| 1. |
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| 2. |
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| 3. |
- Ekström, Per A R, et al.
(författare)
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Impaired nerve regeneration in streptozotocin-diabetic rats. Effects of treatment with an aldose reductase inhibitor
- 1989
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Ingår i: Journal of the Neurological Sciences. - 0022-510X. ; 93:2-3, s. 231-237
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Forskningsöversikt (refereegranskat)abstract
- Rats with streptozotocin-induced diabetes have a decreased rate of sciatic nerve regeneration. We studied the effects on this defect of treatment with the aldose reductase inhibitor, ponalrestat (25 mg/kg per day via an endogastric tube). The nerves of diabetic rats were crush-injured at 5 weeks of diabetes and regeneration evaluated 7 days later with the pinch-reflex test. Ponalrestat treatment was started at day 3 after streptozotocin injection and was continued for the whole experimental period, i.e. until 6 weeks of diabetes. The treatment prevented effectively the accumulation of sorbitol and fructose in the nerves of diabetic rats, but was without effect on the sciatic nerve regeneration (controls 21.8 ± 1.2 mm/7 days (mean ± SEM, n = 6), untreated diabetics 15.8 ± 1.8 (n = 7), ponalrestat-treated diabetics 16.2 ± 1.0 (n = 10)). The results indicate that there is no connection between increased sorbitol pathway flux and impaired regeneration in streptozotocin diabetic rats.
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| 4. |
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| 5. |
- Hansson, H A, et al.
(författare)
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Evidence indicating trophic importance of IGF-I in regenerating peripheral nerves
- 1986
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Ingår i: Acta Physiologica Scandinavica. - : Wiley. - 0001-6772 .- 1365-201X. ; 126:4, s. 14-609
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Tidskriftsartikel (refereegranskat)abstract
- The mechanisms influencing regeneration of peripheral nerves are incompletely known, but growth factors are supposed to play a key role. In the present study, we demonstrate, with the aid of immunohistochemical methods, that somatomedin C (Sm-C/insulin-like growth factor I/IGF-I) rapidly increased from low to high concentrations, reaching peak values in 2 weeks, in regenerating sciatic nerves of adult rats. In addition, IGF-I was demonstrated extracellularly, never observed in the control nerves. Reactive Schwann cells appeared to be the major source for IGF-synthesis. Higher concentrations were seen in tubulated nerves as compared to sutured ones. It is proposed that IGF-I exerts important growth supporting effects on regenerating peripheral nerves.
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| 6. |
- Agardh, Carl-David, et al.
(författare)
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Endogenous substrates utilized by rat brain in severe insulin-induced hypoglycemia
- 1981
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Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 36:2, s. 490-500
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Tidskriftsartikel (refereegranskat)abstract
- Several previous studies have demonstrated that severe hypoglycemia is accompanied by consumption of endogenous brain substrates (glycolytic and citric acid cycle metabolites and free amino acids) and some have shown a loss of structural components as well, notably phospholipids. In the present study, on paralysed and artificially ventilated rats, we measured cerebral oxygen and glucose consumption during 30 min of hypoglycemic coma (defined as hypoglycemia of sufficient severity to cause cessation of spontaneous EEG activity) and calculated the non-glucose oxygen consumption. In an attempt to estimate the missing substrate we measured tissue concentrations of phospholipids and RNA. After 5 min of hypoglycemic coma, tissue phospholipid content decreased by about 8% with no further change during the subsequent 55 min. A similar reduction remained after 90 min of recovery, induced by glucose administration following 30 min of coma. Since no preferential loss of polyenoic fatty acids or of ethanolamine phosphoglycerides occurred, it is concluded that loss of phospholipids was due to phospholipase activity rather than to peroxidative degradation. The free fatty acid concentration increased sixfold after 5 min of coma and remained elevated during the course of hypoglycemia. A 9% reduction in tissue RNA content was observed after 30 min of hypoglycemia. Calculations indicated that available endogenous carbohydrate and amino acid substrates were essentially consumed after 5 min of coma, and that other non-glucose substrates must have accounted for approximately 50μmol·g−1 of oxygen (8.3 μmol·g−1 in terms of glucose equivalents) within the 5–30 min period. The 10% reduction in phospholipid-bound fatty acids was more than sufficient (in four- to fivefold excess) to account for this oxygen consumption. However, since no further degradation occurred in the 5–30 min period, there is no simple, direct, quantitative relationship between oxygen consumption and cortical fatty acid oxidation during this interval. The possibility thus remains that unmeasured exogenous or endogenous substrates were utilized.
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| 7. |
- Agardh, Carl-David, et al.
(författare)
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Hypoglycemic brain injury. I. Metabolic and light microscopic findings in rat cerebral cortex during profound insulin-induced hypoglycemia and in the recovery period following glucose administration
- 1980
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Ingår i: Acta Neuropathologica. - 1432-0533. ; 50:1, s. 31-41
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Tidskriftsartikel (refereegranskat)abstract
- Profound hypoglycemia causing the disappearance of spontaneous EEG activity was induced by insulin in rats. For analysis of cerebral cortical concentrations of labile phosphates, glycolytic metabolites and amino acids, the brain was frozen in situ. For microscopic analysis of the corresponding cerebral cortical areas the brain was fixed by perfusion. Hypoglycemia with an isoelectric EEG for 30 and 60 min caused severe perturbation of the cerebral energy metabolites. After both 30 and 60 min of isoelectric EEG, two microscopically different types of nerve cell injury were seen. Type I injury was characterized by angulated, darkly stained neurons with perineuronal vacuolation, mainly affecting small neurons in cortical layer 3. Type II injured neurons, mainly larger ones in layers 5–6, were slightly swollen with vacuolation or clearing (depending on the histotechnique used) of the peripheral cytoplasm, but had no nuclear changes. Recovery was induced by glucose injection. Improvement in the cerebral energy state occurred during the 30 min recovery period even after 60 min of hypoglycemia. However, the persisting reduction in the size of adenine nucleotide and amino acid pools after 30 or 180 min recovery suggested that some cells remained damaged. In confirmation many type I injured neurons persisted during the recovery suggesting an irreversible injury. The disappearance of virtually all type II injuries indicated reversibility of these histopathological changes. The microscopic changes in hypoglycemia were different from those in anoxia-ischemia suggesting a dissimilar pathogenesis in these states despite the common final pathway of energy failure.
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| 8. |
- Agardh, Carl-David, et al.
(författare)
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Influence of severe hypoglycemia on mitochondrial and plasma membrane function in rat brain
- 1982
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Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 38:3, s. 662-668
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Tidskriftsartikel (refereegranskat)abstract
- Abstract: Previous experiments have shown that severe hypoglycemia disrupts cerebral energy state in spite of a maintained cerebral oxygen consumption, suggesting uncoupling of oxidative phosphorylation. Other studies have demonstrated that hypoglycemia leads to loss of cerebral cortical phospholipids and phospholipid-bound fatty acids. The objective of the present study was, therefore, to study respiratory characteristics of brain mitochondria during severe hypoglycemia and to correlate respiratory activity to mitochondrial phospholipid composition. Mitochondria were isolated after 30 or 60 min of hypoglycemia with ceased EEG activity, and after a 90-min recovery period, and their resting (state 4) and ADP-stimulated (state 3) oxygen consumption rates and phospholipids and phospholipid-bound fatty acid content were measured. After 30 min of hypoglycemia, state 3 respiration decreased without any increase in state 4 respiration or change in ADP/O ratio. This decrease, which occurred with glutamate plus malate—but not with succinate—as substrates, was partly reversed by addition of bovine serum albumin and KCI. Chemical analyses of isolated mitochondria did not reveal changes in their phospholipid or fatty acid content. The results thus failed to account for the dissociation of cerebral energy state and oxygen consumption. It is emphasized, though, that uncoupling may well occur in vivo due to accumulation of free fatty acids and "futile cycling" of K+ and Ca2+. After 60 min of hypoglycemia, a moderate decrease in state 3 respiration was observed also with succinate as substrate, and there was some decrease in ADP/O ratios in KCI-containing media. However, the changes in ADP/O ratios were more conspicuous during recovery; in addition, state 4 respiration increased significantly. It is concluded that changes in mitochondrial function after 30 min of hypoglycemia are potentially reversible but that true mitochondrial failure develops in the recovery period following 60 min of hypoglycemia. This conclusion was corroborated by results demonstrating incomplete recovery of cerebral energy state. Since EEG and sensory evoked potentials return after 30 min but not after 60 min of hypoglycemia it seemed difficult to explain failure of return of electrophysiological function after 60 min of hypoglycemia solely by mitochondrial dysfunction; plasma membrane function was therefore assessed by measurements of extracellular potassium activity ([K+]e). The results showed that whereas [K+]e remained close to control in the recovery period following 30 min of hypoglycemia it rose progressively during recovery following 60 min of hypoglycemia. Possibly, inhibition of Na+ K+–activated ATPase could contribute to the permanent loss of spontaneous or evoked electrical activity.
