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  • 1
    Electronic Resource
    Electronic Resource
    Cytofluorescence localization of adriamycin in the nervous system (1982)
    Springer
    Acta neuropathologica 57 (1982), S. 130-136 
    Details
    ISSN: 1432-0533
    Keywords: Adriamycin ; Doxorubicin ; Bloodnerve barrier ; Peripheral nervous system (PNS)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685380
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  • 2
    Electronic Resource
    Electronic Resource
    Uptake of macromolecules into neurons from a focal vasogenic cerebral edema and subsequent axonal spread to other brain regions (1982)
    Springer
    Acta neuropathologica 57 (1982), S. 233-235 
    Details
    ISSN: 1432-0533
    Keywords: Cerebral trauma ; Vasogenic brain edema ; Axonal transport ; Blood-brain barrier ; Nerve cell injury
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 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 calledgranular 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 “wound 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685395
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  • 3
    Electronic Resource
    Electronic Resource
    The brain in extreme respiratory acidosis (1982)
    Springer
    Acta neuropathologica 58 (1982), S. 87-94 
    Details
    ISSN: 1432-0533
    Keywords: Hypercapnia ; Rat brain ; Ultrastructure ; Cerebral edema
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary It is presently debated how much cellular acidosis contributes to brain cell damage during ischemia and hypoxia. To study the influence of acidosis occurring in the absence of energy failure, extreme hypercapnia was produced in anesthetized, artificially ventilated, and well oxygenated rats by increasing the inspired CO2 concentration until arterialPCO2 reached 150 or 300 mm Hg. At these CO2 tensions intracellular pH falls from a control value of about 7.05 to about 6.85 and 6.65, respectively. After 45 min the brains were fixed in perfusion and processed for light and electron microscopy. AtPaCO2 150 mm Hg no clear neuronal abnormality was detected, but atPaCO2 300 mm Hg some neuronal changes were observed. Notably, the nuclei showed slightly coarser chromatin than normally. In a few nerve cells mild swelling of mitochondria and dispersion of polysomes as well as detachment of ribosomes from the endoplasmic reticulum appeared. In both groups, slight to moderate astrocytic edema developed. Thus, even extreme hypercapnia, with its acompanying marked tissue acidosis, alters ultrastructure in the brain only to such a moderate extent that irreversible cell damage is unlikely. We conclude, therefore, that acidosis occurring during ischemia or hypoxia is detrimental only if pH is further lowered and/or if it occurs in conjunction with cerebral energy failure.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00691646
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  • 4
    Electronic Resource
    Electronic Resource
    Cytofluorescence localization of adriamycin in the nervous system (1982)
    Springer
    Acta neuropathologica 58 (1982), S. 193-202 
    Details
    ISSN: 1432-0533
    Keywords: Adriamycin ; Doxorubicin ; Blood-brain barrier ; Circumventricular organs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary By a fluorescence-microscopic technique the distribution of the antineoplastic anthracyclic compound adriamycin (doxorubicin) was determined in the brain of normal adult mice after intraventricular and arachnoidal injections. These experiments were carried out to circumvent the blood-brain barrier since there are indications that vascular permeability properties determine the extent to which the drug will spread into the brain after systemic administration. In line with this concept we found previously that after i.v. injection the drug leaks into circumventricular organs of the brain. These are special areas which have permeable vessels to a number of substances including adriamycin (Bigotte et al. 1982a). After intraventricular injection the nuclei of ependymal cells throughout the ventricular system contained intensely fluorescent orange-red material characteristic of adriamycin. A thin layer of the brain parenchyma adjacent to the ventricular walls showed fluorescent nuclei. In the corpus callosum, fascia dentata of the hippocampus, and the hypothalamic preoptic nuclei the drug penetrated deeper into the tissue, and the intensity of the drug-induced fluorescence was very high there. In the circumventricular organs two different patterns of intraventricularly injected adriamycin movement were revealed. The organum vasculosum of the lamina terminalis, the subcommissural organ, and the choroid plexus showed a very strong drug-induced nuclear fluorescence both within the parenchyma and in the covering ependyma. The median eminence, the subfornical organ, the postremal area, the neurohypophysis, and the pineal gland did not show any labeling of their parenchyma. The tanycyte ependyma lining the median eminence did not take up any tracer from the ventricular fluid. Adriamycin which passed into the leptomeninges labeled a few cells in the arachnoid as well as neurons and glial cells in the adjacent first and second cortical layers. The drug also penetrated into the optic tracts and nerves. In these areas a marked adriamycin-induced fluorescence was present in the nuclei of oligodendrocytes. Our study thus shows that when the blood-brain barrier is by-passed different types of neurons and glial cells have the capacity to take up and accumulate the drug in their nuclei. Adriamycin can spread into the periventricular parenchyma after intraventricular administration but its movement into the circumventricular organs differs considerably from one area to another. Knowledge about these phenomena is essential for future studies on the neurotoxic action of adriamycin.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00690801
