Human origins and ancient human DNA.
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Africa↗
Biomedical subjects
A J Hansen
Publications and source records attributed to A J Hansen.
Nociceptin is a potent inhibitor of N-type Ca(2+) channels in rat sympathetic ganglion neurons.
Nociceptin, an endogenous agonist of the opioid receptor-like(1) (ORL(1)) receptor, is implicated in a wide range of physiological functions including cardiovascular control. However, the effect of nociceptin on peripheral sympathetic ganglion neurons has not been studied. Whole-cell voltage clamp was used to study Ca(2+) currents on freshly dissociated sympathetic superior cervical ganglion neurons from juvenile rats. Nociceptin (1 microM) caused a fast inhibition of the peak currents by 69+/-3% in all neurons. Strong positive prepulses counteracted the inhibition of the peak current by 64% and no effect of nociceptin was observed when the cells were pre-incubated with Pertussis toxin. The inhibition was reversible and dose-dependent with an EC(50) of 508+/-50 pM. Blockade of N-type channels by 1 microM omega-conotoxin GVIA reduced the peak currents by 83+/-1% and abolished the action of nociceptin. Naloxone could not prevent the inhibition by nociceptin and [D-Ala(2), N-Me-Phe(4), Gly(5)-ol] enkephalin (DAMGO) only depressed a small proportion of the current in 1/7 neurons. These data suggests that nociceptin inhibits transmitter release from sympathetic neurons by a selective blockade of N-type channels, which may be of importance for its depressive effect on the cardiovascular system.
Animals↗
Release of calcitonin gene-related peptide (CGRP) from guinea pig dura mater in vitro is inhibited by sumatriptan but unaffected by nitric oxide.
Migraine attacks can be provoked by administration of nitroglycerin, suggesting a role for nitric oxide (NO). The fact that release of the neuropeptide CGRP from trigeminal sensory nerves occurs during the pain phase of migraine and that NO can augment transmitter release prompted us to study CGRP release from the in situ dura mater in guinea pig skulls. Release of CGRP by capsaicin or by high potassium concentration was concentration-dependent and counteracted in calcium-free medium. The anti-migraine compound, sumatriptan, inhibited CGRP release via the 5-HT1-receptor. The NO donors, nitroglycerin, sodium nitroprusside and S-nitroso-N-acetylpenicillamine did not influence CGRP release, alone or together with the stimulants. We concluded that the skull preparation is well suited for scrutinizing CGRP release from dura mater. The fact that sumatriptan inhibits CGRP release as in migraine patients suggests a use for the present preparation in headache research.
Animals↗
Correlation between N-acetylaspartate levels and histopathologic changes in cortical infarcts of mice after middle cerebral artery occlusion.
The aim of the present study was to evaluate the use of the endogenous neuronal compound N-acetylaspartate (NAA) as a marker of neuronal damage after focal cerebral ischemia in mice. After occlusion of the middle cerebral artery (MCAO) the ischemic cortex was sampled, guided by 2,3,5-triphenyltetrazolium chloride (TTC) staining, and the NAA concentration was measured by high-pressure liquid chromatography (HPLC). Conventional histology and immunohistological methods using antibodies against neuron-specific enolase (NSE), neurofilaments (NF), synaptophysin, glial fibrillary acidic protein (GFAP), and carbodiamide-linked NAA and N-acetylaspartylglutamate (NAAG). The level of NAA rapidly declined to 50% and 20% of control levels in infarcted tissue after 6 hours and 24 hours, respectively. No further decrease was observed during the observation period of 1 week. Within the first 6 hours the number of normal-appearing neurons in the infarcted cortical tissue decreased to 70% of control, of which the majority were eosinophilic. After 24 hours almost no normal-appearing neurons were seen. The number of eosinophilic neurons decreased steadily to virtually zero after 7 days. The number of immunopositive cells in the NSE, NF, and synaptophysin staining within the infarct was progressively reduced, and after 3 to 7 days the immunoreactions were confined to discrete granulomatous structures in the center of the infarct, which otherwise was infested with macrophages. This granulomatous material also stained positive for NAA. The number of cells with positive GFAP immunoreactions progressively increased in the circumference of the infarct. They also showed increased immunoreaction against NAA and NSE. The study shows that the level of NAA 7 days after ischemia does not decline to zero but remains at 10% to 20% of control values. The fact NAA is trapped in cell debris and NAA immunoreactivity is observed in the peri-infarct areas restricts its use as a marker of neuronal density.
