Showing papers in "Molecular and Chemical Neuropathology in 1992"
TL;DR: A permanent loss of energy by at least 7-20% in incipient and progressively advancing dementia of the Alzheimer type may be assumed, with an increasing tendency in stable advanced dementia to around 50% energy loss.
Abstract: Reduction of the cerebral metabolic rate of glucose is one of the most predominant abnormalities generally found in the Alzheimer brain, whereas the cerebral metabolic rate of oxygen is only slightly diminished or not at all the beginning of this dementive disorder. This metabolic abnormality may induce severe functional disturbances, obviously preceding morphobiological changes. From the cerebral metabolic rates of oxidized glucose and oxygen, the cerebral ATP formation rate was calculated in incipient early-onset, incipient late-onset and stable advanced dementia of Alzheimer type. A reduction of ATP formation was found from at least 7% in incipient early-onset, to around 20% in incipient late-onset DAT, and from 35% to more than 50% in stable advanced dementia. This approximation was adjusted to findings demonstrating diminished activities of enzymes active in glucose metabolism and formation of oxidation equivalents for ATP production from substrates other than glucose. A reduction for energy formation to the same rrange was found, as was also recently reported, in vivo in Alzheimer patients. From this rather theoretical point of view, a permanent loss of energy by at least 7–20% in incipient and progressively advancing dementia of the Alzheimer type may by assumed, with an increasing tendency in stable advanced dementia to around 50% energy loss. This energy deficit may have drastic impacts on brain function.
162 citations
TL;DR: The ganglioside composition of seven experimental brain tumors was examined in C57BL/6J mice and it was found that the high content of NeuGcgangliosides in the solid tumors may arise from infiltration of nonneural tissue elements, e.g., macrophages, lymphocytes, and endothelial cells.
Abstract: The ganglioside composition of seven experimental brain tumors was examined in C57BL/6J mice. The tumors were produced from 20-methylcholanthrene (20-MC) implantation into either the cerebrum or cerebellum and were maintained in serial transplants through many generations. The tumors studied were grown subcutaneously as solid tumors, and cells from two of the tumors were also studied in culture. Histologically, all of the tumors were similar and could be broadly classified as highly malignant, poorly differentiated anaplastic astrocytomas. The total ganglioside sialic acid content of the solid tumors was markedly lower than that in adult mouse brain. In addition to N-acetylneuraminic acid (NeuAc), the gangliosides in the solid tumors contained significant amounts of N-glycolylneuraminic acid (NeuGc). The seven solid tumors fell into two general groups with respect to ganglioside composition. Furthermore, the differences in ganglioside composition between the two tumor groups were strongly associated with differences in tumor cell cohesion. The tumors in one group had high levels of GM3 hematosides, low levels of oligosialogangliosides, and grew as firm cohesive tissues. The tumors in the other group, however, had lower levels of GM3 hematosides, noticeable amounts of oligosialogangliosides and grew as soft noncohesive tissues. In culture, clonal cells from one of the tumors in the first group grew as clumps or islands and contained GM3 as the only major ganglioside, whereas clonal cells from a tumor in the second group grew as sheets or monolayers and contained little GM3, but expressed several gangliosides with complex structures. In marked contrast to the gangliosides in the solid tumors, the gangliosides in the cultured tumor cells contained trace amounts of NeuGc. Since NeuGc containing gangliosides are abundant in mouse nonneural tissues, the high content of NeuGc gangliosides in the solid tumors may arise from infiltration of nonneural tissue elements, e.g., macrophages, lymphocytes, and endothelial cells.
95 citations
TL;DR: Studying stress-induced changes in polyamine synthesis and metabolism may help to elucidate the molecular mechanisms involved in the development of cell injury induced by severe stress.
Abstract: Biosynthesis of the polyamines spermidine and spermine and their precursor putrescine is controlled by the activity of the two key enzymes ornithine decarboxylase (ODC) andS-adenosylmethionine decarboxylase (SAMDC). In the adult brain, polyamine synthesis is activated by a variety of physiological and pathological stimuli, resulting most prominently in an increase in ODC activity and putrescine levels. The sharp rise in putrescine levels observed following severe cellular stress is most probably the result of an increase in ODC activity and decrease in SAMDC activity or an activation of the interconversion of spermidine into putrescine via the enzymes spermidineN-acetyltransferase and polyamine oxidase. Spermidine and spermine levels are usually less affected by stress and are reduced in severely injured areas. Changes of polyamine synthesis and metabolism are most pronounced in those pathological conditions that induce cell injury, such as severe metabolic stress, exposure to neurotoxins or seizure. Putrescine levels correlate closely with the density of cell necrosis. Because of the close relationship between the extent of poststress changes in polyamine metabolism and density of cellular injury, it has been suggested that polyamines play a role in the manifestation of structural defects. Four different mechanisms of polyamine-dependent cell injury are plausible: (1) an overactivation of calcium fluxes and neurotransmitter release in areas with an overshoot in putrescine formation; (2) disturbances of the calcium homeostasis resulting from an impairment of the calcium buffering capacity of mitochondria in regions in which spermine levels are reduced; (3) an overactivation of the NMDA receptor complex caused by a release of polyamines into the extracellular space during ischemia or after ischemia and prolonged recirculation in the tissue surrounding severely damaged areas; (4) an overproduction of hydrogen peroxide resulting from an activation of the interconversion of spermidine into putrescine via the enzymes spermidineN-acetyltransferase and polyamine oxidase. Insofar as a sharp activation of polyamine synthesis is a common response to a variety of physiological and pathological stimuli, studying stressinduced changes in polyamine synthesis and metabolism may help to elucidate the molecular mechanisms involved in the development of cell injury induced by severe stress.
