pattern of Brain Damage of White Mice Infected with Experimental Anthrax

Background. Bacillus anthracis is a microorganism that causes anthrax. Because of irrational therapy, this particularly dangerous infectious disease leads to a systemic spread of bacteria in the body through histohematological barriers. Bacilli entering the brain subsequently lead to hemorrhagic meningitis. Despite intensive antibiotic therapy, that kind of meningitis is difficult to cure and therefore highly lethal. Studying characteristics of anthrax’s isolates of different origin and genotype is an actual area of research.The aim of the study is searching for pathomorphological and histological changes in the brain regions of experimental animals with anthrax infection, caused by B. anthracis with different plasmid spectrum.Materials and methods: The study was conducted on 200 certified white mice, three B. anthracis strains were used as research objects: B. anthracis I-323 (рХО1– /рХО2– ), B. anthracis I-275 (рХО1- /рХО2- ), and B. anthracis I-217 (рХО1+ / рХО2– ). The material for histological examination was the brain of mice, embedded in paraffin, and then sections were prepared using a microtome and stained with hematoxylin-eosin and Nissl toluidine blue. The degree of neuronal damage was assessed by calculating the semi-quantitative factor and determining the average size of the neuron nuclei, and the numerical density of cells in 1mm2 was studied. Microphotography and quantitative analysis was performed using the Motic Images Plus 2.0 application package. Statistical processing of the results was performed using the program “Statistica 6.0”.The results of the study showed that the brain of infected mice shows signs of hemorrhagic leptomeningitis, the manifestations of which are more pronounced in mice infected with weakly virulent plasmid strains of B. anthracis and fallen mice.Conclusion. Multicomponent exotoxin and specialized proteins, encoded in the pathogenicity plasmid of microorganisms, allow B. anthracis to easily overcome histohematological barriers and cause severe septic anthrax. The results obtained during the study supplement the available information on the pathogenesis of anthrax and indicate the need for further research in this direction.

Trans-generational effect of neurotoxicity and related stress response in Caenorhabditis elegans exposed to tetrabromobisphenol A

Tetrabromobisphenol A (TBBPA), one of the most common brominated flame retardants, has been associated with immunotoxicity, neurotoxicity, and reproductive toxicity. However, little attention has been focused on understanding the trans-generational effects of TBBPA. The present study used the Caenorhabditis elegans (C. elegans) animal model to evaluate the trans-generational effects of neurotoxicity induced by environmentally relevant concentrations of TBBPA (0, 0.1, 1, 10, 100, and 1000 µg/L). Multiple indicators including physiological effects (body length, brood size, head thrashes, body bends, and crawling trajectory), degree of neuronal damage (dopamine, GABAergic, and glutamatergic neurons), oxidative stress-related biochemical indicators (superoxide dismutase [SOD] activity, catalase [CAT] enzyme, malondialdehyde [MDA] production, and reactive oxygen species [ROS] accumulation), and stress-related gene expressions have been evaluated in the exposed parental C. elegans generation (G1) and their progeny (G2) under TBBPA-free conditions. The results showed that TBBPA exposure induced adverse effects on physiological endpoints, among which body bends and head thrashes were the most sensitive ones, detected above 1 µg/L in G1 and 100 µg/L in G2 nematodes, respectively. After contaminant exposure, the three neurons revealed damage related to neurobehavioral endpoints, with no hereditary effects in the progeny. The oxidative stress-related biochemical endpoints demonstrated that when the exposure concentrations were above 1 µg/L in maternal worms, impairment can be detected in both generations, but the progeny recovered at low toxicity concentration (1–100 µg/L). The integrated target gene expression profiles were clearly altered in G1 and G2 worms at concentrations between 1 and 1000 µg/L, and a more significant difference existed in two generations of nematodes at low levels (1–10 µg/L) of TBBPA. Studing trans-generational neurotoxicity and the underlying mechanism can generate a precise evaluation of the environmental risk of TBBPA.