Animals↗
Tissue specific differences in the regulation of the UDP glucuronosyltransferase 2B17 gene promoter.
The human UDP glucuronosyltransferase UGT2B17, glucuronidates androgens and is expressed in the liver and the prostate. Although evidence suggests that variations in UGT2B17 expression between tissues may be a critical determinant of androgen response, the factors that regulate UGT2B17 expression in the liver and prostate are unknown. In this study, we have isolated a 596 bp promoter of the UGT2B17 gene and studied its regulation in the liver cell line, HepG2 and the prostate cell line, LNCaP. The transcription start site of UGT2B17 was mapped and proteins that bound to the proximal promoter were detected by DNase1 footprint analysis. A region (-40 to -52 bp) which resembled a hepatocyte nuclear factor 1 (HNF1) binding site bound proteins in nuclear extracts from HepG2 cells, but did not bind proteins from LNCaP nuclear extracts. In HepG2 cells, HNF1alpha bound to this region and activated the UGT2B17 promoter, as assessed by functional and gel shift assays. HNF1alpha activation of the promoter was prevented by mutation or deletion of the putative HNF1 site. The related transcription factor HNF1beta, which is present in HepG2 cells, did not activate the promoter. The UGT2B17 promoter could also be activated by exogenous HNF1alpha in LNCaP cells. However, because these cells do not contain HNF1alpha, other transcription factors must regulate the UGT2B17 promoter. Cotransfection experiments showed that HNF1beta, elevates promoter activity in LNCaP cells. This activation did not involve the putative HNF1 region (-40 to -52 bp) since mutation of this region did not affect promoter activation by HNF1beta. These results suggest that the UGT2B17 promoter is regulated by different factors in liver-derived HepG2 and prostate-derived LNCaP cells.
Binding Sites↗
Octamer transcription factor-1 enhances hepatic nuclear factor-1alpha-mediated activation of the human UDP glucuronosyltransferase 2B7 promoter.
The human UDP glucuronosyltransferase, UGT2B7, is expressed in the liver and gastrointestinal tract, where it catalyzes the glucuronidation of steroids and bile acids. In this study, the UGT2B7 gene was isolated and its proximal promoter was analyzed. The UGT2B7 gene consists of 6 exons and extends over 16 kilobases (kb). It does not contain a canonical TATA box but has a region (-2 to -40) adjacent to the transcription start site that binds nuclear proteins. This region contains a consensus hepatic nuclear factor-1alpha (HNF1alpha)-binding site and an overlapping AT-rich segment. Varying lengths of the UGT2B7 gene promoter, with and without these sites, were fused to the firefly luciferase reporter gene and transfected into HepG2 cells. UGT2B7 promoter activity with the HNF1/AT-rich element was stimulated by cotransfection with HNF1alpha. Additional activation was observed when HNF1alpha and octamer transcription factor-1 (Oct-1) were cotransfected simultaneously. However, Oct-1 alone did not stimulate promoter activity and did not bind to the promoter in the absence of HNF1alpha. Deletion of the HNF1/AT-rich region, or mutations in this region, abolished UGT2B7 gene promoter activity and prevented HNF1alpha-mediated increases in promoter activity. The presence of HNF1alpha and octamer transcription factor-1 (Oct-1) in the protein complex that bound to the HNF1/AT-rich region was demonstrated by gel shift analyses with antibodies specific to HNF1alpha and Oct-1 protein. These results strongly suggest that the liver-enriched factor HNF1alpha binds to, and activates, the UGT2B7 gene promoter and that the ubiquitous transcription factor, Oct-1, enhances this activation by directly interacting with HNF1alpha. This interaction between HNF1alpha and Oct-1 may fine-tune UGT2B7 expression.
Base Sequence↗
N-substituted adenosines as novel neuroprotective A(1) agonists with diminished hypotensive effects.