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| 9. |
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| 10. |
- Andersson, G, et al.
(författare)
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Evidence for a GABA-mediated cerebellar inhibition of the inferior olive in the cat
- 1988
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Ingår i: Experimental Brain Research. - 0014-4819. ; 72:3, s. 450-456
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Tidskriftsartikel (refereegranskat)abstract
- 1. Climbing fibres were activated by peripheral nerve stimulation at 'high' frequencies (greater than 3 Hz) for 15-25 s and then at 0.9 Hz for about 1 min. The high frequency activation induced a post-conditioning inhibition, lasting up to about 1 min, of climbing fibre responses recorded from the cerebellar surface. 2. Electrolytic lesions were made in the superior cerebellar peduncle (brachium conjunctivum). After the lesion, the post-conditioning inhibition was completely eliminated. 3. Injections of the GABA-receptor blocker bicuculline methiodide into the inferior olive reversibly blocked the post-conditioning inhibition. 4. The results support the hypothesis proposed by Andersson and Hesslow (1987a), that post-conditioning inhibition is mediated by a GABA-ergic interposito-olivary pathway.
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| 11. |
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| 12. |
- Auer, R. N., et al.
(författare)
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The distribution of hypoglycemic brain damage
- 1984
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Ingår i: Acta Neuropathologica. - 0001-6322. ; 64:3, s. 177-191
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Tidskriftsartikel (refereegranskat)abstract
- Rats were exposed to insulin-induced hypoglycemia resulting in periods of cerebral isoelectricity ranging from 10 to 60 min. After recovery with glucose, they were allowed to wake up and survive for 1 week. Control rats were recovered at the stage of EEG slowing. After sub-serial sectioning, the number and distribution of dying neurons was assessed in each brain region. Acid fuchsin was found to stain moribund neurons a brilliant red. Brains from control rats showed no dying neurons. From 10 to 60 min of cerebral isoelectricity, the number of dying neurons per brain correlated positively with the number of minutes of cerebral isoelectricity up to the maximum examined period of 60 min. Neuronal necrosis was found in the major brain regions vulnerable to several different insults. However, within each region the damage was not distributed as observed in ischemia. A superficial to deep gradient in the density of neuronal necrosis was seen in the cerebral cortex. More severe damage revealed a gradient in relation to the subjacent white matter as well. The caudatoputamen was involved more heavily near the white matter, and in more severely affected animals near the angle of the lateral ventricle. The hippocampus showed dense neuronal necrosis at the crest of the dentate gyrus and a gradient of increasing selective neuronal necrosis medially in CA1. The CA3 zone, while relatively resistant, showed neuronal necrosis in relation to the lateral ventricle in animals with hydrocephalus. Sharp demarcations between normal and damaged neuropil were found in the hippocampus. The periventricular amygdaloid nuclei showed damage closest to the lateral ventricles. The cerebellum was affected first near the foramina of Luschka, with damage occurring over the hemispheres in more severely affected animals. Purkinje cells were affected first, but basket cells were damaged as well. Rare necrotic neurons were seen in brain stem nuclei. The spinal cord showed necrosis of neurons in all areas of the gray matter. Infarction was not seen in this study. The possibility is discussed that a neurotoxic substance borne in the tissue fluid and cerebrospinal fluid (CSF) contributes to the pathogenesis of neuronal necrosis in hypoglycemic brain damage.
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| 13. |
- Auer, R., et al.
(författare)
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The dentate gyrus in hypoglycemia : Pathology implicating excititoxin-mediated neuronal necrosis
- 1985
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Ingår i: Acta Neuropathologica. - 0001-6322. ; 67:3-4, s. 279-288
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Tidskriftsartikel (refereegranskat)abstract
- A detailed light- and electron-microscopic study of the damage to the rat dentate gyrus in hypoglycemia was undertaken, in view of the previously advanced hypothesis that hypoglycemic nerve cell injury is mediated by a released neurotoxin. The distribution of neuronal necrosis showed a relationship to the subarachnoid cisterns. Electron microscopy of the dentate granule cells and their apical dendrites revealed dendrosomal, axon-sparing neuronal pathology. Dentate granule cells were affected first in the dendrites in the outer layer of the stratum moleculare, sparing axons of passage and terminal boutons. Subsequently, the neuronal perikarya were affected, and Wallerian degeneration of axons followed. Cell membrane abnormalities preceded the appearance of mitochondrial flocculent densities and degradation of the cytoskeleton, and are suggested to be early lethal changes. The observed early dendrotoxic changes, and the dendrosomal, axon-sparing nature of the lesion implicate an excitotoxin-mediated neuronal necrosis in hypoglycemia.
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| 14. |
- Bassant, M H, et al.
(författare)
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Electrophysiological and pharmacological properties of neurons within solid basal forebrain transplants in the rat brain
- 1988
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Ingår i: Brain Research. - : Elsevier BV. - 0006-8993. ; 460:1, s. 8-16
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Tidskriftsartikel (refereegranskat)abstract
- Electrophysiological and pharmacological properties of neurons within solid basal forebrain transplants were studied in adult rats anesthetized with urethane. No specific topography of the neurons recorded was observed within the graft. The mean spontaneous activity of the grafted neurons (GNs) was relatively low (4.9 impulses/s) but not unlike that of other central neurons in situ. A large proportion of GNs fired with regular discharges, but other modes of discharge were also observed. A few rhythmically bursting GNs were recorded having a discharge pattern very much like that of the rhythmically bursting medial septal neurons. The responses of GNs to glutamate, gamma-aminobutyric acid, acetylcholine, serotonin and norepinephrine was fairly similar to those described in other central structures.
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| 15. |
- Björklund, Anders, et al.
(författare)
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Intracerebral grafting of neuronal cell suspensions. I. Introduction and general methods of preparation.
- 1983
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Ingår i: Acta Physiologica Scandinavica. ; Suppl. 522, s. 1-7
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Tidskriftsartikel (refereegranskat)abstract
- The steps involved in the grafting of mesencephalic and septal embryonic tissue in the form of dissociated cell suspensions are described in detail. This includes dissection of the donor embryos, incubation in trypsin, mechanical dissociation, and stereotaxic injection into the brains of adult recipient rats. Some of the technical problems and limitations are discussed.
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| 16. |
- Björklund, Anders, et al.
(författare)
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Intracerebral grafting of neuronal cell suspensions. II. Survival and growth of nigral cells implanted in different brain sites
- 1983
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Ingår i: Acta Physiologica Scandinavica. ; Suppl. 522, s. 9-18
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Tidskriftsartikel (refereegranskat)abstract
- Dissociated dopamine-rich cell suspensions were prepared from the ventral mesencephalon of rat embryos and injected in one or several sites in striatal and non-striatal regions in the dopaminergically denervated brain of adult rats. While the grafts survived well in all sites, the dopamine fibre outgrowth was markedly different depending on whether the grafts occurred in an area normally innervated by the mesencephalic dopamine neurones (i.e. neostriatum or nc. accumbens) or in areas not normally innervated by these neurones (i.e. parietal cortex, lateral hypothalamus or substantia nigra). Moreover, in grafts placed at different sites along the trajectory of the nigrostriatal pathway the outgrowing fibres remained confined to the graft, and there was little evidence that the implanted neurones could elongate their axons along the pathway of the nigrostriatal tract to reach the striatum from a distance. Thus, the intracerebral suspension grafts provided efficient reinnervation of a denervated target only when placed in the immediate vicinity of the target area. The results of multiple graft placements indicate that a relatively complete restoration of a lost innervation should be possible to achieve in large areas of the brain, such as the striatal complex, with the suspension grafting technique.
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| 17. |
- Björklund, Anders, et al.
