Henrik A. Hartmann

Axonal lesions and waltzing syndrome after IDPN administration in rats

Zusammenfassung1.Der primäre Angriffspunkt der IDPN ist der marklose oder markarme proximale Axonabschnitt der Riesenneuronen des retikulären Systems des Hirnstammes, der Kerne des N. statoacusticus (VIII), der Vorderhörner des Rückenmarks und — zu einem geringeren Grad — einiger Hirnnervenkerne.2.Die Verteilung der schwersten Schäden deckt sich annähernd mit der Verteilung der Neurone, bei denen der Enzymtransport von der axonalen Strömung abhängig ist.3.Durch IDPN erzeugte Schattenzellen („ghost-cells”), die bisher als Reste untergehender Neuronen gedeutet wurden, sind tatsächlich geschwollene Ursprungsabschnitte der Axone („Ballons”) mit angehäuften partikulären Bestandteilen.4.Die zunehmende Anhäufung von Axoplasmabestandteilen nahe den Perikarya wird als Zeichen einer „primären Axostasis” aufgefaßt und nicht als Ergebnis einer Blockierung in der Höhe der Foramina intervertebralia.5.Die fortgesetzte Produktion von Axoplasma, für die die Größe der „Ballons” spricht, deutet darauf hin, daß das Perikaryon noch funktionstüchtig ist.6.Bemerkenswert ist das zeitliche Zusammenfallen der ersten klinischen Syndrome mit den ersten histologischen Veränderungen.7.Der Begriff der „Axostasis” wird vorgeschlagen und diskutiert. „Axostasis” ist wahrscheinlich der für das „Tanz-Syndrom” („waltzing syndrome”) verantwortliche pathogene Prozeß. Die Bedeutung dieses Syndroms in Beziehung zu den retikulären Neuronen des Hirnstammes wird hervorgehoben.

Electron microscopy of focal neuroaxonal lesions produced by β-β′-iminodipropionitrile (IDPN) in rats

Summary and ConclusionsAn electron microscopic study was made on neuroaxonal lesions in the anterior motoneurons of the lumbar spinal cord in IDPN-treated rats which manifested the permanent “waltzing syndrome” during the stages of axonal balloon formation. The following observations and discussion were made.1.Within the axonal balloons, there were focal accumulations of usual axoplasmic constituents, viz., neurofibrils, mitochondria, and small vesicles.2.The balloons, outlined by a thin myelin or axolemmal layer, or axoplasmic contents without definite membrane structure, were often surrounded by edematous spaces filled with granular material.3.Distal to the balloons, there were segmental accumulations of degenerating mitochondria, vesicles, and also of dense complex bodies within the myelinated portions of axons.4.No significant alterations were observed in the perikarya of the anterior motoneurons.5.The present study seems to support a previously held hypothesis of a mechanism of “primary axostasis” as the cause of the lesions as well as of the waltzing syndrome. The intra-axonic dense complex bodies, resembling pigment granules, would provide a plausible explanation for the permanence of the induced syndrome.ZusammenfassungElektronenmikroskopische Untersuchungen der neuroaxonalen Läsionen an den Vorderhornzellen des Lumbalmarks von IDPN-behandelten Ratten mit permanentem “waltzing syndrome” wurden während des Stadiums der axonalen Ballonierung durchgeführt. Es wurden folgende Beobachtungen gemacht und diskutiert:1.Innerhalb der Axonballons finden sich fokale Anhäufungen üblicher Axoplasmabestandteile, z. B. Neurofibrillen, Mitochondrien und kleine Vesikeln.2.Die Ballons, die von einer dünnen Myelin-oder Axolemmschicht oder von Axoplasmaanteilen ohne distinkte Membranstruktur begrenzt sind, werden oft von Ödemräumen umgeben, die von granulärem Material erfüllt sind.3.Distal von den Ballons findet sich eine segmentale Anhäufung von degenerierten Mitochondrien, Vesikeln sowie von dichten zusammengesetzten Körperchen innerhalb der bemarkten Abschnitte des Axons.4.In den Perikarya der Vorderhornzellen finden sich keine nennenswerten Veränderungen.5.Die vorliegende Untersuchung scheint die frühere Hypothese des Mechanismus der “primären Axostase” als Ursache der Läsionen beim “waltzing syndrom” zu unterstützen. Die intraaxonalen dichten zuxammengesetzten Körper dürften eine plausible Erklärung für die Permanenz des induzierten Syndroms geben.

Electron microscopic histochemical study on the localization and distribution of mercury in the nervous system after mercury intoxication

Abstract A recently developed electron microscopic-histochemical method was employed to study the general cellular as well as the precise intracellular localization and distribution of mercury in various parts of the nervous system after mercury intoxication. The general cellular distribution pattern of mercury seems to correspond to the anatomical localization of the pathological changes. Intracellularly, mercury was found binding mainly to the membraneous structures in the cytoplasm. Only very minimal amounts of mercury were found inside the nucleus.

Ultrastructural studies of the nervous system after mercury intoxication

SummaryMercury was first detected histochemically in the Schwann cells between 12 and 24 h after the administration of organic or inorganic mercury compound. After 4 days of intoxication, mercury could be observed in the axoplasm. Pathological changes in the dorsal root fibers were observed 1 week after CH3HgCl and 2 weeks after HgCl2 intoxication.After HgCl2 poisoning, a large axonal space was created in many axons as a result of detachment of the axolemma from the myelin sheath and axonal shrinkage. Axonal degeneration, vacuolation, and collapse were observed in many nerve fibers. Although myelin destruction could be observed occasionally, the regular lamination and periodicity of the myelin sheath were usually preserved.After CH3HgCl poisoning, however, the myelin sheaths seemed to have lost their lamination and have a smudged or solid appearance. Extensive axoplasmic degeneration, axonal collapse, and myelin destruction were the most prominent lesions observed in these nerve fibers.Pathological changes in the ventral root fibers and sciatic nerve were not observed until the second week of intoxication by either organic or inorganic mercury compound. While only limited damages were produced in the ventral root fibers, extensive degradation of the axons and demyelination of the nerve fibers were observed in the sciatic nerve.Disoriented layering of myelin to form concentric myelin structures and active phagocytosis of the degenerative debris by the reactive Schwann cells were also observed.