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  • 5
    Electronic Resource
    Electronic Resource
    Cytofluorescence localization of adriamycin in the nervous system (1983)
    Springer
    Acta neuropathologica 60 (1983), S. 125-131 
    Details
    ISSN: 1432-0533
    Keywords: Adriamycin (Doxorubicin) ; Blood-nerve barrier ; Perineurium
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Adriamycin (Doxorubicin) is a powerful anthracyclic compound, which is widely used in the treatment of maligant disease. In the rat a single systemic injection of the drug can induce pronounced lesions in peripheral ganglia, whereas in other parts of the peripheral nervous system (PNS) no changes have been reported. Since adriamycin can be directly traced in tissue sections by fluorescence microscopy it is very well suited for experimental studies on the relation between cytotoxic effects and distribution of the drug following various modes of administration. We have previously shown that after an intravenous (i.v.) injection there is an absence of adriamycin-induced nuclear fluorescence in the endoneurium of mouse sciatic nerve (Bigotte et al. 1982b). This could either be due to barrier effects in endoneurial vessels and the perineurium or to a lacking capacity of the endoneurial cell population to take up and retain adriamycin. In the present study the blood-nerve and the perifascicular diffusion barriers were therefore bypassed by endoneurial microinjections of adriamycin. After this mode of administration, Schwann cells, endoneurial mast cells, endothelial cells, and pericytes became labeled. Experimental damage of these barriers induced by ligation of the nerve also resulted in a diffusion of the drug into the endoneurial area and labeling of the same cells. The absence of nuclear binding in the endoneurium of mouse sciatic nerves after i.v. injection of adriamycin is therefore most probably due to a low or absent passage of the drug from the blood into the endoneurium, i.e., a combined barrier action of endoneurial vessels and the perineurium. Other experiments with epineurial application of the drug showed that thin intramuscular (i.m.) nerve branches differ from the sciatic nerve fascicles in allowing small amounts of adriamycin to enter the endoneurium. The present observations are of interest since it can be assumed that patients receiving adriamycin as a cytostatic drug may suffer nerve lesions whenever defects of nerve barriers are present.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685356
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  • 6
    Electronic Resource
    Electronic Resource
    Influence of systemic factors on experimental epileptic brain injury (1983)
    Springer
    Acta neuropathologica 60 (1983), S. 81-91 
    Details
    ISSN: 1432-0533
    Keywords: Brain injury ; Status epilepticus ; Hyperoxia ; Hypoxia ; Hypotension ; Vitamin E
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A previous study from the laboratory showed that status epilepticus induced by bicuculline administration to ventilated rats produced astrocytic swelling and nerve cell changes (“type 1 and 2 injury”) particularly in layers 3 and 5 of the neocortex (Söderfeldt et al. 1981). The type 1 injured neurons were characterized by condensation of cyto-and karyoplasm and the less common type 2 cells were characterized by swelling of endoplasmic reticulum including the nuclear envelope. In the present study we explored whether changes in cerebral oxygen availability altered the extent or character of the cellular alterations. Animals with 2 h of status epilepticus were made either hyperoxic (administration of 100% O2), hypoxic (arterialpO2 50 mm Hg) or hypotensive (arterial blood pressure of either 70–75 or 50 mm Hg). Furthermore, we explored whether “oxidative” damage occurred by manipulating tissue levels of α-tocopherol, a known free radical scavenger. Non-epileptic control animals exposed to comparable degrees of hypoxia or hypotension showed no or minimal structural alterations. In the epileptic animals the results were as follows.Hyperoxia did not change the quality or extent of the structural alterations previously observed in normoxic epileptic animals. Neither administration nor deficiency ofvitamin E did modify this pattern of alterations. Inhypoxia the extent of cell damage was the same or somewhat larger than in normoxic, epileptic animals. In addition, neurons often showed cytoplasmic microvacuoles due to swelling of mitochondria. The hypoxic animals also showed swelling of astrocytic nuclei with clumped chromatin. Changes similar to those observed in hypoxic animals also appeared in moderatehypotension (mean arterial blood pressure 50 mm Hg), whereas mild hypotension (70–75 mm Hg) did not change the character of the tissue injury from that seen in hyperoxic or normoxic epileptic rats. The present results demonstrate that the neuronal cell damage that can be observed when the brain is fixed by perfusion after status epilepticus of 2 h duration is not exaggerated by hyperoxia or vitamin E deficiency nor is it ameliorated by a moderate restriction in cerebral oxygen supply or by vitamin E administration. If anything, hypoxia (or moderate hypotension) appears to increase the extent of damage and it clearly alters its ultrastructural characteristics. However, although the results fail to support the notion that epileptic cell damage is “oxidative”, definite conclusions must await information on the cell damage that remains upon arrest of the epileptic activity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685351
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  • 7
    Electronic Resource
    Electronic Resource
    Toxic effects of adriamycin on the central nervous system (1983)