(författare)
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Intracerebral grafting of neuronal cell suspensions. VI. Survival and growth of intrahippocampal implants of septal cell suspensions
- 1983
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Ingår i: Acta Physiologica Scandinavica. ; Suppl. 522, s. 49-58
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Tidskriftsartikel (refereegranskat)abstract
- The survival and growth of intrahippocampal septal suspension grafts were investigated by acetylcholine esterase (AChE) histochemistry in animals with lesions of the intrinsic septohippocampal cholinergic pathways. AChE was demonstrable in the grafts after the first postoperative week, and AChE-positive fibres were seen to extend into the host hippocampus by 3 weeks. Rapid fibre outgrowth occurred between 3 weeks and 3 months after grafting, and continued at a slower rate thereafter. By 6 months a fairly complete reinnervation of the initially denervated hippocampus was achieved in most specimens, and this persisted at 14 months, the longest postoperative time analysed. A comparison between the development of the AChE-positive neurones in the suspension grafts with that seen during ontogeny in situ suggested that the grafted neurones lagged behind normal development by at least 1 week. Similar to our previous observations on septal grafts implanted as solid tissue pieces, the pattern of the newly-formed AChE-positive innervation in the host hippocampal formation, established from the septal suspension grafts, was remarkably similar to that of the normal AChE-positive septal innervation. This pattern became established as soon as the graft-derived fibres first grew in, suggesting that the ingrowing axons extended and ramified preferentially into those hippocampal subfields which normally receive an AChE-positive innervation from the septal-diagonal band area.
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| 18. |
- Björklund, Anders, et al.
(författare)
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Intracerebral grafting of neuronal cell suspensions. VII. Recovery of choline acetyltransferase activity and acetylcholine synthesis in the denervated hippccampus reinnervated by septal suspension implants
- 1983
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Ingår i: Acta Physiologica Scandinavica. ; Suppl. 522, s. 59-66
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Tidskriftsartikel (refereegranskat)abstract
- The time-course and magnitude of fibre outgrowth from septal suspension grafts injected into the previously denervated hippocampal formation was monitored by measurements of choline acetyltransferase (ChAT), and the activity of the grafted neurons was assessed by measurements of [14C]acetylcholine (ACh) synthesis from [14C]glucose in vitro. Graft-derived ChAT activity was barely detectable 10 days after grafting, but increased sharply between 10 days and 1 month in the areas of the hippocampus located close to the septal implants. By 6 months ChAT activity was restored to near normal levels in all segments of the previously denervated hippocampus. The overall hippocampal [14C]ACh synthesis was also restored to normal levels in the grafted animals, and estimates of the ACh turnover rate suggested that the transmitter machinery of the newly established "septo-hippocampal" connections operated at a rate similar to that of the intrinsic septohippocampal pathway. The intrahippocampal septal suspension grafts, similar to the intrastriatal nigral grafts, thus seem to be capable of maintaining function at a relatively "physiological" level despite their abnormal positions.
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| 19. |
- Blomqvist, Photjanee, et al.
(författare)
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Cyclic AMP Concentrations in Rat Neocortex and Hippocampus During and Following Incomplete Ischemia : Effects of Central Noradrenergic Neurons, Prostaglandins, and Adenosine
- 1985
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Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 44:5, s. 1345-1353
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Tidskriftsartikel (refereegranskat)abstract
- Abstract: The concentrations of cyclic AMP, noradrenaline, glycogen, glucose, lactate, pyruvate, labile phosphate compounds, and free fatty acids were investigated in the rat neocortex and hippocampus during and following cerebral ischemia. An incomplete ischemia of 5 and 15 min duration was induced by bilateral carotid clamping combined with hypotension. The postischemic events were studied after 5, 15, and 60 min of recirculation. Five minutes of ischemia did not significantly alter the neocortical or hippocampal concentrations of cyclic AMP. After 15 min of ischemia the neocortical levels decreased significantly below control values. In the recirculation period following ischemia a significant elevation of the cyclic AMP concentrations was observed. Following 5 min of recirculation after 5 min of ischemia the levels increased from 2.53 ± 0.21 nmol ± g−1 to 5.18 ± 0.09 nmol ± g−1 in the neocortex and from 2.14 ± 0.16 nmol ± g−1 to 3.52 ± 0.35 nmol ± g−1 in the hippocampus. Five minutes of recirculation following 15 min of ischemia led to a significant increase in the levels of cyclic AMP, to 12.86 ± 1.43 nmol ± g−1 in the neocortex to 5.58 ± 0.57 nmol ± g−1 in the hippocampus. With longer recirculation periods the cyclic AMP levels progressively decreased and were similar to control values after 60 min. Depletion of cortical noradrenaline by at least 95% was performed by injections of 6‐hydroxydopamine into the ascending axon bundles from the locus ceruleus. The lesion did not significantly change the ischemic or postischemic neocortical and hippocampal levels of cyclic AMP, glycogen, or free fatty acids including arachidonic acid. Treatment of the animals with theophyllamine (23, 46, and 92 mg ± kg−1) or indomethacin (10 mg ± kg−1) did not affect the postischemic levels of cyclic AMP. It is concluded that central noradrenergic neurons, prostaglandins, and adenosine are not of major importance for the observed postischemic elevations of cyclic AMP and that the changes in the concentrations of free fatty acids measured during and following ischemia are not mediated by noradrenergic neurons.
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| 20. |
- Blomqvist, P., et al.
(författare)
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Delayed postischemic hypoperfusion : Evidence against involvement of the noradrenergic locus ceruleus system
- 1984
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 4:3, s. 425-429
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Tidskriftsartikel (refereegranskat)abstract
- This study explores the possibility that the delayed hypoperfusion observed after an ischemic insult might be due to vasoconstriction induced by the release of noradrenaline from nerves originating in the locus ceruleus. Bilateral 6-hydroxydopamine lesions of the ascending bundles from the locus ceruleus were carried out in the caudal mesencephalon of rats. Local CBF was measured with an autoradiographic technique 60 min following the start of recirculation after incomplete forebrain ischemia. No significant differences in CBF between nonoperated, sham-operated, and noradrenaline-depleted animals were observed in any structure of the forebrain. It is concluded that the noradrenergic locus ceruleus system does not contribute to the development of delayed postischemic hypoperfusion.
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| 21. |
- Blomqvist, P., et al.
(författare)
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Ischemic brain damage in rats following cardiac arrest using a long-term recovery model
- 1985
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 5:3, s. 420-431
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Tidskriftsartikel (refereegranskat)abstract
- A model is described in which transient complete cerebral ischemia is induced in rats by intracardiac injection of potassium chloride. The animals were intubated and mechanically ventilated with a nitrous oxide/oxygen (70:30) mixture. Cardiac arrest was achieved following a brief period of ventricular fibrillation. After 5-6 min, the circulation was restored by cardiopulmonary resuscitation and partial exchange transfusion. Local CBF (LCBF) during ischemia and cardiac resuscitation was studied by injection of [14C]iodoantipyrine into the right auricle at various periods during cardiac arrest, and was subsequently analyzed by autoradiography. No radioactive tracer could be visualized in any brain structure, demonstrating the absence of CBF during the cardiac standstill. LCBF was also studied at 5 min and 6.5 h after cardiac resuscitation. Five minutes of recirculation showed an increase in blood flow in all brain structures studied, ranging between 130 and 400% of control values. After 6.5 h of recirculation, the CBF was decreased in 13 of 24 brain structures by 20-50%, concomitantly with the depressed rate of glucose utilization found in 15 brain structures. The neocortical, hippocampal, and striatal concentrations of labile phosphates, lactate, pyruvate, phosphocreatine, glucose, and glucogen were measured 5 min after cardiac arrest. Extensive energy failure and elevation of lactate levels were observed and were similar to earlier reported values. One week following recovery from the ischemic insult, the animals were perfusion-fixed with formaldehyde. The brains were embedded in paraffin, subserially sectioned, and stained with cresyl violet/acid fuchsin. Histopathological changes were assessed by light microscopy as the number of acidophilic or pyknotic neurons. Morphological changes were observed in the hilus of the dentate gyrus, the hippocampal CA1 and subicular regions, the dorsal and lateral septum, the olfactory tubercle, the primary olfactory cortex, the entorhinal cortex, the amygdaloid nuclei, and the reticular nucleus of the thalamus. The distribution of the morphological changes suggests a transsynaptic mechanism, causing neuronal necrosis primarily in the limbic brain areas.
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| 22. |
- Blomqvist, Photjanee, et al.
