Pathogenesis of brain lesions caused by experimental epilepsy. Light- and electron-microscopic changes in the rat hippocampus following bicuculline-induced status epilepticus.
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Animals↗
Biomedical subjects
Y Olsson
Publications and source records attributed to Y Olsson.
FITC-Dextrans as tracers for macromolecular movements in the nervous system. A freeze-drying method for dextrans of various molecular sizes injected into normal animals.
A freeze-drying method has been developed by which fluorescein thiocarbamoyl dextrans (FITC-dextrans) can be localized in thin sections from nervous tissue and muscles. Labelled dextrans with molecular weights of 3,000, 20,000, 70,000 and 150,000 were injected intravenously (i.v.) into golden hamsters and samples from brain, trigeminal ganglia and sciatic nerves were examined 30 min or 4 h later. For comparison experiments were also carried out in mice and some other tracers were tested as well. The dextrans did not pass out of blood vessels in cerebral cortex and white matter. The blood vessels in the trigeminus ganglion were permeable to all of the tested compounds, i.e. even the FITC-dextran with mol.wt. 150,000. Little, if any, i.v. injected dextran could be detected in the endoneurium of sciatic nerve fascicles. Even very high concentrations of dextrans (mol.wt. 3,000 and 150,000) injected around the sciatic nerves did not penetrate the perineurium of the sciatic nerve. As compared with other tracers dextrans have the advantage that they can be obtained in a wide range of molecular sizes. With the proposed technique presented at the end of this article they can be used for studies on vascular permeability in deep tissue like brain, ganglia and peripheral nerve. The use of these tracers will probably be particularly advantageous in investigations concerning the etiology of edematous conditions.
Animals↗
Brain lactic acidosis and ischemic cell damage: quantitative ultrastructural changes in capillaries of rat cerebral cortex.
Excessive tissue lactic acidosis has earlier been shown to aggravate structural damage of both neurons and glial cells in the rat cerebral cortex. To study the reactions of cortical capillaries, light- and electronmicroscopic morphometry was used. Rats were subjected to severe incomplete ischemia (cerebral blood flow below 5% of normal) for 30 min by clamping their carotid arteries and by lowering the blood pressure. Lactate production during ischemia was modified by preischemic administration of either saline (low lactic acidosis group) or glucose (high lactic acidosis group). In the animals with low lactic acidosis, only minimal vascular changes were seen after both 5 min and 90 min recirculation. In the high lactic acidosis group, the endothelial cells were swollen after 5 min of recirculation, and the changes grew markedly worse during 90 min of recirculation. Nuclear chromatin coarsened and mitochondria swelled up. Morphometry showed that the lumen narrowed as a result of endothelial swelling. In spite of variable degree of perivascular astrocytic edema, the outer capillary diameter was little changed in the experimental groups. It seems likely that endothelial swelling hampers postischemic circulation in incomplete ischemia accompanied by high lactic acidosis.
Acidosis↗
Cytotoxic effects of adriamycin on mouse hypoglossal neurons following retrograde axonal transport from the tongue.
We reported recently that the fluorescent, cytostatic drug, adriamycin (Doxorubicin) may reach the hypoglossal neurons by retrograde axonal transport from the nerve terminals of the tongue. The present investigation was undertaken to ascertain whether morphological changes occur in the hypoglossal neurons due to retrograde transport of adriamycin. Neuronal degeneration was observed in the hypoglossal nucleus 14 days after i.m. injection of adriamycin into the tongue. Early neuronal changes, such as rarefaction of the nuclear chromatin and segregation and fragmentation of the nucleolar components, were succeeded by cytoplasmic vacuolation, disappearance of ribosomes and other degenerative features. These observations are important from a neurotoxicologic viewpoint since they demonstrate that retrograde axonal transport may provide a route for the entry of adriamycin into the nervous system. Thus far, adriamycin appears to be the only known substance which can be traced directly in the neurons and cause their degeneration. An experimental method of damaging the motor neurons of the CNS has been introduced. A new toxic model for the investigation of experimental motor neuron disease is therefore available by the use of adriamycin.