95 citations
TL;DR: Histopathological examination of gerbil brains 24 h after systemic injection of KA revealed severe neuronal lesions in different regions of the brain, especially the cerebellar and hippocampal areas, suggesting that the free radical reaction is a primary cause of neuronal degeneration after KA administration.
Abstract: Kainic acid (KA) is a known potent neuroexcitotoxin, although the biochemical mechanism producing its underlying neurotoxic effect is not quite clear. Histopathological examination of gerbil brains 24 h after systemic injection of KA revealed severe neuronal lesions in different regions of the brain, especially the cerebellar and hippocampal areas. We have detected free radical formation in the brain 1 h after KA administration by using an in vivo spin trapping technique. We have also observed increased lipid peroxidation in the brain after KA-treatment by analyzing thiobarbituric acid reactive substances and conjugated diene formation. Diminished brain specific (Na+, K+)-ATPase activity was also found 2 h after KA injection and persisted to 24 h. It is possible that the free radical reaction is a primary cause of neuronal degeneration after KA administration.
92 citations
TL;DR: HOG cells should provide a useful model for studying the extracellular regulation and phosphorylation of oligodendrocyte-specific proteins.
Abstract: A novel clonal cell line derived from a human glioma (HOG) was found to express some oligodendrocyte-specific proteins including a 15-kDa form of myelin basic protein (MBP) and high 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) activity. Expression of the myelin lipids galactosylceramide and sulfogalactosylceramide (sulfatide) was low. HOG cells did not express the characteristic astrocyte markers glial fibrillary acidic protein (GFAP) or significant glutamine synthetase (GS) activity. After initial plating, HOG cells were flat and epitheloid and thus showed a limited oligodendrocyte-like morphology. However, after cells became more confluent, some cells were phase-bright and elaborated short processes. Receptor types expressed by HOG cells included A2-adenosine, prostaglandin E1 (PGE1), and beta 2-adrenergic receptors (beta-ARs) linked to stimulation of adenylate cyclase, and muscarinic cholinergic and H1-histamine coupled to phosphatidyinositol turnover (Post and Dawson, 1991). HOG cells should therefore provide a useful model for studying the extracellular regulation and phosphorylation of oligodendrocyte-specific proteins.
82 citations
TL;DR: Recent data are reviewed that suggest that neoplastic cells in childhood primitive neuroectodermal tumors (PNETs) of the central nervous system may represent a cluster of molecular abnormalities that underly the emergence of the highly malignant phenotype that characterizes childhood PNETs.
Abstract: We review here recent data that have brought into sharper focus a number of important biological properties of the neoplastic cells in childhood primitive neuroectodermal tumors (PNETs) of the central nervous system (CNS). Studies of this group of tumors, as exemplified by posterior fossa medulloblastomas (MBs), suggest that neoplastic cells in PNETs partially recapitulate stages in the maturation of normal human neuroblasts. These findings may contribute to the elucidation of the mechanisms involved in tumor initiation and progression because oncogenes and antioncogenes appear to exert their effects in a cell type-specific manner that also depends on the maturational state of a given cell. Currently, a large body of data suggests that populations of cells in PNETs (e.g., MBs) exhibit one or more molecular stem cells or partially committed neuron-like precursors from the cell cycle, followed by their terminal differentiation into neurons. This, together with the orchestrated interactions of as yet unidentified oncogenes and antioncogenes in these PNET cells, may represent a cluster of molecular abnormalities that underly the emergence of the highly malignant phenotype that characterizes childhood PNETs.
56 citations
TL;DR: The results were observed by both a homogenate-collagen binding assay and a cell-surface adhesion assay, thus providing further evidence for the adhesion role of APP and posing the question of the possible role of the heparin-binding properties of APP in the genesis of the neuritic plaques characteristic of Alzheimer's disease.
Abstract: The amyloid precursor protein (APP) is a glycoprotein consisting of at least four isoforms derived from a single gene by a process of alternative splicing. The membrane-bound forms of APP have been suggested to have adhesive properties and to mediate neural cell adhesion. Previous studies have demonstrated the ability of Fab’ fragments of antibodies to extracellular domains of APP to inhibit neural cell binding to a collagen substrate, suggesting a physiological role for the collagen-binding properties of APP.