(författare)
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Lesions of the locus coeruleus system aggravate ischemic damage in the rat brain
- 1985
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Ingår i: Neuroscience Letters. - : Elsevier BV. - 0304-3940. ; 58:3, s. 353-358
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Tidskriftsartikel (refereegranskat)abstract
- The possibility that the noradrenergic locus coeruleus system influences brain damage following ischemia was explored in rats. Bilateral lesions of the locus coeruleus projections to the forebrain aggravated the neuronal necrosis in the hippocampal CAI region and neocortex following complete cerebral ischemia induced by transient cardiac arrest. These findings provide evidence that the postischemic activation of the inhibitory locus coeruleus system could counteract a possible detrimental neuronal hyperexcitation, thereby limiting neuronal necrosis.
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| 23. |
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| 24. |
- Brundin, P, et al.
(författare)
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Behavioural effects of human fetal dopamine neurons grafted in a rat model of Parkinson's disease
- 1986
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Ingår i: Experimental Brain Research. - 0014-4819. ; 65:1, s. 40-235
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Tidskriftsartikel (refereegranskat)abstract
- The ventral mesencephalon, containing the developing dopaminergic neurons of the substantia nigra-ventral tegmental region, was obtained from aborted human fetuses of 9-19 weeks of gestation. The tissue was grafted into the striatum of rats previously subjected to a 6-hydroxydopamine lesion of the mesostriatal dopamine pathway. The graft recipients were immunosuppressed by daily injections of Cyclosporin A. Amphetamine-induced motor asymmetry was reduced, and finally totally reversed, only in rats receiving grafts from the 9-week old fetal donor. The fluorescence microscopic analysis revealed large numbers of surviving dopamine neurons, and extensive fiber outgrowth into the host striatum, in these rats. By contrast, rats receiving grafts from 11-19 week old donors had at most only few surviving dopamine neurons. These results indicate that human fetal mesencephalic tissue may be an efficient source of dopamine neurons for functional intracerebral grafting in patients with Parkinson's disease.
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| 25. |
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| 26. |
- Brundin, P, et al.
(författare)
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Cyclosporin A increases survival of cross-species intrastriatal grafts of embryonic dopamine-containing neurons
- 1985
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Ingår i: Experimental Brain Research. - 0014-4819. ; 60:1, s. 8-204
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Tidskriftsartikel (refereegranskat)abstract
- The survival and function of cross-species (mouse-to-rat) grafts of fetal mesencephalic dopamine (DA) neurons, implanted as a cell suspension in the striatum of rats with lesions of the mesostriatal DA system, have been studied in animals with and without immunosuppression induced by Cyclosporin A (CyA). At 6 weeks after grafting 3 out of 7 non-CyA treated animals showed some degree of graft survival and variable functional compensation. In those three animals an average of 92 DA neurons per graft was counted. In the grafted animals treated with daily CyA injections, all grafts survived and produced partial or complete functional compensation, and they had an average of 557 DA neurons per graft. It is concluded that intracerebral graft survival and function can be greatly improved by CyA treatment and that the immunological protection of neural transplants in the brain is only partial.
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| 27. |
- Brundin, Patrik, et al.
(författare)
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Dopamine neurons grafted unilaterally to the nucleus accumbens affect drug-induced circling and locomotion
- 1987
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Ingår i: Experimental Brain Research. - 0014-4819. ; 69:1, s. 183-194
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of the present study was to investigate the amplifying function of the nucleus accumbens septi region (NAS) in 6-hydroxydopamine (6-OHDA)-induced rotational behaviour by implanting fetal dopamine (DA)-rich mesencephalic cell suspensions unilaterally in the NAS of rats previously subjected to combined mesostriatal (MS) and NAS 6-OHDA lesions. First, all the rats received a unilateral 6-OHDA lesion of the ascending MS DA pathway, which produced an amphetamine-induced rotational asymmetry towards the lesioned side. In a second step, the rats received a local bilateral 6-OHDA lesion of the NAS which, as previously shown, caused a significant attenuation of the amphetamine-induced locomotor (1.5 mg/kg) and rotational (5 mg/kg) behaviour. Finally, some of these MS + NAS lesioned rats received a unilateral mesencephalic DA graft into the NAS ipsilateral to the original MS lesion. The unilateral DA-rich grafts in the NAS significantly elevated the amphetamine-induced locomotion and ipsilateral circling (opposite to the direction of rotation produced when a graft is placed in the ipsilateral caudate-putamen), suggesting that the NAS plays only an amplifier role in locomotor behaviour and not a directional role. In addition, these grafts significantly attenuated the supersensitive locomotor response observed in lesioned rats when given apomorphine (0.05 mg/kg). The findings emphasize the amplifying role of the NAS in locomotion and circling behaviour and they extend previous findings demonstrating the functional heterogeneity of the striatal complex as well as the regional specificity of the graft-derived functional effects. Moreover, the results argue against the notion that DA grafts can function through a diffusion of transmitter over large distances since, despite the large size of the grafts, the functional graft effects were well localized to the reinnervated NAS and ventromedial striatal regions. We conclude, therefore, that graft-induced amelioration of postural and locomotor deficits are affected through different parts of the striatal complex, and that multiple graft placements are required to produce more complete recovery of motoric behaviour in the DA-depleted brain.
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| 28. |
- Brundin, Patrik, et al.
(författare)
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Human fetal dopamine neurons grafted in a rat model of Parkinson's disease : immunological aspects, spontaneous and drug-induced behaviour, and dopamine release
- 1988
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Ingår i: Experimental Brain Research. - 0014-4819. ; 70:1, s. 192-208
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Tidskriftsartikel (refereegranskat)abstract
- We have used a rat model of Parkinson's disease (PD) to address issues of importance for a future clinical application of dopamine (DA) neuron grafting in patients with PD. Human mesencephalic DA neurons, obtained from 6.5-8 week old fetuses, were found to survive intracerebral cell suspension xenografting to the striatum of rats immunosuppressed with Cyclosporin A. The grafts produced an extensive new DA-containing terminal network in the previously denervated caudate-putamen, and they normalized amphetamine-induced, apomorphine-induced and spontaneous motor asymmetry in rats with unilateral lesions of the mesostriatal DA pathway. Grafts from an 11.5-week old donor exhibited a lower survival rate and smaller functional effects. As assessed with the intracerebral dialysis technique the grafted DA neurons were found to restore spontaneous DA release in the reinnervated host striatum to normal levels. The neurons responded with large increases in extracellular striatal DA levels after the intrastriatal administration of the DA-releasing agent d-amphetamine and the DA-reuptake blocker nomifensine, although not to the same extent as seen in striata with an intact mesostriatal DA system. DA fiber outgrowth from the grafts was dependent on the localization of the graft tissue. Thus, grafts located within the striatum gave rise to an extensive axonal network throughout the whole host striatum, whereas grafted DA neurons localized in the neocortex had their outgrowing fibers confined within the grafts themselves. In contrast to the good graft survival and behavioural effects obtained in immunosuppressed rats, there was no survival, or behavioural effects, of human DA neurons implanted in rats that did not receive immunosuppression. In addition, we found that all the graft recipients were immunized, having formed antibodies against antigens present on human T-cells. This supports the notion that the human neurons grafted to the non-immunosuppressed rats underwent immunological rejection. Based on an estimation of the survival rate and extent of fiber outgrowth from the grafted human fetal DA neurons, we suggest that DA neurons that can be obtained from one fetus may be sufficient to restore significant DA neurotransmission unilaterally, in one putamen, in an immunosuppressed PD patient.
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| 29. |
- Cardell, M., et al.