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An improved Percoll density gradient for measurements of experimental brain edema. Addition of sucrose to an isotonic gradient in an attempt to balance osmotic conditions during density determinations.
Microgravimetric methods are very useful for quantitative studies on brain edema. One of the techniques available is based on a gradient made up by NaCl and polyvinyl pyrrolidone-coated silica particles (Percoll). The present study was performed to find a way of minimizing fluid shifts between the gradient and the samples. For this purpose, five Percoll density gradients containing various concentrations of sucrose in isotonic saline were prepared. Equivalent samples of normal mouse brain were then added and their second slow movement (drift) indicating interactions between the tissue and the gradient was followed. A concentration of 0.125 M sucrose eliminated the drift of the samples almost entirely. The capacity of this sucrose-containing gradient to reveal brain edema was then evaluated by comparing the density values obtained with those measured in the traditional bromobenzene-kerosene gradient as described by Nelson et al. (1971). For this purpose, we produced in the mouse an acute cytotoxic edema by triethyltin intoxication and a vasogenic edema by a cortical cryogenic injury. The two gradients showed almost identical results. We conclude, therefore, that the 0.125 M sucrose-containing Percoll gradient is a very good alternative to bromobenzene-kerosene gradients used for brain density determinations. Furthermore, Percoll gradients are very stable and contain only non-toxic ingredients.
Animals↗
Toxic effects of adriamycin on the central nervous system. Ultrastructural changes in some circumventricular organs of the mouse after intravenous administration of the drug.
Recent experimental studies have shown that the cytotoxic antibiotic adriamycin (doxorubicin) after systemic administration can enter the so-called circumventricular organs (CVO) of the brain of the mouse. The present experiments were performed to find out whether such penetration of the brain is associated with signs of neurotoxic injury. For this purpose, light- and electron-microscopic observations were carried out on three of these organs: the neurohypophysis (NH), median eminence (ME), and postremal area (PA). Pronounced widening of the extracellular space indicating the presence of edema was present in all the regions, particularly in animals examined within 3 days of injection of the drug. Many degenerated axon terminals were observed in the NH and ME. The glial cells within these regions showed rarefaction of the nuclear chromatin, nucleolar segregation, and also cytoplasmic changes. The PA presented marked cellular changes resulting in degeneration of neurons, which was most evident 30 days after the injection. Hence, regions of the CNS outside the blood-brain barrier can be reached by adriamycin after systemic administration, and the drug can induce morphological changes there. The doses of the drug used in the present experiments were comparable to those given to patients for the treatment of malignant tumors.
Animals↗
Nerve repair using a polyglactin tube and nerve graft: an experimental study in the rabbit.
Defects in a sectioned tibial nerve were bridged by a new method using a polyglactin mesh-tube and compared with conventional nerve grafting in the rabbit. The capability of healing was evaluated by morphometrical observations and repeated EMG-recordings. Only minor differences between the two different techniques were observed and the possible advantage of the polyglactin method is discussed.
Animals↗
Horseradish peroxidase histochemistry. A comparison between various methods used for identifying neurons labeled by retrograde axonal transport.
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Animals↗
Acute pandysautonomia and severe sensory deficit with poor recovery. A clinical, neurophysiological and pathological case study.
A patient with acute loss of autonomic functions and virtually all afferent functions of peripheral nerves is described. The course was chronic and the outcome fatal. The clinical course was followed with measurements of sensory thresholds and conduction velocities, autonomic tests and microneurographic recordings. Neuropathological changes were severe and localised in the peripheral nervous system. Previously reported similar cases were reviewed. It was concluded that acute pandysautonomia is a disorder similar to the Guillain-Barré syndrome; the course is often protracted and residual neurological deficit common.
Adult↗
Formation of neuromuscular junctions in transplanted peroneus longus muscles in the rat. A quantitative comparison with reinnervation of the muscle in situ.