The synthesis and pharmacological profile of a series of neuroprotective adenosine agonists are described. Novel A(1) agonists with potent central nervous system effects and diminished influence on the cardiovascular system are reported and compared to selected reference adenosine agonists. The novel compounds featured are derived structurally from two key lead structures: 2-chloro-N-(1-phenoxy-2-propyl)adenosine (NNC 21-0041, 9) and 2-chloro-N-(1-piperidinyl)adenosine (NNC 90-1515, 4). The agonists are characterized in terms of their in vitro profiles, both binding and functional, and in vivo activity in relevant animal models. Neuroprotective properties assessed after postischemic dosing in a Mongolian gerbil severe temporary forebrain ischemia paradigm, using hippocampal CA1 damage endpoints, and the efficacy of these agonists in an A(1) functional assay show similarities to some reference adenosine agonists. However, the new compounds we describe exhibit diminished cardiovascular effects in both anesthetized and awake rats when compared to reference A(1) agonists such as (R)-phenylisopropyladenosine (R-PIA, 5), N-cyclopentyladenosine (CPA, 2), 4, N-[(1S,trans)-2-hydroxycyclopentyl]adenosine (GR 79236, 26), N-cyclohexyl-2'-O-methyladenosine (SDZ WAG 994, 27), and N-[(2-methylphenyl)methyl]adenosine (Metrifudil, 28). In mouse permanent middle cerebral artery occlusion focal ischemia, 2-chloro-N-[(R)-[(2-benzothiazolyl)thio]-2-propyl]adenosine (NNC 21-0136, 12) exhibited significant neuroprotection at the remarkably low total intraperitoneal dose of 0.1 mg/kg, a dose at which no cardiovascular effects are observed in conscious rats. The novel agonists described inhibit 6, 7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate-induced seizures, and in mouse locomotor activity higher doses are required to reach ED(50) values than for reference A(1) agonists. We conclude that two of the novel adenosine derivatives revealed herein, 12 and 5'-deoxy-5'-chloro-N-[4-(phenylthio)-1-piperidinyl]adenosine (NNC 21-0147, 13), representatives of a new series of P(1) ligands, reinforce the fact that novel selective adenosine A(1) agonists have potential in the treatment of cerebral ischemia in humans.
Adenosine↗
Diversity of Holocene life forms in fossil glacier ice.
Studies of biotic remains of polar ice caps have been limited to morphological identification of plant pollen and spores. By using sensitive molecular techniques, we now demonstrate a much greater range of detectable organisms; from 2000- and 4000-year-old ice-core samples, we obtained and characterized 120 clones that represent at least 57 distinct taxa and reveal a diversity of fungi, plants, algae, and protists. The organisms derive from distant sources as well as from the local arctic environment. Our results suggest that additional taxa may soon be readily identified, providing a plank for future studies of deep ice cores and yielding valuable information about ancient communities and their change over time.
Base Sequence↗
Astroglia contain a specific transport mechanism for N-acetyl-L-aspartate.
N-Acetylaspartate (NAA) is the second most abundant amino acid in the adult brain. It is located and synthesized in neurons and probably degraded in the glia compartment, but the transport mechanisms are unknown. Rat primary neuron and astrocyte cell cultures were exposed to the L isomer of [3H]NAA and demonstrated concentration-dependent uptake of [3H]NAA with a Km approximately 80 microM. However, Vmax was 23+/-6.4 pmol/mg of protein/min in astrocytes but only 1.13+/-0.4 pmol/mg of protein/min in neurons. The fact that neuron cultures contain 3-5% astrocytes suggests that the uptake mechanism is expressed only in glial cells. The astrocyte uptake was temperature and sodium chloride dependent and specific for L-NAA. The affinity for structural analogues was (IC50 in mM) as follows: L-NAA (0.12) > N-acetylaspartylglutamate (0.4) > N-acetylglutamate (0.42) > L-aspartate (>1) > L-glutamate (>1) > or = DL-threo-beta-hydroxyaspartate > N-acetyl-L-histidine. The naturally occurring amino acids showed no inhibitory effect at 1 mM. The glutamate transport blocker trans-pyrrolidine-2,4-dicarboxylate exhibited an IC50 of 0.57 mM, whereas another specific glutamate transport inhibitor, DL-threo-beta-hydroxyaspartate, had an IC50 of >1 mM. The experiments suggest that NAA transport in brain parenchyma occurs by a novel type of sodium-dependent carrier that is present only in glial cells.
Animals↗
N-Acetylaspartate distribution in rat brain striatum during acute brain ischemia.