52 citations
TL;DR: In this article, a case with description of the distribution of mercury in the systemic organs, and the ultrastructural changes of the nervous system after a survival of 29 years was reported.
Abstract: Our knowledge concerning the pathology of fetal cases of human Minamata disease (methylmercury poisoning) is relatively limited. We report here a case with description of the distribution of mercury in the systemic organs, and the ultrastructural changes of the nervous system after a survival of 29 yr.
50 citations
TL;DR: In this article, the location and nature of brain lesions induced in rats and dogs by 2,5-hexanedione, misonidazole, clioquinol, and acrylamide are reported.
Abstract: Dose- and term-dependent differences in the location and nature of brain lesions induced in rats and dogs by 2,5-hexanedione (2,5-HD), misonidazole, clioquinol, and acrylamide are reported. Subchronic neuropathies (“distal axonopathy”) were induced by low-dose administration of these neurotoxicants and at high doses, lesions caused by acute or subacute neurotoxicity were found in the central nervous system (CNS). In rats, 2,5-HD induced extracellular edema, nerve cell degeneration, and axonal degeneration in the cerebellar and vestibular nuclei. Similar lesions were observed in misonidazole-treated dogs and clioquinol induced nerve cell degeneration in the hippocampus and malacia in the piriform lobes of these animals. In rats, acrylamide induced degeneration of Purkinje cells.
33 citations
TL;DR: The results suggest that poly-PI hydrolysis coupled to DG-lipase may contribute to theInitial release of FFA, whereas the FFA released subsequent to the initial phase may be mainly a result of activation of phospholipase A2 acting on phosphatidylcholines and phosphatodylinositols.
Abstract: In this study, the release of lysophospholipids (to depict phospholipase A2 activity) and diacylglycerols (DG) (to depict stimulated hydrolysis of polyphosphoinositides) was related to the decapitation-induced release of free fatty acid (FFA) in the mouse brain. To assay for lysophospholipids, Balb/c mice were injected intracerebrally with either [3H]choline or [3H]inositol for 16 h in order to label their respective phospholipids. These lipids were examined at various times (30 s to 30.5 min) after decapitation. Between 30 s and 1.5 min after decapitation, the rate of FFA release (3 μg FA/mg FA in phospholipids/min) was three times more rapid than that between 10 and 15 min (0.8 μg FA/mg FA in phospholipids/min). FFA released during the initial phase were enriched in 20∶4 and 18∶0 whereas those released during the latter phase were nonspecific. The DG fatty acids are enriched in 18∶0 and 20∶4. Ischemia induced a rapid release of DG as measured by its fatty acid content (3.2 μg FA/mg FA in phospholipids/min). Unlike FFA, the level of DG reached a plateau after 1.5 min and remained elevated for the entire 30.5 min. In agreement with previous notions indicating the involvement of phospholipase A2 in ischemic insult, steady increases in radioactivity of both lysophosphatidylcholines and lysophosphatidylinositols were observed with time after decapitation. Based on the preferential increase in both 18∶0 and 20∶4 during the initial time period, the results suggest that poly-PI hydrolysis coupled to DG-lipase may contribute to the initial release of FFA, whereas the FFA released subsequent to the initial phase may be mainly a result of activation of phospholipase A2 acting on phosphatidylcholines and phosphatidylinositols.
27 citations
TL;DR: It is concluded that freshly isolated neurons and glia are viable insofar as the basal rate of eicosanoid synthesis is concerned and the spectrum itself accorded with early data on the biosynthetic activity of the intact tissue in vivo.
Abstract: Despite the extensive literature on brain eicosanoids, no information is available on the cellular source of individual compounds in the mature organ and the relative contribution of different cell types to the total synthetic product. To address this problem, neurons and glia were isolated from the cerebral cortex of the adult rat by a process comprising, in order, trypsinization, selective sieving, differential centrifugation, and density gradient centrifugation. Enrichment of cells in the appropriate fractions was verified by morphological, immunocytochemical, and biochemical criteria. Both neuron- and glia-rich fractions retained synthetic activity throughout the period of incubation (max. 60 min). Among the eicosanoids examined, prostaglandin (PG) E2 was the predominant compound, followed by leukotriene (LT) E4 and thromboxane (TX) B2, whereas LTC4 occurred in minimal amounts. Although the rank order of eicosanoids did not vary with the cell type, absolute values of PGE2 and TXB2 were greater with neurons. PGE2 synthesis was increased by supplementation of the medium with arachidonic acid (2.6 microM), whereas indomethacin (5.6 microM) had the opposite effect. Conversely, LT synthesis was not altered by arachidonic acid and was only marginally reduced by the 5-lipoxygenase inhibitor, U-60,257 (10 microM). Several agonists (12-O-tetradecanoyl-phorbol-13-acetate, TPA; Ca ionophore A23187; platelet-activating factor; endotoxin; recombinant IL-1) were tested on both neuron- and glia-rich fractions but none of them had an effect. We conclude that freshly isolated neurons and glia are viable insofar as the basal rate of eicosanoid synthesis is concerned. No qualitative difference was noted between the two cell types in the spectrum of products formed and the spectrum itself accorded with early data on the biosynthetic activity of the intact tissue in vivo. Our isolation procedure appears useful for the analysis of the cellular source of eicosanoids under resting conditions, although it cannot be applied to the study of the site and mode of action of activators.