The formation of neuromuscular junctions in free heterotopic muscle transplants in the rat has been studied quantitatively and compared with the reinnervation of the muscle in situ. The AChE-containing area and the nerve terminal were stained in the same longitudinal section and the length of end-plate, the average number of nerve terminal branch points within the end-plate and the terminal innervation ratio (TIR) were determined. In denervated muscles we noticed early disappearance of nerves whereas the AChE-stained end-plates were visible after eight weeks. The reinnervation of the muscle in situ and after transplantation showed considerable similarities. Early during reinnervation the number of AChE positive areas increased and many of them were innervated by more than one axon. Terminal axons were also seen innervating more than one end-plate situated on the same or on different muscle fibres. Later the number of end-plates decreased and they were innervated by only one axon. The end-plate length reached normal value in the reinnervated muscle in situ but remained smaller in the transplanted muscle. In all reinnervated muscles ultraterminal sprouting was found as indicated by an increased number of nerve terminal branch points within the end-plate area. The TIR was increased in all reinnervated muscles due to terminal and ultraterminal sprouting of the axon. No significant difference in reinnervation was noted between normal and predenervated transplants. The reinnervation of transplanted muscles obviously has similarities not only with the reinnervation of normal muscles but also with the development of muscular innervation during early postnatal growth. In spite of the plasticity of the peripheral nerve the transplanted muscles underwent considerable atrophy which may have been enhanced by the unphysiological placement of the muscles in the abdomen. However, this experimental model made it possible to study reinnervation of muscle fibres only originating from the graft.
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Histopathological changes in the rat brain during bicuculline-induced status epilepticus.
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Animals↗
Retrograde transport of doxorubicin (adriamycin) in peripheral nerves of mice.
Doxorubicin (adriamycin) is a fluorescent compound which is widely used in the treatment of malignant tumors due to its capacity to bind and influence the DNA in the nucleus of cells. We have now observed that the compound after injection into a skeletal muscle of adult mice is transported to the corresponding nerve cell bodies, i.e. can be used as a retrograde tracer in neuroanatomical and neuropathological research. Six hours after injection into the tongue nerve cell nuclei were labeled in the hypoglossal nuclei of the brainstem. The fluorescent tracer had the same distribution as the chromatin. Glial nuclei in the vicinity of the hypoglossal neurons were also labeled presumably due to a transfer from the neurons to the glial cells during life or during the histochemical procedure. Since doxorubicin is also neurotoxic it might be a useful tool in neurobiological research, particularly if the labeled neurons later on will show toxic effects. In this way the compound could be used in models for experimental motor neuron disease and provide a means by which retrograde fluorescent tracing and a degeneration method can be combined for studies on various neuronal systems.
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Regeneration of peripheral nerve through a polyglactin tube.
Polyglactin 910, a resorbable synthetic material, was used as a mesh-tube to bridge defects (7 to 9 mm in length) in a sectioned rabbit tibial nerve. After absorption of the mesh a new nerve sheath was formed which enclosed numerous minute fascicles of regenerating axons. The polyglactin tube influenced the direction taken by the regenerating axons and guided them into the distal segment. The tube also reduced the formation of neuromas and the growth of scar tissue from surrounding structures.
Animals↗
Cytofluorescence localization of adriamycin in the nervous system. I. Distribution of the drug in the central nervous system of normal adult mice after intravenous injection.
By a fluorescence-microscopic technique the distribution of the antineoplastic glycoside, adriamycin (doxorubicin), was studied in the CNS of normal adult mice after i.v. injection. Doses comparable to those used in patients for the treatment of malignant diseases were used. The drug did not have access to areas of the brain within the blood-brain barrier but, except for the subcommissural organ, it was consistently localized in the nuclei of neurons and/or glial cells of the circumventricular organs (postremal area, subfornical organ, median eminence, neurohypophysis) as well as in cells of the choroid plexus and lamina cribrosa of the optic nerve. The nuclear fluorescence was accompanied by a less intense extracellular fluorescence when the survival time was shorter than 1 min after the injection. The fluorescence emitted by adriamycin was seen as early as 15 s after injection and showed its highest intensity at 1 and 15 min later. After 24 h fluorescence was no longer observed except for the ependymal zone of the median eminence. Our study thus shows that adriamycin passes from the blood into the nervous parenchyma in those areas of the brain located outside the blood-brain barrier. This finding raises the question whether in such regions there are any neurotoxicologic effects produced by the drug which have not yet been detected.