ИНГАЛЯЦИОННАЯ СЕДАЦИЯ У ПАЦИЕНТОВ С СЕПСИС-АССОЦИИРОВАННЫМ ДЕЛИРИЕМ

Delirium in the intensive care ward is actively being discussed by anesthesiologists for a long period of time. However at present there are fairly scarce evidences on the efficiency of various techniques of prevention and management of this disorder. Goal of the research: to assess the impact of inhalation sedation on the intensity and duration of sepsis-associated delirium in the intensive care ward of the surgical hospital. Methods. The one-centered, prospective, randomized comparative study was conducted in order to assess the efficiency of inhalation sedation in the patients with sepsis-associated delirium. Propofol was used for the intravenous sedation in the control group. 187 adult patients, admitted to the intensive care ward of Vorokhobov City Clinical Hospital no. 67, were included into the study. Results. Inhalation sedation reduced the delirium duration compared to intravenous use of propofol: delirium was fully managed on the 5th day in the group where sevorane was used [4; 7], while in the group where propofol was used delirium lasted for 7 days [6; 8] (p = 0.03). The study did not detect any effect of inhalation sedation on the intensity of oxidative stress (level of oxidized peptides in the blood plasma of the patients) and degree of neuronal damage (differences between groups are not significant, p = 0.37). No differences were recorded in the value of procalcitonin and SOFA score at any stage of the study. Conclusion. The frequency of delirium in the mixed population of sepsis patients makes 27.9%. Use of inhalation sedation with sevoflurane compared to intravenous administration of propofol reduces the duration of delirium therapy from 7 to 5 days.

Reversible recovery of neuronal structures depends on the degree of neuronal damage after global cerebral ischemia in mice

It has been observed by in vivo imaging that damaged neuronal structures can be reversibly restored after ischemic insults with the application of timely therapeutic interventions. However, what degree of neuronal damage can be restored and the time frame for reversible recovery of neuronal structures remain unclear. Here, transcranial two-photon imaging, histological staining and electron microscopy were used to investigate the reversible recovery of neuronal structures from dendrites to soma after different durations of global cerebral ischemia in mice. Intravital imaging revealed that the damage to dendritic structures was reversible when ischemia time was <1h, but they became difficult to restore after >3h of ischemia. Data from fixed YFP brain slice and Golgi staining indicated that the damage of dendritic structures progressively extended to deeper dendritic shafts with the extension of ischemia time. Furthermore, longer duration of ischemia caused an increasing number of degenerating neurons. Importantly, significant chromatin margination and karyopyknosis of neuron were observed after 6h of ischemia. These data suggested that neuronal structures could be reversibly restored when ischemia time was <1h, but irreversible and progressive damage to neurons occurred with longer duration of ischemia. Consistently, behavioral performance of post-ischemic animals experienced an ischemia time-dependent recovery. Taken together, our data suggested that recovery of neuronal structures following ischemia was dependent on the duration of ischemia, and prevention of neuronal loss is a key target for therapeutic interventions in ischemic stroke.

Abstract PR161

Background & Objectives: Hydrogen gas is widely considered to be a novel antioxidant1). It has been demonstrated that inhalation of hydrogen gas reduced ischemic cerebral injury in several investigations. However, it remains unclear whether the neuroprotective effect of hydrogen gas is reproducible in a rat transient forebrain ischemia model (i.e. the Smith model). The current study was conducted to evaluate the effect of hydrogen gas on histological outcome after 7-day recovery period in rats subjected to transient forebrain ischemia. Materials & Methods: After approval by the animal research committee, male Sprague-Dawley rats were randomly assigned to one of the following 2 groups: control group, or hydrogen gas group (n=6 in each group). In the hydrogen gas group, transient forebrain ischemia was induced by a combination of hemorrhagic hypotension (mean arterial pressure= 40 mmHg) and bilateral carotid artery occlusion following 2.5% of sevoflurane anesthesia. The brain was reperfused 10 minutes after the onset of ischemia, and after 1 hour, the sevoflurane anesthesia was discontinued. 1.3% hydrogen gas inhalation began 10 min prior to the onset of ischemia, and was continued until the discontinuation of the anesthesia. Temporalis muscle temperature was maintained at approximately 37.5 degrees throughout the procedure. In the control group, all treatments were the same as the hydrogen gas group except for the hydrogen gas inhalation. Seven days after ischemia, the rats were sacrificed for histological evaluation. The brain slices were stained with hematoxilin and eosin, and the coronal sections at hippocampal level were examined light-microscopically. The degree of neuronal damage in the CA1 subfield of the hippocampus was assessed using the following scale: 1 = no ischemic neurons; 2 = less than 20% ischemic neurons; 3 = 20~50% ischemic neurons; 4 = 50~80% ischemic neurons; 5 = more than 80% ischemic neurons; 6 = no intact neurons. Statistical analysis was performed with Mann-Whitney U test for group comparison. Results: The median hippocampal injury scale was greater in the control group than in the hydrogen gas group (5[0] vs. 4[2]; median [interquartile range], respectively, p=0.07). Conclusion: The current study indicates that the treatment with 1.3% hydrogen gas is likely to provide a modest neuroprotective effect in a rat transient forebrain ischemia model.