TL;DR: In the review, some examples that may provide new avenues for treatment or altering the course of infections are focused on, i.e., antibodies to fusogenic virus membrane proteins, drugs that interfere with lipid metabolism, calcium channel blockers, immunoregulatory molecules, and, and inhibitors of excitotoxic amino acids.
Abstract: Viruses have the capacity to induce alterations and degenerations of neurons by different direct and indirect mechanisms. In the review, we have focused on some examples that may provide new avenues for treatment or altering the course of infections, i.e., antibodies to fusogenic virus membrane proteins, drugs that interfere with lipid metabolism, calcium channel blockers, immunoregulatory molecules, and, and inhibitors of excitotoxic amino acids. Owing to their selectivity in attack on regions of nervous tissue, governed by viral factors and by routes of invasion, viral receptors or metabolic machineries of infected cells, certain viral infections show similarities in distribution of their resulting lesions in the nervous system to that of the common human neurodegenerative diseases (namely, motor neurons disease, Parkinson’s disease, and Alzheimer’s disease). However, it should be emphasized that no infectious agent has as yet provided a complete animal model for any of these diseases, nor has any infectious agent been linked to them from observations on clinical or postomortem materials.
TL;DR: It is demonstrated that rapid transport of Al across the blood-brain barrier (BBB) and the acute nature of Al neurotoxicity in rats is acute, and the rapid transport across the BBB is unacceptable.
Abstract: In the present study the acute effect of intravenous aluminum chloride (1 mg/kg) on choline acetyltransferase (ChAT) and acetyl-cholinesterase (AChE) activities of rats was investigated. Aluminum was found to cross the blood-brain barrier (BBB) as indicated by the detection of aluminum in the cerebrospinal fluid (CSF) 30 min after femoral vein injection. Two hours following aluminum injection, ChAT activity in the basal forebrain and hippocampus was significantly reduced by 30% and 22%, respectively, whereas no change was observed in the caudate nuclei. On the other hand, AChE activity was significantly increased by 45% in the caudate nuclei, whereas little change was observed in other brain areas. This report demonstrates that rapid transport of Al across the BBB, and the acute nature of Al neurotoxicity in rats.
TL;DR: Levels of delta binding and lambda binding were unaffected by TBI, and evidence that mu and kappa opioid receptor subtypes in neocortex and hippocampus may have different functions in TBI is provided.
Abstract: Sprague-Dawley rats were subjected to a moderate level (2.2 atm) of traumatic brain injury (TBI) using fluid percussion. Injured animals were allowed to survive posttrauma for periods of 5 min, 3 h, and 24 h. The effect of TBI on binding to forebrain opiate receptors was assessed using quantitative receptor autoradiography, and compared to a sham control group. Binding of [3H]DAGO to mu receptors in neocortex and the CA1 pyramidal layer of the hippocampus was significantly decreased in the 24-h group (p<0.05). [3H]Bremazocine binding to kappa receptors was unchanged at 5 min and 24 h, but showed large decreases 3 h after TBI in the CA1 pyramidal layer (65%,p<0.05) and dentate gyrus (43%,p<0.05). Levels of delta binding (measured with [3H]DSLET) and lambda binding (measured with [3H]naloxone) were unaffected by TBI. These data support previous suggestions of a role for endogenous opioids in TBI, and provide further evidence that mu and kappa opioid receptor subtypes in neocortex and hippocampus may have different functions in TBI.
TL;DR: This work has shown that the mode of action of chloral hydrate in producing sleep seems to be through its reduced metabolite, trichloroethanol, which is the first synthetic CNS depressant.
Abstract: Chloral hydrate was introduced into therapeutics more than 120 years ago, and soon became popular as a somnifacient. It is the first synthetic CNS depressant. Its metabolite, urochloralic acid, was detected early. Studies of the biochemical pharmacology of chloral hydrate have engaged the attention of many investigators in succeeding years. Its mode of action in producing sleep was initially attributed to the possibility that it gives rise to chloroform in vivo. Although this hypothesis did not stand up to scientific scrutiny, it led to efforts to establish how chloral hydrate brings about its action. This seems to be through its reduced metabolite, trichloroethanol. The precise mode of action on the nervous system remains to be worked out.