Brain N-acetylaspartate (NAA) can be quantified by in vivo proton magnetic resonance spectroscopy (1H-MRS) and is used in clinical settings as a marker of neuronal density. It is, however, uncertain whether the change in brain NAA content in acute stroke is reliably measured by 1H-MRS and how NAA is distributed within the ischemic area. Rats were exposed to middle cerebral artery occlusion. Preischemic values of [NAA] in striatum were 11 mmol/L by 1H-MRS and 8 mmol/kg by HPLC. The methods showed a comparable reduction during the 8 hours of ischemia. The interstitial level of [NAA] ([NAA]e) was determined by microdialysis using [3H]NAA to assess in vivo recovery. After induction of ischemia, [NAA]e increased linearly from 70 micromol/L to a peak level of 2 mmol/L after 2 to 3 hours before declining to 0.7 mmol/L at 7 hours. For comparison, [NAA]e was measured in striatum during global ischemia, revealing that [NAA]e increased linearly to 4 mmol/L after 3 hours and this level was maintained for the next 4 h. From the change in in vivo recovery of the interstitial space volume marker [14C]mannitol, the relative amount of NAA distributed in the interstitial space was calculated to be 0.2% of the total brain NAA during normal conditions and only 2 to 6% during ischemia. It was concluded that the majority of brain NAA is intracellularly located during ischemia despite large increases of interstitial [NAA]. Thus, MR quantification of NAA during acute ischemia reflects primarily changes in intracellular levels of NAA.
Acute Disease↗
Gap-junction-mediated propagation and amplification of cell injury.
Gap junctions are conductive channels that connect the interiors of coupled cells. We determined whether gap junctions propagate transcellular signals during metabolic stress and whether such signaling exacerbates cell injury. Although overexpression of the human proto-oncogene bcl2 in C6 glioma cells normally increased their resistance to injury, the relative resistance of bcl2+ cells to calcium overload, oxidative stress and metabolic inhibition was compromised when they formed gap junctions with more vulnerable cells. The likelihood of death was in direct proportion to the number and density of gap junctions with their less resistant neighbors. Thus, dying glia killed neighboring cells that would otherwise have escaped injury. This process of glial 'fratricide' may provide a basis for the secondary propagation of brain injury in cerebral ischemia.
Animals↗
C/EBPalpha is a regulator of the UDP glucuronosyltransferase UGT2B1 gene.
The rat UDP glucuronosyltransferase, UGT2B1, is expressed in the liver where it glucuronidates steroids, environmental toxins, and carcinogens. A region between -88 and -111 base pairs upstream from the UGT2B1 gene transcription start site contains a CCAAT enhancer binding protein (C/EBP)-like element and was previously shown by Dnase I footprint analysis to bind to proteins in both rat liver and human hepatoma (HepG2) cell nuclear extracts. In this study, the importance of this region in the regulation of the UGT2B1 gene was assessed by functional and DNA binding assays. Varying lengths of the UGT2B1 gene promoter, with and without the C/EBP-like element, were fused to the chloramphenicol acetyltransferase reporter gene and transfected into HepG2 cells. Transcriptional activity of the UGT2B1 promoter construct containing the C/EBP-like element was strongly elevated in the presence of a cotransfected C/EBPalpha expression vector. In contrast, no change was observed when an expression vector encoding C/EBPbeta was cotransfected with the UGT2B1 promoter constructs. Introduction of point mutations into the C/EBP-like element prevented any C/EBPalpha-mediated increase in chloramphenicol acetyltransferase activity. Gel shift analyses demonstrated that the C/EBP-like element binds a complex of nuclear proteins present in both HepG2 cells and rat liver. The presence of C/EBPalpha in this complex was confirmed by supershift analysis with antiserum to this factor. These data strongly suggest that the liver-enriched factor C/EBPalpha binds to, and activates, the UGT2B1 gene promoter. The importance of C/EBPalpha in the regulation of the homologous mouse UGT2B1 gene was also assessed in vivo. Transcripts homologous to UGT2B1 were detected in the livers of mice containing intact c/ebpalpha and c/ebpbeta genes and in mice containing a homozygous null mutation in the c/ebpbeta gene. In contrast, these transcripts were not detected in mice with a disrupted hepatic c/ebpalpha gene. These data extend the findings with the rat UGT2B1 gene promoter and establish that C/EBPalpha, but not C/EBPbeta, is an essential transcriptional regulator of the homologous UGT2B1 gene in the mouse.
Animals↗
Possible mechanism of c-fos expression in trigeminal nucleus caudalis following cortical spreading depression.