(författare)
-
Pyruvate dehydrogenase activity in the rat cerebral cortex following cerebral ischemia
- 1989
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 9:3, s. 350-357
-
Tidskriftsartikel (refereegranskat)abstract
- The effect of cerebral ischemia on the activity of pyruvate dehydrogenase (PDH) enzyme complex (PDHC) was investigated in homogenates of frozen rat cerebral cortex following 15 min of bilateral common carotid occlusion ischemia and following 15 min, 60 min, and 6 h of recirculation after 15 min of ischemia. In frozen cortical tissue from the same animals, the levels of labile phosphate compounds, glucose, glycogen, lactate, and pyruvate were determined. In cortex from control animals, the rate of [1-14C]pyruvate decarboxylation was 9.6 ± 0.5 nmol CO2/(min-mg protein) or 40% of the total PDHC activity. This fraction increased to 89% at the end of 15 min of ischemia. At 15 min of recirculation following 15 min of ischemia, the PDHC activity decreased to 50% of control levels and was depressed for up to 6 h post ischemia. This decrease in activity was not due to a decrease in total PDHC activity. Apart from a reduction in ATP levels, the acute changes in the levels of energy metabolites were essentially normalized at 6 h of recovery. Dichloroacetate (DCA), an inhibitor of PDH kinase, given to rats at 250 mg/kg i.p four times over 2 h, significantly decreased blood glucose levels from 7.4 ± 0.6 to 5.1 ± 0.3 mmol/L and fully activated PDHC. In animals in which the plasma glucose level was maintained at control levels of 8.3 ± 0.5 μmol/g by intravenous infusion of glucose, the active portion of PDHC increased to 95 ± 4%. In contrast, the depressed PDHC activity at 15 min following ischemia was not affected by the DCA treatment. In both DCA + glucose-treated control and recovery groups, the pyruvate levels decreased by 50%. No significant difference in the lactate levels was seen. We conclude that the depressed postischemic PDHC activity is not due to loss of enzyme protein nor to an increased PDH kinase activity, but is probably due to a decreased activity of PDH phosphatase. This could in turn be secondary to a change in the cellular levels of PDH phosphatase regulators, most probably a decreased intramitochondrial concentration of calcium. The postischemic decrease in PDH activity may be related to the postischemic metabolic depression.
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| 30. |
- Cervero, F., et al.
(författare)
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Cutaneous inputs to dorsal horn neurones in adult rats treated at birth with capsaicin
- 1984
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Ingår i: Brain Research. - : Elsevier BV. - 0006-8993. ; 301:1, s. 47-57
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Tidskriftsartikel (refereegranskat)abstract
- Single unit electrical activity has been recorded from dorsal horn neurons in the lumbar spinal cord of adult rats which had been treated at birth with either capsaicin (50 mg kg-1) or with the solvent-vehicle only. The responses of these neurones to electrical stimulation of A- and C-fibres in the sural nerve and to natural stimulation of their cutaneous receptive fields have been studied. In vehicle-injected rats, 54% of the units driven by electrical stimulation of the A-fibres in the sural nerve could also be driven by stimulation of the C-fibers in this nerve. In capsaicin-treated animals, only 30% of such units had a C-fibre input from the sural nerve. In vehicle-injected rats, 51.5% of the neurones with a C-fibre input showed a 'wind-up' effect on repetitive C-fibre stimulation of the sural nerve at 1 Hz. A similar proportion of neurones (55%) displayed this effect in capsaicin-treated rats. There were fewer neurones with very intense 'wind-up' in capsaicin-treated compared to vehicle-treated rats. In capsaicin-treated animals, greater proportions of neurones with 'wind-up' were superficially located in the dorsal horn, had small receptive fields and were driven only by cutaneous nociceptors. The proportions of neurones driven by innocuous mechanical stimulation of the skin, by noxious mechanical stimulation or by both forms of stimulation were similar in vehicle-injected and capsaicin-treated animals. In capsaicin-treated rats, more neurones had 'medium-sized' receptive fields than in vehicle-injected rats. In capsaicin-treated rats, more neurones had receptive fields in the foot and ankle than in vehicle-injected animals, where receptive fields in the toes were predominant. Some neurones showed expanded receptive fields after repetitive electrical stimulation of C-fibres at 1 Hz. This expansion occurred more often in neurones recorded from capsaicin-treated animals than in those of vehicle-injected rats. These results are discussed in relation to the role of afferent C-fibres in sensory mechanisms.
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| 31. |
- Chang, Jing-Yu, et al.
(författare)
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Serotonin uptake into cerebrovascular nerve fibers of rat, visualization by immunohistochemistry, disappearance following sympathectomy, and release during electrical stimulation
- 1989
-
Ingår i: Brain Research. - : Elsevier BV. - 1872-6240 .- 0006-8993. ; 492:1-2, s. 79-88
-
Tidskriftsartikel (refereegranskat)abstract
- Immunohistochemistry as well as in vitro uptake and release of [3H]5-HT were performed on pial arteries of rat to investigate the nature of 5-HT containing nerve fibers. Immunoreactive fibers were constantly found only in the basilar, vertebral and superior cerebellar arteries, while in the other parts of the circle of Willis, 5-HT immunofluorescent fibers were absent. After systemic treatment with tryptophan following inhibition of monoamine oxidase with nialamide the immunofluorescence intensity was markedly enhanced. The 5-HT immunoreactive fibers disappeared after superior cervical ganglionectomy or intraventricular administration of 6-hydroxydopamine, but persisted after administration of 5,6-dihydroxytryptamine. When isolated vessels were incubated in low concentration of 5-HT (1 nM) together with nialamide, a very dense plexus of 5-HT immunoreactive fibers appeared in all branches of the circle of Willis. Uptake and release experiments were carried out by incubation of arterial preparations with 3 nM [3H]5-HT (together with nialamide), followed by electrical field stimulation, or by exposure to tyramine or 124 mM potassium, all of which induced a 100%-350% increase in the tritium release over prestimulation values. Preincubation with cocaine and bilateral superior cervical ganglionectomy abolished or markedly attenuated the release upon all modes of stimulation. The results suggested that the 5-HT observed by immunohistochemistry in pial arteries is located in sympathetic nerve terminals where it may serve as a neuromodulator that is released during nerve activation.
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| 32. |
- Clarke, D J, et al.
(författare)
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Synaptogenesis of grafted cholinergic neurons
- 1987
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Ingår i: Annals of the New York Academy of Sciences. - : Wiley. - 0077-8923 .- 1749-6632. ; 495:1, s. 268-282
-
Tidskriftsartikel (refereegranskat)
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| 33. |
- Deshpande, J. K., et al.
(författare)
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Amelioration of ischaemic brain damage by postischaemic treatment with flunarizine
- 1985
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Ingår i: Neurological Research. - : Informa UK Limited. - 0161-6412 .- 1743-1328. ; 7:1, s. 27-29
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Tidskriftsartikel (refereegranskat)abstract
- The effect of flunarizine, a calcium entry blocker, on ischaemic damage was investigated using a new model of forebrain ischaemia. Fasted rats were subjected to nine minutes ischaemia and one week recovery. One group served as control; a second was pretreated orally with flunarizine; a third group received postischaemic flunarizine treatment Focussing on the hippocampus, an area of high susceptibility to ischaemic damage, we report that flunarizine treatment significantly reduced neuronal necrosis. Importantly, the amelioration of necrosis was also observed when flunarizine was administered 5 min following resumption of cerebral perfusion.
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| 34. |
- Deshpande, J. K., et al.
(författare)
-
Calcium accumulation and neuronal damage in the rat hippocampus following cerebral ischemia
- 1987
-
Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 7:1, s. 89-95
-
Tidskriftsartikel (refereegranskat)abstract
- The present study was undertaken to correlate calcium accumulation with the development of neuronal necrosis following transient ischemia. After 10 min of forebrain ischemia in the rat—a period that leads to reproducible damage of CA1 pyramidal cells—determination of calcium concentration and evaluation of morphological signs of cell body necrosis in the dorsal hippocampus were performed at various recirculation times. Tissue calcium concentration was not different from control at the end of ischemic period and did not change after 3, 6, 12, or 24 h of recirculation. However, after 48 h, calcium content increased significantly, with a further increase being seen after 72 h. At early recovery periods, only scattered necrotic neurons were observed. after 48 h, only 2 of 12 hemispheres showed more than 25 necrotic cells per section. More conspicuous neuronal death was observed after 72 h. The results thus demonstrate that net accumulation of calcium in regio superior of the hippocampus precedes marked necrosis of CA1 pyramidal cells. The results suggest that one primary event in the delayed death of these cells is membrane dysfunction with increased calcium cycling.
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| 35. |
- Dunnett, S B, et al.