    Springer
    Acta neuropathologica 61 (1983), S. 291-299 
    Details
    ISSN: 1432-0533
    Keywords: Adriamycin ; Doxorubicin ; Neurotoxicity ; Blood-brain barrier ; Circumventricular organs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 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, particulary 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00692000
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  • 8
    Electronic Resource
    Electronic Resource
    Pathogenesis of brain lesions caused by experimental epilepsy (1981)
    Springer
    Acta neuropathologica 54 (1981), S. 219-231 
    Details
    ISSN: 1432-0533
    Keywords: Status epilepticus ; Nerve cell injury ; Brain edema ; Rat cerebral cortex
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Status epilepticus was induced in rats by the GABA receptor blocking agent, bicuculline, during artificial ventilation and with closely monitored physiologic parameters. After 1 or 2 h of status epilepticus the brains were fixed by perfusion with glutaraldehyde and processed for light and electron microscopy. In the cerebral cortex two different types of changes were present, i.e., nerve cell injuries and status spongiosus. Type 1 injured neurons, mainly in the areas of most marked sponginess (layer 3), displayed progressive condensation of both karyo-and cytoplasm. In the most advanced stages the nucleus could no longer be distinguished from the cytoplasm in the light microscope, and vacuoles of apparent Golgi cisterna origin appeared in the darkly stained cytoplasm. This type of injured neurons comprised 41 and 56% of the cortical neurons after 1 or 2 h of status epilepticus, respectively. Seven to 9% of the neurons showed another type of injury (type 2). They were mainly located in the deeper cortical layers, and showed slit-formed cytoplasmic vacuoles chiefly due to swelling of the endoplasmic reticulum including the nuclear envelope. Marked sponginess of the cortex developed principally in layer 3 and it spread into deeper layers with longer duration of status epilepticus, but the outermost layers retained a compact structure. As judged by electron microscopy, the sponginess resulted mainly from swelling of astrocytes and their processes causing both perivascular and perineuronal vacuolation. The structural changes observed are considered to be caused by astrocytic and to a lesser extent intraneuronal edema related to the seizure activity. Although the exact pathogenetic mechanisms are not known, our findings indicate that hypoxia-ischemia is not a major determinant of the tissue damage observed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00687745
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  • 9
    Electronic Resource
    Electronic Resource
    Reply to the remarks by J. B. Brierley and A. W. Brown (1981)
    Springer
    Acta neuropathologica 55 (1981), S. 323-325 
    Details
    ISSN: 1432-0533
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00690997
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  • 10
    Electronic Resource
    Electronic Resource
    Pathogenesis of brain lesions caused by experimental epilepsy (1983)
    Springer
    Acta neuropathologica 59 (1983), S. 11-24 
    Details
    ISSN: 1432-0533
    Keywords: Status epilepticus ; Nerve cell injury ; Brain edema ; Rat hippocampal formation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Status epilepticus with a duration of 1 or 2 h was induced in rats by i. v. injection of the GABA receptor blocking agent, bicuculline. Immediately there-after, or following a 2 h recovery period, the brains were fixed by vascular perfusion and processed for light and electron microscopy to characterize the type and distribution of morphological changes in the hippocampal formation. In a previous study (Söderfeldt et al. 1981) astrocytic edema and wide-spread neuronal changes of two different kinds occurred in the fronto-parietal cortex of the same animals. Type 1 injured neurons were characterized by condensation of karyoplasm and cytoplasm (type 1a), which in some neurons became so intense that the nucleus could no longer be clearly discerned (type 1b). The type 2 injured neurons had slitformed cytoplasmic vacuoles chiefly caused by dilatation of the rough endoplasmic reticulum. In the hippocampus the most conspicuous alteration was astrocytic edema which was most marked around the perikarya of pyramidal neurons in CA1-CA4 and subiculum. In the dentate gyrus the edema was less pronounced and, when present, affected particularly the hilar zone of the stratum granulosum. The nerve cell changes were less pronounced than in the cerebral cortex. The vast majority of the hippocampal pyramidal neurons in CA1-CA4 showed minor configurational and tinctorial abnormalities (incipient type 1a change). Severe nerve cell alterations (type 1b) were present but very rarely affected the pyramidal neurons of CA1-CA4 and subiculum, whereas in the dentate gyrus pyramidal basket neurons of stratum granulosum and pyramidal nerve cells in stratum polymorhe showed the severe type 1b changes. As compared with the frontoparietal cortex (Söderfeldt et al. 1981) the type 2 changes were extremely rare. In the early recovery period after 1 h of status epilepticus the astrocytic edema and the incipient type 1a changes had almost entirely disappeared, whereas a few condensed and dark-staining type 1b injured neurons remained. Thus, in this model of status epilepticus the most marked response in the hippocampal formation is astrocytic edema in the layers where pyramidal perikarya are located. Incipient, mild nerve cell changes which appear to be reversible were frequent and widespread in the entire hippocampal formation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00690312
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