Cortical spreading depression (CSD) is characterized by a transient, reversible depression of EEG activity which advances across the cortical surface at a velocity of 2-5 mm/min. CSD was originally linked to the aura phase of migraine, but recently also to migraine headache. The theory is that CSD activates meningeal trigeminal C-fibers causing neurogenic inflammation and pain (Moskowitz, M.A., Nozaki, K. and Kraig, R.P., Neocortical spreading depression provokes the expression of c-fos protein-like immunoreactivity within trigeminal nucleus caudalis via trigeminovascular mechanisms, J. Neurosci., 13 (1993) 1167-1177). The present study is an examination of the proposed link between CSD elicited in rats and activation of trigeminal nerve fibers. Multiple CSDs were elicited unilaterally for 1 h by KCl injections (1 M, 5 microliters) into the right hemisphere, while NaCl (1 M, 5 microliters) was injected into the left as control. After an additional 1 h the animals were sacrificed and trigeminal activation assessed by the expression of c-fos in trigeminal nucleus caudalis (TNC) using immunohistochemistry. The correlation between the number of CSDs and the extent of c-fos expression was determined. In addition the effect of sumatriptan (0.3 mg/kg) and morphine (3 mg/kg) given i.v. 30 min before elicitation of CSD was evaluated. CSD caused increased c-fos expression in lamina I and II of TNC where C-fibers, end, the response being greater ipsilaterally. Morphine, but not sumatriptan, reduced c-fos expression in both the ipsilateral and contralateral TNC by 71% (P < 0.05 and P = 0.19, respectively), confirming that nociceptors have been activated. No positive correlation was seen between the number of CSDs and the extent of c-fos expression in TNC. Instead we observed a positive, linear correlation between the number of KCl injections and the extent of c-fos expression in TNC (correlation coefficient r = 0.709, P < 0.05). We suggest that the C-fiber activation observed is caused by hyperosmolar KCl/NaCl and not CSD. Hence, our results do not support the hypothesis of Moskowitz et al. (Moskowitz, M.A., Nozaki, K. and Kraig, R.P., Neocortical spreading depression provokes the expression of c-fos protein-like immunoreactivity within trigeminal nucleus caudalis via trigeminovascular mechanisms, J. Neurosci., 13 (1993) 1167-1177) which links CSD with migraine headache.
Animals↗
Transient elevation of interstitial N-acetylaspartate in reversible global brain ischemia.
We evaluated the changes of interstitial N-acetylaspartate (NAA) concentration ([NAA]e) in rat striatum by microdialysis following transient global ischemia and depolarization. The dialysate NAA concentration ([NAA]d) values were corrected for the in vivo recovery to obtain [NAA]e, by the use of [3H]mannitol in the perfusion fluid. During global ischemia the relative loss (RL) of [3H]mannitol decreased to 40% of preischemic values, reflecting the decrease in extracellular volume fraction. During reperfusion RL of [3H]mannitol quickly normalized. The [NAA]d doubled during transient ischemia, which, after correction for in vivo recovery, corresponds to a fivefold increase in [NAA]e (p < 0.05). Reperfusion induced a > 10-fold increase of [NAA]e (p < 0.01) with subsequent normalization after 45 min. KCl at 100 microM caused a reversible 50% reduction in RL of [3H]mannitol and a three times increase in [NAA]e (p < 0.05) but no further increase when normal perfusate was reintroduced. The mechanisms of NAA release from neurons are unknown but may involve the activation of unknown channels/carriers-possibly in relation to a volume regulatory response. The present study shows that the distribution of NAA in brain is dynamically regulated in acute ischemia and suggests that changes of NAA levels could be caused by other means than neuronal loss.
Animals↗
HNF1 alpha activates the rat UDP glucuronosyltransferase UGT2B1 gene promoter.
The rat UDP glucuronosyltransferase UGT2B1 is expressed mainly in the liver where it glucuronidates steroids and environmental toxins and carcinogens. A region between -42 and -55 bp upstream from the UGT2B1 gene transcription start site was previously identified as sharing sequence similarity with the hepatocyte nuclear factor 1 (HNF1) consensus binding site. In this study, the importance of this region in the regulation of the UGT2B1 gene was confirmed by functional and DNA binding assays. A minimal UGT2B1 gene promoter containing the putative HNF1 binding site was fused to the CAT reporter gene and transfected into HepG2 cells. Only low levels of CAT activity were detected. This activity was increased 50-fold when an HNF1 alpha expression vector was co-transfected with the UGT2B1 promoter CAT construct but was not altered when a HNF1 beta expression vector was used. A UGT2B1 promoter construct with the HNF1-like region deleted was not activated by either co-transfected HNF1 expression vector. DNase 1 footprinting and gel-shift analysis demonstrated that nuclear proteins present in both HepG2 cells and rat liver bind to the HNF1-like element. The presence of HNF1 alpha in these nuclear proteins that bind to the HNF1-like element was confirmed by supershift analysis with antisera to HNF1 alpha. Specific binding of nuclear proteins to the HNF1-like element was not seen in extracts from three cell lines derived from nonhepatic tissues. These data strongly suggest that the liver-enriched factor HNF1 alpha binds to, and activates, the UGT2B1 gene promoter
Animals↗
Membrane stiffness and channel function.