(författare)
-
Intracerebral grafting of neuronal cell suspensions. IV. Behavioural recovery in rats with unilateral implants of nigral cell suspensions in different forebrain sites
- 1983
-
Ingår i: Acta Physiologica Scandinavica. ; Suppl. 522, s. 29-38
-
Tidskriftsartikel (refereegranskat)abstract
- Single and multiple implants of nigral cell suspensions were grafted to the forebrains of rats with unilateral 6-hydroxydopamine-induced dopamine denervations. Control lesions alone induced a marked behavioural asymmetry, as assessed by amphetamine- and apomorphine-induced rotation, sensorimotor tests and side bias in an unbaited T-maze, and the animals were hyperactive to a low dose of apomorphine. Single suspension placements into different denervated striatal regions were capable of reversing the behavioural asymmetries dependent upon the specific placement for each test. Multiple suspension grafts were capable of reversing all behavioural asymmetries, and additionally abolished the supersensitive hyperactivity to apomorphine. By contrast, single suspension grafts placed into the substantia nigra or lateral hypothalamus had no detectable effect on any functional measure. The results indicate that nigral suspension grafts can be at least as effective as solid grafts in reversing the functional deficits induced by dopamine denervation, provided that placements are selected within appropriate dopamine terminal regions of the forebrain (e.g. caudate-putamen or nucleus accumbens).
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| 36. |
- Dunnett, S B, et al.
(författare)
-
Intracerebral grafting of neuronal cell suspensions. V. Behavioural recovery in rats with bilateral 6-OHDA lesions following implantation of nigral cell suspensions.
- 1983
-
Ingår i: Acta Physiologica Scandinavica. ; Suppl. 522, s. 39-48
-
Tidskriftsartikel (refereegranskat)abstract
- Bilateral 6-hydroxydopamine-induced lesions of the ascending forebrain dopamine neurones induce a behavioural syndrome in rats which includes profound aphagia, adipsia, akinesia and bilateral sensorimotor neglect. Such animals will die unless maintained by intragastric feeding. Three experiments are reported in which we have attempted to ameliorate this syndrome with single or multiple placements of nigral cell suspensions into the forebrains of rats with bilateral dopamine depletions. Although the grafts were efficient in reversing the sensorimotor and akinetic impairments, and produced a significant increase in eating, the grafted rats remained hypophagic and adipsic. The results indicate that although many components of the bilateral dopamine denervation syndrome can be reversed by intrastriatal nigral suspension grafts, the severe eating and drinking deficits remain unameliorated.
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| 37. |
- Ekström, Per A R, et al.
(författare)
-
Nerve regeneration and serum levels of insulin-like growth factor-I in rats with streptozotocin-induced insulin deficiency
- 1989
-
Ingår i: Brain Research. - : Elsevier BV. - 0006-8993. ; 496:1-2, s. 141-147
-
Tidskriftsartikel (refereegranskat)abstract
- Peripheral nerve regeneration was studied in female Sprague-Dawley rats with streptozotocin-induced insulin deficiency. Nerve regeneration was provoked by a crush lesion on the sciatic nerve 21 days after the streptozotocin injection. The regeneration was assessed by a pinch test at different time-points after injury. The rate ofregeneration in insulin-deficient animals, 2.5 mm/day, was significantly lower than in control animals, 2.9 mm/day(P < 0.05). There was no difference in the initial delay, i.e. the period before regeneration attains a constant velocity. One group of insulin-deficient rats was treated with insulin during the regeneration period by means of implanted osmotic mini-pumps. This treatment prevented the decrease in regenerationsw. After 6 days the sciatic nerves of insulin-deficient rats had regenerated 12.3 ±0.3 mm (mean ±S.E.M.), while the corresponding value for insulin-treated rats was 15.7 ±0.6 mm (P > 0.01). The streptozotocin-treated rats were found to have a 39% reduction in the serum level of insulin-like 1 growth factor-I (IGF-I)_compared to control rats (0.33 ± 0.22 μg/ml and 0.54 ± ml respectively, (P < 0.001). Insulin treatment 1830 1732 during the regeneration period completely restored the IGF-I level back to normal.
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| 38. |
- Ekström, Peter, et al.
(författare)
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Distribution of 5‐hydroxytryptamine (serotonin) in the brain of the teleost Gasterosteus aculeatus L.
- 1984
-
Ingår i: Journal of Comparative Neurology. - : Wiley. - 0021-9967. ; 226:3, s. 307-320
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Tidskriftsartikel (refereegranskat)abstract
- The distribution of serotoninergic neurons in the brain of the three‐spined stickleback was demonstrated with the indirect peroxidase‐antiperoxidase (PAP) immunohistochemical method with antibodies against serotonin. Serotoninergic perikarya were demonstrated in the brainstem reticular formation (nucleus raphe dorsalis, nucleus raphe medialis, and nucleus tegmenti dorsalis lateralis) and in the periventricular ventral thalamus and hypothalamus (nucleus ventromedialis thalami, nucleus posterioris periventricularis, nucleus recessus lateralis, and nucleus recessus posterioris). After pharmacological pretreatment of the animals with a monoamine oxidase inhibitor, serotoninergic perikarya were also visualized in area praetectalis and in the medial brainstem, caudal to nucleus raphe medialis. Whereas the cell groups of the brainstem give rise to both ascending and descending pathways, it was not possible to analyze the distribution of efferent projections from the diencephalic cell groups. Distribution of serotoninergic axons showed marked regional differences. Only scattered varicose fibers were demonstrated in the cerebellum, the facial lobes, and the lateral line lobes. In the mesencephalon, the dorsal periventricular tegmentum and the central gray receive only small numbers of serotoninergic axons, while torus semicircularis and the visual layers of tectum opticum are profusely innervated. In the diencephalon, the hypothalamus and ventral thalamus generally display the highest density of serotoninergic axons. Exceptions are found in nucleus glomerulosus and the ventromedial portion of lobus inferioris, where densities are low. In the telencephalon, the density of serotoninergic axons is very high in area dorsalis pars medialis and pars lateralis dorsalis, but low in area dorsalis pars dorsalis and pars lateralis ventralis, and intermediate in area ventralis.
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| 39. |
- Ekström, Peter, et al.
(författare)
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Pineal neurons projecting to the brain of the rainbow trout, Salmo gairdneri Richardson (Teleostei) - In-vitro retrograde filling with horseradish peroxidase
- 1985
-
Ingår i: Cell and Tissue Research. - 0302-766X. ; 240:3, s. 693-700
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Tidskriftsartikel (refereegranskat)abstract
- The morphology of intrapineal neurons that give rise to the pineal tract and project to the brain in the rainbow trout was visualized by the use of neuronal backfilling with horseradish peroxidase (HRP). The tracing was performed on excised pineal organs under in-vitro conditions at 4° C, with filling times ranging from 6 to 24 h. Large multipolar, bipolar and unipolar neurons were visualized in the rostral tip of the pineal organ ("pineal ganglion"). These neurons possessed extended dendritic trees participating in the formation of a circumscribed neuropil-like area. Throughout the pineal organ small bipolar elements were the most ubiquitous type of neuron, however, with markedly smaller numbers in the proximal portion of the pineal end-vesicle. In the pineal stalk, some bipolar neurons were observed to contact the pineal lumen, which is continuous with the third ventricle, via dendritic processes of various types. It could not be established whether any of these CSF-contacting processes were identical with photoreceptor outer segments. The basal processes of the bipolar neurons sometimes possessed distally projecting collaterals. In conclusion, it has been shown that (i) different types of neurons displaying varied patterns of regional distribution contribute to the pineal tract, and (ii) certain CSF-contacting neurons in the pineal organ send axonal processes directly toward the brain.
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| 40. |
- Ernfors, P, et al.
(författare)
-
Developmental and regional expression of beta-nerve growth factor receptor mRNA in the chick and rat.
- 1988
-
Ingår i: Neuron. - 0896-6273 .- 1097-4199. ; 1:10, s. 983-96
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Tidskriftsartikel (refereegranskat)abstract
- Hybridization probes from the transmembrane region of the chick NGF receptor (NGF-R) that show high homology with the rat NGF-R were used to demonstrate an abundant 4.5 kb NGF-R mRNA in the chick embryo at E3.5. The level remained high until E12 but decreased to adult levels by E18. The highest levels at E8 were in spinal cord, bursa of Fabricius, gizzard, femoralis muscle, and skin. In situ hybridization to E7 embryos showed high expression of the NGF-R gene in spinal cord, particularly the lateral motor column, and in dorsal root, sympathetic, and nodose ganglia. NGF-R mRNA expression was observed throughout brain development and in all regions of the adult brain, with high levels in cerebellum and septum. Lymphoid tissues of chick and rat also expressed the receptor. The complex and widespread expression of NGF-R mRNA in areas not known to be NGF targets suggests broader functions for NGF.
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| 41. |
- Fredriksson, K, et al.