Neuroprotective effects of oxysophocarpine on neonatal rat primary cultured hippocampal neurons injured by oxygen-glucose deprivation and reperfusion

Context: Oxysophocarpine (OSC), a quinolizidine alkaloid extracted from leguminous plants of the genus Robinia, is traditionally used for various diseases including neuronal disorders.Objective: This study investigated the protective effects of OSC on neonatal rat primary-cultured hippocampal neurons were injured by oxygen–glucose deprivation and reperfusion (OGD/RP).Materials and methods: Cultured hippocampal neurons were exposed to OGD for 2 h followed by a 24 h RP. OSC (1, 2, and 5 μmol/L) and nimodipine (Nim) (12 μmol/L) were added to the culture after OGD but before RP. The cultures of the control group were not exposed to OGD/RP. MTT and LDH assay were used to evaluate the protective effects of OSC. The concentration of intracellular-free calcium [Ca2+]i and mitochondrial membrane potential (MMP) were determined to evaluate the degree of neuronal damage. Morphologic changes of neurons following OGD/RP were observed with a microscope. The expression of caspase-3 and caspase-12 mRNA was examined by real-time quantitative PCR.Results: The IC50 of OSC was found to be 100 μmol/L. Treatment with OSC (1, 2, and 5 μmol/L) attenuated neuronal damage (p < 0.001), with evidence of increased cell viability (p < 0.001) and decreased cell morphologic impairment. Furthermore, OSC increased MMP (p < 0.001), but it inhibited [Ca2+]i (p < 0.001) elevation in a dose-dependent manner at OGD/RP. OSC (5 μmol/L) also decreased the expression of caspase-3 (p < 0.05) and caspase-12 (p < 0.05).Discussion and conclusion: The results suggested that OSC has significant neuroprotective effects that can be attributed to inhibiting endoplasmic reticulum (ER) stress-induced apoptosis.

Diffusional kurtosis imaging: a promising technique for detecting microstructural changes in neural development and regeneration

Diffusional kurtosis imaging: a promising technique for detecting microstructural changes in neural development and regeneration

Research of the serum level of neuron⁃specific enolase in children with various types of seizure

Objective To explore the relevance between the level changes of serum neuron⁃specific enolase (NSE) and neuronal damage in various seizure types of children with epilepsy. Methods According to the classification criteria of seizure types formulated by International League Against Epilepsy (ILAE) in 1981, 190 children with epilepsy were enrolled including tonic⁃clonic seizure group (41 cases), tonic seizure group (34 cases), clonic seizure group (22 cases), myoclonic seizure group (12 cases), atonic seizure group (17 cases), absence seizure group (22 cases), simple partial seizure group (21 cases) and complex partial seizure group (21 cases), and 64 healthy children were enrolled as control group. The long⁃ range vedio⁃electroencephalogram (VEEG) was operated and the blood samples were collected from these cases within 72 h after their seizures. Results The serum NSE levels of epileptic children were significantly higher than control group (P = 0.000). Among these seizure groups, serum NSE in myoclonic seizure group [(32.42 ± 6.62) ng/ml] was significantly higher than the other types, except for tonic⁃clonic seizure group (P = 0.062). There was no significant difference among the other types (P > 0.05, for all). According to rank correlation analysis, there was positive corrlation between serum NSE levels and VEEG abnormal intensity (rs = 0.613, P = 0.000). Conclusion The serum NSE were markedly increased in children with epilepsy after seizures, suggesting that a certain degree of neuronal damage may result from seizures; the higher NSE levels were, the more serious neuronal damage caused by epileptiform discharges was. The serum NSE levels in myoclonic seizure group and tonic⁃clonic seizure group were significantly higher than other seizure types, indicating the two kinds of seizures may result in greater neuronal damage. DOI：10.3969/j.issn.1672⁃6731.2012.05.013

SAPPα rescues deficits in amyloid precursor protein knockout mice following focal traumatic brain injury

The amyloid precursor protein (APP) is thought to be neuroprotective following traumatic brain injury (TBI), although definitive evidence at moderate to severe levels of injury is lacking. In the current study, we investigated histological and functional outcomes in APP-/- mice compared with APP+/+ mice following a moderate focal injury, and whether administration of sAPPα restored the outcomes in knockout animals back to the wildtype state. Following moderate controlled cortical impact injury, APP-/- mice demonstrated greater impairment in motor and cognitive outcome as determined by the ledged beam and Barnes Maze tests respectively (p < 0.05). This corresponded with the degree of neuronal damage, with APP-/- mice having significantly greater lesion volume (25.0 ± 1.6 vs. 20.3 ± 1.6%, p < 0.01) and hippocampal damage, with less remaining CA neurons (839 ± 245 vs. 1353 ± 142 and 1401 ± 263). This was also associated with an impaired neuroreparative response, with decreased GAP-43 immunoreactivity within the cortex around the lesion edge compared with APP+/+ mice. The deficits observed in the APP-/- mice related to a lack of sAPPα, as treatment with exogenously added sAPPα post-injury improved APP-/- mice histological and functional outcome to the point that they were no longer significantly different to APP+/+ mice (p < 0.05). This study shows that endogenous APP is potentially protective at moderate levels of TBI, and that this neuroprotective activity is related to the presence of sAPPα. Importantly, it indicates that the mechanism of action of exogenously added sAPPα is independent of the presence of endogenous APP.