Alterations in the stiffness of lipid bilayers are likely to constitute a general mechanism for modulation of membrane protein function. Gramicidin channels can be used as molecular force transducers to measure such changes in bilayer stiffness. As an application, we show that N-type calcium channel inactivation is shifted reversibly toward negative potentials by synthetic detergents that decrease bilayer stiffness. Cholesterol, which increases bilayer stiffness, shifts channel inactivation toward positive potentials. The voltage activation of the calcium channels is unaffected by the changes in stiffness. Changes in bilayer stiffness can be predicted from the molecular shapes of membrane-active compounds, which suggests a basis for the pharmacological effects of such compounds.
Calcium Channels↗
Is calcium accumulation post-injury an indicator of cell damage?
It is generally agreed that excessive intracellular calcium accumulation is the main culprit for nerve cell damage following brain injury. Many autoradiographic studies of the post-injury brain have demonstrated an accumulation of 45Ca2+ in regions exhibiting neuronal damage. We have recently observed, after cortical contusion trauma [10], that there was a discrepancy between the extent of cell damage and the extent of 45Ca2+ in autoradiograms; rather the distribution of 45Ca2+ followed that of serum proteins. In addition 45Ca2+ was also observed in white matter, which had no signs of damage. We tested the hypothesis that 45Ca2+ accumulation was coupled to the presence of protein by directly injecting albumin into the brain cortex. There was a highly significant correlation between the content of 45Ca2+ and of albumin as measured by ELISA. A similar pattern was found after a cortical freeze-lesion in the contralateral hemisphere. However, in the ipsilateral hemisphere where cell damage was observed, the relation broke down and calcium accumulated in excess. We conclude that calcium accumulation in the brain is not only the result of cell damage but also the presence of calcium-binding proteins, e.g. albumin.
Animals↗
Calcium movements in traumatic brain injury: the role of glutamate receptor-operated ion channels.
Ion-selective microelectrodes were used to study acute effects of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy- 5-methyl-4-isoxazole (AMPA) receptor blockade on posttraumatic calcium disturbances. An autoradiographic technique with 45 Ca2+ was used to study calcium disturbances at 8, 24, and 72 h. Compression contusion trauma of the cerebral cortex was produced by a 21-g weight dropped from a height of 35 cm onto a piston that compressed the brain 2 mm. Pre- and posttrauma interstitial [Ca2+] ([Ca2+]e) concentrations were measured in the perimeter, i.e., the shear stress zone (SSZ) and in the central region (CR) of the trauma site. For the [Ca2+]e studies the animals were divided into controls and groups pretreated with dizocilipine maleate (MK-801) or with 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[F]quinoxaline (NBQX). In all groups, [Ca2+]e decreased from pretrauma values of approximately 1 mM to posttraumatic values of 0.1 mM in both the CR and the SSZ. This was followed by a slow restitution toward pretraumatic levels during the 2-h observation period. There was no significant difference in recovery pattern between controls and pretreated animals. Accumulation of 45Ca2+ and serum proteins was seen in the entire SSZ, while neuronal necrosis was confined to a narrow band within the SSZ. The CR was unaffected apart from occasional eosinophilic neurons and showed no accumulation of 45Ca2+. Posttraumatic treatment with MK-801 or NBQX had no obvious effect on neuronal injury in the SSZ. We conclude that (a) acute [Ca2+]e disturbances in compression contusion brain trauma are not affected by blockade of NMDA or AMPA receptors, (b) 45Ca2+ accumulation in the SSZ reflects mainly protein accumulation due to blood-brain barrier breakdown rather than cell death, and (c) acute cellular Ca2+ over-load per se does not seem to be a major determinant of cell death after cerebral trauma in our model.
Animals↗