TL;DR: The results indicate the existence of a negative association between platelet MAO-B activity and serum levels of vitamin B12 and confirm the exist of biological differences between presenile and senile dementia of Alzheimer type.
Abstract: Platelet MAO-B activity, serum vitamin B12 levels, and plasma folate were measured in patients suffering from presenile (AD) and senile (SDAT) dementia of Alzheimer-type, and vascular dementia (VD). MAO-B was higher in the SDAT group than in AD and controls. An inverse relationship between MAO-B activity and vit. B12 levels was documented in the whole group and in each category studied; furthermore, MAO-B was positively related to age. All the patients were then divided into two groups, according to vit. B12 levels (Group I: <200 pg/mL; Group II: ≥200 pg/mL); Group I showed a significantly higher MAO-B activity with respect to Group II. The results indicate the existence of a negative association between platelet MAO-B activity and serum levels of vitamin B12 and confirm the existence of biological differences between presenile and senile dementia of Alzheimer type.
TL;DR: Murine neuroblastoma cells behave differently in the presence of Al(acac)3 or Al(malt)3, and a remarkable cytotoxic effect was observed in the first case; on the contrary, an evident cytostatic and neuritogenic effect was produced by aqueous Al(lac) 3.
Abstract: Murine neuroblastoma cells behave differently in the presence of Al(acac)3 [acac=2,4-pentanedionate; acetylacetonate] or Al(malt)3 [malt=3-hydroxy, 2-methyl, 4-pyronate; maltolate] with respect to Al(lac)3 [lac=2-hydroxypropionate; lactate]. Thus, a remarkable cytotoxic effect was observed in the first case; on the contrary, an evident cytostatic and neuritogenic effect was produced by aqueous Al(lac)3. The hydrolytically stable complexes Al(acac)3 and Al(malt)3 were both toxic in the concentration range of 0.10–0.30 and 0.10–0.50 mM, respectively, over 24 h. In contrast with this behavior Al(lac)3 displayed a potent cytostatic activity with induction of neurites at 0.2–10 mM. Al(OH)3 manifested biological effects comparable to those exhibited by Al(lac)3. AlPO4 was also cytostatic and led to a morphological differentiation of the neuroblastoma cells, qualitatively different from that elicited by Al(lac)3. The morphological effects induced by Al(lac)3, Al(OH)3, and AlPO4 were irreversible.
TL;DR: It is postulated that stimulation of phosphoinositide hydrolysis is neither necessary nor sufficient for neurotoxicity, although only activation of NMDA receptors is involved in Ibo neurotoxicity.
Abstract: Ibotenic acid (Ibo) has been shown to have agonist activity at both theN-methyl-d-aspartate (NMDA) andtrans-ACPD or metabolotropic quisqualate (Qm) receptor sites in several systems. Both of these receptor sites have been implicated in excitotoxicity. Like NMDA neurotoxicity, Ibo neurotoxicity can be enhanced by glycine and blocked by MK-801. Ibo induced stimulation of phosphoinositide (PI) hydrolysis, on the other hand, is unaffected by either of these treatments. We therefore conclude that Ibo is capable of acting at both NMDA andtrans-ACPD receptors in the CNS, although only activation of NMDA receptors is involved in Ibo neurotoxicity. This conclusion leads us to postulate that stimulation of phosphoinositide hydrolysis is neither necessary nor sufficient for neurotoxicity.
TL;DR: In this paper, a permanent cell line derived from human glioblastoma multiforme with the capacity to maintain glial fibrillary acidic protein (GFAP) production over repeated in vitro passages, was evaluated for the expression of three neuron-associated proteins (Class III beta-tubulin, MAP2, and tau) in three different in vitro systems: as free-floating suspensions, on coverslips, and on a gelatin foam (Gelfoam) matrix.
Abstract: U-251 MG, a permanent cell line derived from human glioblastoma multiforme with the capacity to maintain glial fibrillary acidic protein (GFAP) production over repeated in vitro passages, was evaluated for the expression of three neuron-associated proteins (Class III beta-tubulin, MAP2, and tau) in three different in vitro systems: as free-floating suspensions, on coverslips, and on a gelatin foam (Gelfoam) matrix. Cells grown under the three in vitro conditions were analyzed by immunoblotting techniques, whereas immunohistochemical analyses were performed on cells grown on Gelfoam. By immunohistochemistry, cells were positive for Class III beta-tubulin isotype, a neuron-associated beta-tubulin, for microtubule-associated protein 2 (MAP2), but not for tau. Immunoblotting studies confirmed the presence of Class III beta-tubulin in extracts of cells grown under the three in vitro conditions. MAP2 and tau were clearly evident only in cell extracts grown in Gelfoam cultures. GFAP expression was observed in all three in vitro conditions by immunoblotting and also in foam matrix cultures by immunohistochemistry. In matrix cultures, Class III beta-tubulin- and GFAP-positive cells were found immediately adjacent to each other, but coexpression of these proteins was not observed, and the cells were morphologically indistinguishable. Our findings confirm the heterogeneity of malignant gliomas in vitro, and the implications of these observations require further study.