Neuronal Injury Marker ATF-3 Is Induced in Primary Afferent Neurons of Monoarthritic Rats

Activating transcription factor 3 (ATF-3) expression has been associated with several signaling pathways implicated in cellular stress response in many cell types and is usually regarded as a neuronal damage marker in dorsal root ganglia (DRG). We investigated ATF-3 expression in primary afferents in the monoarthritic (MA) model of chronic inflammatory joint pain. Immunohistochemistry revealed that ATF-3 is highly induced mainly in small and medium neurons, especially at 2 and 4 days of MA in L₅ DRGs. Colocalization with calcitonin gene-related peptide (CGRP) and isolectin B4 (IB4) demonstrated that ATF-3-immunoreactive cells are mainly peptidergic. The lack of significant differences in ATF-3 and pAkt colocalization indicated that ATF-3 is probably not involved in a pAkt-mediated survival pathway. Anti-inflammatory (ketoprofen) administration failed to reverse ATF-3 induction in MA rats, but significantly increased CGRP expression. These data suggest that ATF-3 expression is definitely involved in MA, actually marking injured neurons. Some degree of neuronal damage seems to occur right from the first days of disease, mainly affecting small-to-medium peptidergic neurons. The intra-articular injection of complete Freund’s adjuvant and the generation of a neuroinflammatory environment seem to be the plausible explanation for the local nerve damage.

Operational Anaesthesia for the Management of Traumatic Brain Injury

The primary brain insult that occurs at the time of head injury, is determined by the degree of neuronal damage or death and so cannot be influenced by further treatment....

Brain-derived proteins in the CSF, do they correlate with brain pathology in CJD?

BackgroundBrain derived proteins such as 14-3-3, neuron-specific enolase (NSE), S 100b, tau, phosphorylated tau and Aβ1–42 were found to be altered in the cerebrospinal fluid (CSF) in Creutzfeldt-Jakob disease (CJD) patients. The pathogenic mechanisms leading to these abnormalities are not known, but a relation to rapid neuronal damage is assumed. No systematic analysis on brain-derived proteins in the CSF and neuropathological lesion profiles has been performed.MethodsCSF protein levels of brain-derived proteins and the degree of spongiform changes, neuronal loss and gliosis in various brain areas were analyzed in 57 CJD patients.ResultsWe observed three different patterns of CSF alteration associated with the degree of cortical and subcortical changes. NSE levels increased with lesion severity of subcortical areas. Tau and 14-3-3 levels increased with minor pathological changes, a negative correlation was observed with severity of cortical lesions. Levels of the physiological form of the prion protein (PrPc) and Aβ1–42 levels correlated negatively with cortical pathology, most clearly with temporal and occipital lesions.ConclusionOur results indicate that the alteration of levels of brain-derived proteins in the CSF does not only reflect the degree of neuronal damage, but it is also modified by the localization on the brain pathology. Brain specific lesion patterns have to be considered when analyzing CSF neuronal proteins.

Correlation of Cerebrospinal Fluid Levels of Tau Protein Phosphorylated at Threonine 231 With Rates of Hippocampal Atrophy in Alzheimer Disease

The microtubule-associated tau protein abnormally phosphorylated at threonine 231 (p-tau231) has been investigated as a potential marker of Alzheimer disease. Levels of cerebrospinal fluid (CSF) p-tau231 vary across patients with Alzheimer disease. We hypothesized that these variations partially reflect differences in the degree of neuronal damage and therefore may be used to predict structural disease progression. To investigate whether CSF p-tau231 levels correlate with rates of hippocampal atrophy as an in vivo marker of regional neuronal loss. We measured hippocampal volumes on the basis of serial magnetic resonance image examinations in 22 patients with Alzheimer disease. In addition, we determined CSF p-tau231 levels at baseline. Levels of CSF p-tau231 were significantly correlated with baseline hippocampal volumes (P<.001) and rates of hippocampal atrophy (left hippocampus, P<.001; right hippocampus, P = .02), independent of disease duration and severity. These findings suggest that variations in p-tau231 levels may be used to predict progression of brain atrophy in patients with Alzheimer disease.