Blood-brain barrier dysfunction in experimental mercury intoxication.

SummaryMethylmercuric chloride (CH3HgCl) or mercuric bichloride (HgCl2) were administered to the rats at a dosage of 1.0 mg/kg body weight. Toluidine blue-albumin was injected into these animals at various periods after the intoxication. Leakage of the dye into the nervous parenchyma was observed as early as 12 h after the intoxication indicating an impairment and dysfunction of the blood-brain barrier. This dysfunction is believed to be due to an impairment of the endothelial and glial membranes by the mercury.

Quantitative Cytochemical Studies of RNA in Experimental Mercury Poisoning. I. Changes in RNA Content

RNA content in single spinal ganglion neurons and anterior horn motoneurons from mercury intoxicated rats were analyzed by the cytochemical method of Edstrom. The cell volume of these nerve cells was measured by Mickelwrights method. It was found that in the spinal ganglion neurons, there was a continuous decrease in the RNA content after methylmercury poisoning. After inorganic mercury (HgCl2) intoxication, there was in initial decrease in RNA content followed by a partial regaining of RNA after prolonged intoxication. These changes in RNA content were believed to be independent of the morphological changes produced by mercury in these neurons. Except for the cell swelling detected after the first week of methylmercury intoxication, there was a general decrease in cell volume after intoxication by either mercury compound. In the anterior horn motoneurons, there was a moderate increase in RNA after mercury poisoning (organic or inorganic). Since morphological lesions were only observed in the nerve fibers but not in the nerve cell bodies of these neurons, this increase in RNA level was thought to be a reparative response to the axonal injuries produced by the mercury compounds. Only a slight decrease in cell volume was observed at late stages of the intoxication.

RNA content and volume of nerve cell bodies in human brain. I. Prefrontal cortex in aging normal and demented patients.

The age-related change in the neuronal RNA content, volume, and the RNA concentration of 2,160 single cell bodies was examined from the prefrontal cortex. Human brains from 15 normal and 3 demented patients of ages ranging from 8 months to 94 years were obtained at post-mortem examination. The neuronal RNA showed an adult level at age 9 years and remained unchanged until age 66; the mean RNA content was 27.15 pg during this period of time. A decline in the RNA content followed with increasing ages, but it leveled off to an average of 17.97 pg after the age of 80 years. A comparative observation of morphological changes of normal and demented patients reveal the quantitative spectrum of senile plaques. In spite of the presence of significantly more senile plaques, patients with senile dementia showed the RNA content and the volume of the cell body like those of normal patients of similar age. There seems to be no criterion which is characteristic of senile dementia in terms of the RNA content in cortical cell bodies.

RNA Content and Volume of Motor Neurons in Amyotrophic Lateral Sclerosis: II. The Lumbar Intumescence and Nucleus Dorsalis

The content of RNA and volume of individual neurons isolated from the nucleus dorsalis and from the ventrolateral portion of the lumbar swelling were determined in eight cases of amyotrophic lateral sclerosis (ALS) and eight controls whose spinal cords were obtained at autopsy. The mean content of RNA in the lumbar motor neurons of the controls was 557 pg, compared to only 386 pg in the ALS group. This represents approximately a 31% reduction and is highly significant, p<0.01. No difference in RNA content was observed between the ALS group and controls in the nucleus dorsalis, which suggests that the reduction of RNA is restricted to the motor system in ALS. The volume of individual motor neurons of the lumbar intumescence was not significantly different between the controls and ALS.

Quantitative cytochemical studies of RNA in experimental mercury poisoning

SummaryAdult male rats were intoxicated with methylmercuric chloride (CH3HgCl) or mercuric bichloride (HgCl2) at a daily dosage of 1.0 mg/kg body weight for various length of periods. Single neurons were dissected out from the dorsal root ganglia with the aid of a de Fonbrune micromanipulator. The RNA of these neurons was extracted and the base composition of the RNA was analyzed by the microphoretic technique of Edström.Although methylmercury and short-termed mercuric bichloride intoxication induced a marked reduction of the total RNA content in these neurons, there was no change in the base values under these conditions. Change in the RNA base composition and ratios were detected after prolonged mercuric bichloride intoxication (11 weeks). The guanine value was increased from 32 to 37 and the cytosine value was decreased from 28 to 21 with a consequent shift of the G/C ratio from 1.16 to 1.73 and the A+G/C+U ratio from 1.12 to 1.33. The change in the RNA base composition occurred at the same period where there was an increased activity of RNA production. Since some animals showed signs of increasing tolerance and recovery from the mercury toxicity at the same time, it can be speculated that the newly produced RNA may be responsible for these phenomena.

Quantitative studies of neuronal RNA on the subiculum of demented old individuals.

Autopsied human brains from three patients with senile dementia were studied for the effect of neurofibrillary tangles on neuronal RNA content. Nerve cell bodies were dissected out from the subiculum under the phase contrast microscope and were separated into two groups based on the presence or absence of neurofibrillary tangles within the perikaryon. It was found that the mean RNA content of the tangle-bearing cells was 28.61 pg, whereas that measured in nerve cell bodies considered as free from the tangles was 41.21 pg. Thus, a significant decrease in neuronal RNA content could be correlated to an excess accumulation of neurofibrillary tangles.