(författare)
-
Blood-brain barrier leakage and brain edema in stroke-prone spontaneously hypertensive rats. Effect of chronic sympathectomy and low protein/high salt diet
- 1987
-
Ingår i: Acta Neuropathologica. - 1432-0533. ; 74:3, s. 259-268
-
Tidskriftsartikel (refereegranskat)abstract
- Brain edema associated with severe chronic hypertension was studied in stroke-prone spontaneously hypertensive rats (SHRSP), 5 to 9 months of age. Blood-brain barrier (BBB) leakage sites and intracerebral spreading pathways for plasma proteins were delineated by an intravenously (i.v.) injected exogenous dye tracer (Evans blue), known to form a complex with albumin in blood, and by immunohistochemical visualization of extravasated endogenous plasma proteins. The tissue content of edema fluid was estimated by measuring the specific gravity of selected brain regions, stained or unstained by the tracer dye, on a bromobenzene-kerosene gradient column. Multifocal BBB leakage sites were macroscopically detected within the cerebral cortex and the deep gray matter after i.v. circulation of Evans blue-albumin for 30 min. After 24 h of i.v. circulation the dye tracer had spread not only locally in the gray matter but also into the adjacent white matter, where it was widely distributed. Immunohistochemically visualized plasma proteins showed similar distribution. Unilateral superior cervical ganglionectomy performed at 4 weeks of age neither increased the incidence of major BBB opening to Evans blue-albumin nor altered the specific gravity of the ipsilateral cerebral hemisphere in grown-up SHRSP, furthermore, the blood pressure remained unchanged. The lack of significant effect on BBB function may possibly be attributed to the extensive reinnervation of the cerebral arteries, verified in the grown-up SHRSP using the Falck-Hillarp fluorescence method for visualization of catecholaminergic nerve fibers. In SHRSP raised on a low-protein and high-salt diet the mean arterial blood pressure was 212 mm Hg compared to 195 mm Hg in controls (P less than 0.05) and the incidence of BBB opening was 72% compared to 25% in controls (P less than 0.05). After 24 h of i.v. circulation of Evans blue-albumin, brain regions stained by the dye tracer showed significantly reduced specific gravity (P less than 0.001), while unstained regions had normal values. Thus the brain edema fluid spread, as revealed by specific gravity measurements, corresponded to the intracerebral distribution of extravasated plasma proteins.
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| 42. |
- Fredriksson, K, et al.
(författare)
-
Cerebral microangiopathy in stroke-prone spontaneously hypertensive rats. An immunohistochemical and ultrastructural study
- 1988
-
Ingår i: Acta Neuropathologica. - 1432-0533. ; 75:3, s. 241-252
-
Tidskriftsartikel (refereegranskat)abstract
- The morphology of cerebral microvessels was studied immunohistochemically and ultrastructurally in 6- to 9-month-old normotensive Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR), and stroke-prone SHR (SHRSP) with a systolic blood pressure of 138 +/- 15 mm Hg, 189 +/- 9 mm Hg, and 258 +/- 30 mm Hg respectively. Regions with major opening of the blood-brain barrier (BBB) were revealed by an i.v. injection of Evans Blue. Multifocal BBB opening with massive leakage of plasma constituents rich in fibrinogen-fibrin-related antigen occurred in SHRSP with a blood pressure above 210-220 mm Hg. BBB-leakage sites were found in the cerebral cortex and the basal ganglia, most frequently in the arterial border zones. The perivascular tissue spaces were dilated within the BBB-leakage sites, in particular around arterioles. Damaged endothelial and smooth muscle cells were replaced by fibrin-like material, multiple layers of basement membranes and bundles of collagen fibrils surrounded by proliferated fibroblasts. The degenerative-infiltrative-proliferative disease process transformed short segments of single arterioles into severely thickened, tortuous and stenotic vessels. Fibrinoid degeneration, formation of microaneurysms and fibrin-rich vascular occlusions were observed. In contrast, only minor or no vascular alterations were seen in regions with preserved BBB in SHRSP and SHR. A severely increased intraluminal pressure load appears to be of major pathogenetic importance for breakdown of the BBB and initiation of the vascular disease process in SHRSP. However, since only short segments of a limited number of widely separated vessels are severely affected, and the number of affected vessels increase towards arterial end and border zones, additional predisposing and aggravating factors may play significant roles in the development of fibrinoid vascular lesions in arterial hypertension.
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| 43. |
- Fredriksson, K, et al.
(författare)
-
Cerebrovascular lesions in stroke-prone spontaneously hypertensive rats
- 1985
-
Ingår i: Acta Neuropathologica. - 1432-0533. ; 68:4, s. 284-294
-
Tidskriftsartikel (refereegranskat)abstract
- The cerebrovascular lesions of severe chronic hypertension were studied by light microscopy in perfusion-fixed, subserially sectioned brains from stroke-prone spontaneously hypertensive rats (SHRSP). The leakage and spread of plasma proteins were visualized by immunohistochemical detection of extravasated fibrinogen and by using an exogenous marker (Evans blue injected i.v.) for blood-brain barrier (BBB) dysfunction. In most SHRSP the hypertension did not lead to major BBB lesions in spite of a mean arterial pressure around 200 mm Hg at 6-9 months of age. Multifocal BBB damage occurred in a minor group of SHRSP, particularly within the cortex and the deep gray matter. A close spatial correlation was found between the leakage-spread of plasma constituents and the neuropathologic alterations. Fibrinoid degeneration of penetrating arterioles was found within the leakage sites. The surrounding gray matter showed petechial hemorrhages and abundant proteinaceous exudates rich in antifibrinogen-positive material. The current leakage of Evans blue and wide spread of fibrinoid substances suggested long-lasting damage to the BBB. Most neurons within the edematous gray matter had well preserved nuclei surrounded by a rim of cytoplasm with ill-defined outline as if vacuolation or lysis of the peripheral cytoplasm had occurred. The sponginess of the tissue progressed in severe cases to formation of necrotic cysts. Condensed acidophilic neurons were seen in the border zone between the edematous and more compact gray matter. The appearance and distribution of the gray matter lesions deviated in many respects from those commonly seen in regional ischemic infarcts. The fibrin thrombi found close to the cysts might be regarded as secondary events. The extensive spread of antifibrinogen-positive material within the white matter seemed to originate mainly from the chronic leakage sites in the gray matter. Increased number of large astrocytes were seen within the leakage sites and along the spreading pathways for the edema constituents. The white matter showed a rarefied texture with widely dispersed nerve fiber tracts, volume expansion, and occasional cyst formation. The results indicate a crucial pathophysiologic role for the egress, spread, and accumulation of vasogenic edema in the development of the cerebrovascular lesions in SHRSP.
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| 44. |
- Fredriksson, K, et al.
(författare)
-
Cyst formation and glial response in the brain lesions of stroke-prone spontaneously hypertensive rats
- 1988
-
Ingår i: Acta Neuropathologica. - 1432-0533. ; 76:5, s. 441-450
-
Tidskriftsartikel (refereegranskat)abstract
- The brain lesions in spontaneously hypertensive stroke-prone rats (SHRSP) are characterised by multifocal microvascular damage, breakdown of the blood-brain barrier, massive extravasation of plasma constituents and severe brain oedema, with consequent spongy and cystic tissue destruction in the cerebral cortex and basal ganglia as well as loosening of the white matter. In this paper we analyse in greater detail the pathogenetic mechanisms by which the spongy and cystic lesions are formed and the response of astrocytic cells. For this purpose, tracer (Evans blue)-stained brain lesions were examined in 8-month-old SHRSP immunohistochemically and electron microscopically. Sponginess of the neuropil in small lesions and at the periphery of larger lesions was due to swollen neuronal and astrocytic cell processes, i.e. at this stage the oedema was mainly intracellular. Cystic lesions were formed in the grey matter both by expansion of the extracellular space (ECS) containing protein-rich oedema fluid, and by rupture and subsequent loss of massively swollen cellular elements. In the white matter small slit-formed cysts along the fibre tracts were also formed by the expansion of ECS. In apparently recent lesions astrocytes displayed cyto-plasmic oedema but otherwise were still fairly normal. In more chronic lesions increased numbers of enlarged astrocytes with prominent staining for glial fibrillary acidic protein were present. Their distribution corresponded well to the spread of oedema, i.e. they were prominent around the leaky vessels in the grey matter, in the subpial zone and in the white matter. In the reparative phase the grey matter cysts became lined by astrocytic processes, a new glia limitans. Profuse sheets of glial processes in the neuropil around the cysts reestablished the compactness of the brain parenchyma.