TL;DR: CSF levels of the main metabolites of monoamines (MHPG, 5-HIAA, and HVA) were measured in patients with early onset (AD) and late-onset (SDAT) Alzheimer's disease, vascular dementia (VD), and elderly controls to support the evidence of SDAT heterogeneity.
Abstract: Cerebrospinal Fluid (CSF) levels of the main metabolites of monoamines (MHPG, 5-HIAA, and HVA) were measured in patients with early onset (AD) and late-onset (SDAT) Alzheimer's disease, vascular dementia (VD), and elderly controls. Psychobehavioral assessment was carried out by means of MMSE and GBS. Mean MHPG levels did not differ from controls; 5-HIAA was lower in VD when compared to both controls and SDAT. HVA was decreased in AD, SDAT, and VD with respect to controls. Significant correlations between HVA and psycho-behavioral parameters were observed in SDAT and VD groups, whereas no relationship was documented in AD. The SDAT group was divided in SDAT-A (age at onset: greater than 65 less than or equal to 80 yr) and SDAT-B (age at onset: greater than 80 yr). SDAT-A had significantly lower CSF HVA values than SDAT-B (165 +/- 64 vs 235.7 +/- 85). SDAT-B HVA levels were similar to those observed in controls. Correlation analysis between HVA and neuropsychological variables was significant in SDAT-A, but not in SDAT-B. These results might support the evidence of SDAT heterogeneity.
TL;DR: A progressive degeneration of these cholinergic neurons characterized by the formation of immunoreactively atypical NFT is found, which suggests a unique pathogenesis of the basal forebrain separate from other cortical regions in AD.
Abstract: An immunohistochemical analysis utilizing antibodies to glial fibrillary acid protein (GFAP), microglia, beta-amyloid, amyloid P-component, neurofibrillary tangles (NFT), and microtubule associated protein-tau (MAP-tau) was performed on the cholinergic basal forebrain in Alzheimer's disease (AD). This severely compromised system, which includes the nucleus basalis of Meynert, is largely responsible for the massive loss of cortical and subcortical cholinergic innervation in the diseased state. Our study juxtaposes the basal forebrain immunohistopathology to the hippocampus, amygdala, and entorhinal cortex in AD. Key findings include a progressive degeneration of these cholinergic neurons characterized by the formation of immunoreactively atypical NFT, the loss of intraneuronal lipofuscin, a lack of senile plaque and beta-amyloid deposition within the basal forebrain, and end-stage gliosis without residual extracellular NFT. These structural and compositional differences suggest a unique pathogenesis of the basal forebrain separate from other cortical regions in AD.
TL;DR: In this article, a rat brain synaptosomes and mitochondria with LPO inducers (Fe2+ and ascorbate) were incubated with rat brain mitochondria, and a decrease of deamination of serotonin (substrate of MAO-A) in mitochondria was observed.
Abstract: Incubation of rat brain synaptosomes and mitochondria with LPO inducers (Fe2+ and ascorbate) was accompanied by a decrease of deamination of serotonin (substrate of MAO-A) in mitochondria, but not in synaptosomes, with simultaneous stimulation of GABA and GLCA deamination, apparently owing to modification of catalytic properties of brain membrane-bound MAO. Oxidation of PEA (substrate of MAO-B) was insignificantly altered in both fractions. Reactions of deamination of serotonin, GABA, and GLCA (but not PEA), were highly sensitive to a selective inhibitor of MAO-A pyrazidol (pyrlindole). Isoniazid and hydrazides of quinoline carbonic acids (inhibitors of both modified MAO and copper-containing amine oxidases) strongly inhibited deamination of GABA and GLCA. During epileptiformic seizures in rats, genetically selected for high incidence of audiogenic epilepsia, stimulation in brain synaptosomes and mitochondria of LPO was observed. This was accompanied by a marked decrease in serotonin and PEA deamination, with a simultaneous increase in GABA and GLCA deamination in both fractions. The data obtained suggest that appearance of GABA-deaminating activity owing to modification of catalytic properties of MAO, might be an essential pathogenetic component in the development of epileptic seizures.
TL;DR: It is concluded that diabetes is associated with development of a time-related alteration of cerebral Gi/Go proteins and that this defect is not owing to gross changes in either content of G proteins or mRNA level, but probably reflects modifications of G protein's structure or physiological status affecting the coupling with membrane effector systems and the sensitivity to PTX.