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Cytofluorescence localization of adriamycin in the nervous system. II. Distribution of the drug in the somatic and autonomic peripheral nervous systems of normal adult mice after intravenous injection.
By a fluorescence-microscopic technique, the distribution of the antineoplastic glycoside adriamycin (doxorubicin) was studied in the peripheral nervous system (PNS) of normal adult mice after i.v. injection. Doses comparable to those used in patients for treatment of malignant diseases were used. The orange-red fluorescence of the drug was observed in dorsal root ganglia, in the trigeminal ganglia, and in the superior cervical sympathetic ganglia where it was preferentially accumulated in the nuclei of satellite cells. This nuclear labeling was a very quick process which occurred in the superior cervical ganglion within 15 s after the injection. Adriamycin-fluorescent nuclei were also observed in the suprarenal medulla. Fluorescent nuclei were present within the pre- and postganglionic sympathetic nerve trunks close to the superior cervical ganglion but not in the endoneurium of the trigeminal and the sciatic nerves or in the spinal nerve roots. In such structures labeled cells appeared in the connective tissue sheaths covering the nerves and the roots. No adriamycin-induced fluorescence was detected in the myenteric plexus of the intestine. Our study thus shows that i.v. injected adriamycin is distributed preferentially within areas of the PNS where the blood vessels are known to be highly permeable.
Adrenal Medulla↗
Measurement of edema in the nervous system. Use of Percoll density gradients for determination of specific gravity in cerebral cortex and white matter under normal conditions and in experimental cytotoxic brain edema.
A method is presented by which density measurements can be performed on samples from cerebral cortex and white matter of normal and intoxicated animals using nontoxic ingredients as an alternative to the bromobenzene-kerosene technique described by Nelson et al. (1971). A continuous density gradient is prepared in a calibrated glass cylinder by using a new product, Percoll, which consists of colloidal silica particles coated with polyvinyl pyrrolidone. The gradient is stable and the same column can be used for repeated experiments over a long period of time. Interactions between the gradient media and the samples are evaluated and various methodological aspects concerning removal and handling of the tissue samples are presented. Experiments with acute triethyltin (TET) intoxication in the mouse and the hamster show that the Percoll technique can be used as an alternative to the bromobenzene-kerosene method in quantitative studies on cytotoxic brain edema.
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Uptake of macromolecules into neurons from a focal vasogenic cerebral edema and subsequent axonal spread to other brain regions. A preliminary study in the mouse with horseradish peroxidase as a tracer.
Intravenously (i.v.) injected horseradish peroxidase (HRP) which has leaked out of the vessels in a cryogenic cortical injury of adult mice is taken up into a large number of neurons resulting in two different forms of labeling. Diffuse neuronal labeling of the type previously reported in many conditions with vasogenic brain edema occurred particularly within the primary lesion. The other and more frequent type, here called granular neuronal labeling, was present in a wide zone immediately outside the injury. Such neurons contained HRP in numerous cytoplasmic granules and had the same characteristics as normal neurons accumulating HRP after retrograde axonal transport. By using highly sensitive histochemical methods for demonstration of HRP we could also follow bundles of labeled axons out from the primary lesion. Some of them passed the corpus callosum to the fronto-parietal cortex of the contralateral hemisphere. With this report we would like to put emphasize on certain phenomena occurring in neurons which previously have not been particularly recognized in studies on vasogenic brain edema. It can be assumed that in a focal brain lesion components from the edematous fluid and other "would substances" can be taken up into nerve cell processes and then be intracellularly transported in different directions. In this way, nerve cell populations located in other brain areas and even in the contralateral hemisphere may be influenced by components from the primary injury.
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Cytofluorescence localization of adriamycin in the nervous system. III. Distribution of the drug in the brain of normal adult mice after intraventricular and arachnoidal injections.
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Animals↗