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| 45. |
- Fredriksson, K, et al.
(författare)
-
Nerve cell injury in the brain of stroke-prone spontaneously hypertensive rats
- 1988
-
Ingår i: Acta Neuropathologica. - 1432-0533. ; 76:3, s. 227-237
-
Tidskriftsartikel (refereegranskat)abstract
- The brain lesions in stroke-prone spontaneously hypertensive rats (SHRSP) are characterized by multifocal microvascular and spongy-cystic parenchymal alterations particularly in the gray matter. An essential feature of the lesions is the presence of edema with massive extravasation of plasma constituents as evidenced by specific gravity measurements, Evans blue technique and immunohistochemistry. The nerve cell injury occurring in the brain lesions in SHRSP is further characterized by light and electron microscopy in the present study. Two types of neuronal changes were seen within the blood-brain barrier (BBB) leakage sites. A small number of neurons with dark condensed nucleus and cytoplasm were found most often at the periphery of recent lesions. The majority of injured neurons were pale and showed intracellular edema confined to the dendrites and perikarya sparing axons and synapses. Their nuclei were well preserved with finely dispersed chromatin. The swollen and watery cell processes of neurons and astrocytes gave a spongy appearance to the neuropil. The intracellular edema seemed to result in cytolysis. The results suggest that primary anoxia-ischemia is not the major pathogenetic mechanism behind the nerve cell injury in severely hypertensive SHRSP, rather it is the massive BBB leakage and consequent brain edema that causes cytolytic destruction of neurons. Secondary focal ischemia as a consequence of occlusion in microvessels may, however, contribute to the nerve cell destruction.
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| 46. |
- Freedman, J, et al.
(författare)
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Vasoconstrictor effects in spinal cord of the substance P antagonist [D-Arg, D-Trp7,9 Leu11]-substance P (Spantide) and somatostatin and interaction with thyrotropin releasing hormone
- 1988
-
Ingår i: Neuroscience. - : Elsevier BV. - 1873-7544 .- 0306-4522. ; 27:1, s. 267-278
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Tidskriftsartikel (refereegranskat)abstract
- The present study was undertaken to investigate the possible effects of Spantide [D-Arg1, D-Trp7,9 Leu11]-substance P, a substance P antagonist, and of somatostatin on spinal cord blood flow. The experiments were performed with the laser-doppler technique on the L1 spinal cord segment exposed by laminectomy. The effect of Spantide was also studied in the rat with the [14C]iodoantipyrine technique. In addition, experiments were performed on rabbit skeletal muscle in vivo after administration of Spantide to the local vasculature. In the experiments on spinal cord, approximately the same doses were employed as those earlier shown to be "neurotoxic". When the vehicle alone (0.9% saline) was administered intrathecally, a slight decrease of brief duration was noted in the blood flow. Spantide, however, caused a dose-dependent decrease, where 2 micrograms caused an immediate drop of the blood flow to approx. 20% of its normal value. A total circulatory arrest was found in several animals. In most cases, the flow was gradually normalized, whereas the effect persisted for up to 60 min in others. Virtually the same effect was exerted by somatostatin. The experiments using the iodoantipyrine technique confirmed the effect of Spantide. Here, the high resolution of this method showed that the gray matter was affected preferentially, with a complete ischemic state or a drastically reduced flow in 4 out of 5 animals 10 min after 2 micrograms of Spantide; one animal was unaffected, and this animal did not show any signs of motor impairment. The vasoconstriction of Spantide was not affected by simultaneous injections with substance P. However, after i.v. pretreatment with thyrotropin-releasing hormone, at a dose that previously has been reported to be protective against the neurodegenerative effects of Spantide, blood flow was markedly increased as compared to Spantide alone. Results from the experiments using intravital microscopy flow studies in the rabbit tenuissimus muscle revealed that Spantide at the doses used had no vasoconstrictor effect in the skeletal muscle of this species. The results suggest that previous demonstrations of motor impairment and "neurotoxic" actions of intrathecally injected substance P antagonists and somatostatin may be related to a marked decrease in spinal cord blood flow. Counteraction of the effect of Spantide by thyrotropin-releasing hormone may be explained by its effect to increase blood flow.
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| 47. |
- Gabrielsson, Britt, 1957, et al.
(författare)
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Effects of divalent metal ions on the uptake of glutamate and GABA from synaptosomal fractions
- 1986
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Ingår i: Brain Research. - 0006-8993. ; 384:2, s. 218-23
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Tidskriftsartikel (refereegranskat)abstract
- The effects of divalent metal ions on high affinity uptake glutamate and GABA were examined, using crude and purified synaptosomal fractions prepared from brains of DBA/2CBI. The uptake velocities of both amino acids are severely reduced in the presence of Cu2+, Fe2+ and Zn2+ but remain unaffected by Co2+.
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| 48. |
- Gage, F H, et al.
(författare)
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Intracerebral grafting of neuronal cell suspensions. VIII. Cell survival and axonal outgrcwth of dcpaminergic and cholinergic cells in the aged brain.
- 1983
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Ingår i: Acta Physiologica Scandinavica. ; Suppl. 522, s. 67-75
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Tidskriftsartikel (refereegranskat)abstract
- Neuronal cell suspensions prepared from the ventral mesencephalon and the septal-diagonal band area of rat embryos were implanted into the depth of the intact neostriatum or hippocampus of 21-23 month old female rats. Graft survival, assessed 3-4 months after grafting, was comparable to that seen in our previous studies of young adult recipients. Fibre outgrowth into the host brain was evaluated in animals which were subjected to lesions of the intrinsic nigrostriatal or septohippocampal system 6-10 days before killing. Dense dopamine fibre outgrowth was seen within a zone of up to about 1 mm radius around the nigral implants, and dense growth of acetylcholine esterase (AChE) positive fibres occurred up to about 2 mm away from the septal implants. The overall magnitude of fibre outgrowth was less than that generally seen in previously denervated targets in young adult recipients, but it appeared to be as extensive as in young recipients when the grafts are placed in non-denervated targets. The distribution of the AChE-positive fibres from the septal implants in the host hippocampus suggested that the pattern found in the non-denervated target of the aged recipients was more diffuse, and partly different, from normal, and that age-dependent synapse loss in intrinsic connections may influence the patterning of the graft-derived innervation.
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| 49. |
- Gustafson, I., et al.
(författare)
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Postischemic administration of idazoxan, an α-2 adrenergic receptor antagonist, decreases neuronal damage in the rat brain
- 1989
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 9:2, s. 171-174
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Tidskriftsartikel (refereegranskat)abstract
- The effect of an α-2 receptor antagonist, idazoxan, on ischemic neuronal damage in the hippocampus and neocortex was studied in rats following 10 min of forebrain ischemia. Idazoxan was given 0.1 mg/kg i.v. immediately after recirculation, followed by 48 h of continuous infusion at a rate of 10 μg/kg/min. A histopathological examination of the CA1 region of the dorsal hippocampus and neocortex from each hemisphere was made on paraffin-embedded sections following 7 days of survival. In ischemic animals receiving an infusion of saline, 71% of the neurons in the hippocampal CA1 region were degenerated. In contrast, in the idazoxan-treated animals only 31% of the neurons were irreversibly damaged (p < 0.01). We conclude that postischemic administration of the α-2 antagonist idazoxan protects neurons against damage following cerebral ischemia. Rapid postischemic administration of α-2 adrenergic receptor antagonists could be an effective treatment after stroke and cardiac arrest.
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| 50. |
- Hallböök, Finn, et al.
(författare)
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Production and characterization of biologically active recombinant beta nerve growth factor
- 1988
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Ingår i: Molecular and Cellular Biology. - 0270-7306 .- 1098-5549. ; 8:1, s. 452-456
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Tidskriftsartikel (refereegranskat)abstract
- DNA fragments encoding either rat or chicken beta nerve growth factor (NGF) were inserted in the expression vector p91023(B) for transient expression in COS cells. The two NGF constructs produced RNA transcripts and proteins of the predicted sizes. Conditioned media from the transfected cells stimulated neurite outgrowth from cultured chicken embryo sympathetic ganglia. The results show that the rat or chicken NGF gene can direct the synthesis of a biologically active NGF protein after transfection of COS cells.
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