Abstract: Previous studies from our laboratory have suggested that diabetes-associated central nervous system abnormalities are characterized by progressive alterations of neurotransmitters and of transductional Gi/Go proteins. In this study, we have further characterized these abnormalities in the striatum of alloxan-diabetic rats by means of adenosine 5'-diphosphate (ADP)-ribosylation, and Western and Northern blotting techniques. Fourteen weeks after diabetes induction, pertussis-toxin (PTX) catalyzed ADP-ribosylation of Gi/Go proteins was markedly reduced in diabetic animals, as shown by a clear decrease of 32P-ADPribose incorporation into G protein alpha subunits. In agreement with our previous pharmacological studies that showed a reduction of Gi-mediated modulation of adenylate cyclase activity only at this stage of diabetes, no changes in PTX-mediated ADP-ribosylation were observed earlier (5-wk diabetes). Immunoblotting studies performed by using antibodies selectively raised against Gi-2, Go, and Gs proteins did not reveal any differences between control and diabetic animals at any stage of diabetes. Similarly, the mRNAs corresponding to the alpha subunits of Gi-2, Go, and Gs proteins did not show any marked changes in chronic diabetic rats with respect to control animals. It is therefore concluded that diabetes is associated with development of a time-related alteration of cerebral Gi/Go proteins and that this defect is not owing to gross changes in either content of G proteins or mRNA level, but probably reflects modifications of G protein's structure or physiological status affecting the coupling with membrane effector systems and the sensitivity to PTX.
TL;DR: The present results suggest that implantation of DA microspheres may promote DA fiber growth and extended recovery of surviving DA neurons, and, therefore, could be of therapeutic usefulness in Parkinson's disease.
Abstract: Injectable local drug delivery formulations—so-called microspheres —have recently been developed, in which drugs are microencapsulated within biocompatible and biodegradable copolymer excipients like poly[DL-lactide-co-glycolide]. In view of its potential therapeutical usefulness, we have studied the microsphere methodology as a means to substitute for experimentally induced subnormal levels of endogenous dopamine (DA). Administration of 6-hydroxydopamine (6-OH-DA) unilaterally in the medial forebrain bundle of rats results in an up-regulation of postsynaptic receptors in the denervated striatum, functionally manifested as contralateral rotational behavior after apomorphine. DA microspheres were implanted in the denervated striatum. The majority of the rats displayed an attenuation of the contralateral rotational behavior induced by apomorphine up to 8 wk postimplantation. Immunocytochemical observations unexpectedly demonstrated growth of DA and tyrosine hydroxylase immunoreactive fibers in the denervated striatum. Interestingly, there was an apparent correlation between functional recovery and the degree of growth of DA fibers. The present results suggest that implantation of DA microspheres may promote DA fiber growth and extended recovery of surviving DA neurons, and, therefore, could be of therapeutic usefulness in Parkinson’s disease.
TL;DR: Antibodies against EGFR deletion-mutant Type III show highly restricted activity with a subset of glioma biopsies (6/35) expressing the mutant EGFR.
Abstract: Operationally specific monoclonal antibodies (MAbs) reactive with tumor but not normal adult tissues offer great potential for diagnosis and therapy of CNS neoplasms. Two targets for specific MAb localization were chosen for this study: (1) glioma-associated gangliosides GM2 [II3NeuAc-GgOse3Cer], GD2 [II3(NeuAc)2-GgOse3Cer], GD3[II3(NeuAc)2-LacCer], 3'-isoLM1 [IV3NeuAc-LcOse4Cer], and 3',6'-isoLD1 [IV3NeuAc,III6NeuAc-LcOse4Cer] and (2) epidermal growth factor receptor (EGFR) variant molecules. Epitopic specificity of isolated ganglioside hybridomas was determined with FAB-MS defined ganglioside standards. All MAb are IgM. Assay of 14 cytologic specimens and 31 frozen sections of primary CNS neoplasms revealed staining with anti-GD3 (14/14, 31/31), anti-GM2 (9/14, 26/31), and anti-GD2 (6/14, 24/30), respectively. 3'-isoLM1 and 3',6' isoLD1, which exhibit a restricted oncofetal expression pattern and are not detectable in adult human brain, are present in 15/31 primary CNS neoplasms and in 1/8 human glioma xenografts, as detected by MAbs SL-50 and DMAb-14, respectively. EGFR proteins, the second target, have unique amino acid spans resulting from gene deletion in the amplified EGFR gene present in subsets of malignant human gliomas. Antibodies against EGFR deletion-mutant Type III show highly restricted activity with a subset of glioma biopsies (6/35) expressing the mutant EGFR. These reagents should be useful for in vitro and in vivo diagnosis and, potentially, for treatment of malignant brain tumors.
TL;DR: It is unlikely that improvements in the classification of brain tumors will be based solely on histological information, so definitions of tumor entities that will provide more accurate prognoses and bases for effective therapy will require considerably more information at the molecular level than is currently available.
Abstract: The purpose of this review is to clarify for the nonneuropathologist some of the confusing issues concerning the classification of brain tumors. Following a short discussion of the commonly used methods to diagnose brain tumors clinically (frozen section, light and electron microscopy, immunohistochemistry), the general principles of classifying neural tumors are presented. Grading of tumors on the basis of histological anaplasia, and the concept that tumor cells can be related to specific cytological stages of normal cellular development (cytogenetic classification) are presented. The World Health Organization system of classifying neural tumors is an attempt to develop a standardized classification scheme with as few interpretative controversies as possible, but it has required revision as new information has been gained. The major clinical and biological features of the commonest tumor groups are then discussed. It is unlikely that improvements in the classification of brain tumors will be based solely on histological information. Definitions of tumor entities that will provide more accurate prognoses and bases for effective therapy will require considerably more information at the molecular level than is currently available.
TL;DR: The hypothesis that ischemia increases cAMP accumulation by facilitating the postreceptor AC activation through a PKC-involving pathway and by promoting the stronger coupling of membrane AC receptors with G-protein is supported.
Abstract: The brain cyclic AMP generation was studied in rats subjected to 15 min of cardiac arrest. We have used a particulate, synaptoneurosomal fraction to demonstrate the effect of ischemia in vivo on the responsiveness of adenylate cyclase (AC) system. It has been shown that, although there is a slight decrease in AC activity after ischemia, the in vitro fractions produce more cAMP in response to a variety of stimuli, suggesting an indirect, nonadenylate cyclase activation mechanism.
TL;DR: The results confirm the extensive degradation of myelin basic protein (MBP), proteolipid protein (PLP), and, to a lesser extent, the other myelin proteins by endo- and exogenous CANP and suggest complex and specific roles for these isoenzymes during myelin formation as discussed further in this article.
Abstract: Calcium-activated neutral protease (CANP) in normal and dysmyelinating mutant, paralytic tremor (PT) rabbit myelin and premyelin fractions was studied using immature (4–5 wk) or adult animals. The enzyme was estimated by determination of its catalytic activity as well as by using immunoblot analysis after SDS-PAGE separation. The presence of two forms of CANP—one activated by calcium in the micromolar concentration (μCANP) range and the other exhibiting low calcium sensitivity in the millimolar concentration range (m-CANP)—was found in the myelin and premyelin fractions. The developmental pattern of the enzyme activity was different for each of these two enzyme isoforms depending on the fraction studied. The higher activity on CANP (both isoforms) found in PT myelin and premyelin could be related to delayed myelination and/or to the higher turnover rate of already formed myelin. These results suggest complex and specific roles for these isoenzymes during myelin formation as is discussed further in this article. Our results confirm the extensive degradation of myelin basic protein (MBP), proteolipid protein (PLP), and, to a lesser extent, the other myelin proteins by endo- and exogenous CANP. This degradation process was significantly elevated in PT rabbit myelin. Moreover as was shown by two-dimensional gel electrophoresis, calcium-controlled proteolysis in nonmutant rabbits affected the net-charge of MBP in a manner similar to that reported for PT myelin, suggesting the possible involvement of CANP in the generation of charge isomers of MBP.
TL;DR: The cerebral energy metabolite profile of tissue from the ipsilateral hemisphere, corresponding to the region where samples were obtained for PKC activity assay, suggests that this tissue may have been part of the ischemic penumbra before further deterioration.
Abstract: Protein kinase C (PKC) activity was investigated in a model of focal stroke in the rat. Following 6 h of left middle cerebral artery occlusion, rat brains were frozenin situ. In the peripheral ischemic zone, total PKC activity declined by close to two-thirds (1.07±0.35 vs 2.77±0.12 nmol/min/mg protein;p<0.05,n=4), and the proportion of total activity associated with the particulate fraction decreased from 33.3±1.5% to 16.2±1.4% (p<0.01,n=4). Thus, overall particulate PKC activity in the ischemic zone was <20% of control. The cerebral energy metabolite profile of tissue from the ipsilateral hemisphere, corresponding to the region where samples were obtained for PKC activity assay, suggests that this tissue may have been part of the ischemic penumbra before further deterioration.
TL;DR: These changes correspond to electrophysiological studies suggesting that peripheral manipulation of the somatosensory system, e.g., nerve transection, is accompanied by changes in GABAergic transmission, as well as high-affinity uptake of GABA is not affected.
Abstract: We have studied the changes in the GABAergic system in the rat somatosensory cortex 1–14 d after sensory deprivation of the hind-limb representation area. Glutamate decarboxylase (GAD) activity was measured in the individual cortical layers using serial sections cut on a freezing microtome parallel to the cortical surface. Gamma-aminobutyric acid (GABA) high-affinity uptake was studied in cortical homogenates of the hind-limb representation area. There was a ≤13% decrease in GAD activity in layer II–IV in both cortical hemispheres 3 d after sciatic nerve injury. In contrast, we found that high-affinity uptake of GABA is not affected.