Hisashi Aikawa

Low energy levels in thiamine-deficient encephalopathy.

Pyrithiamine-induced acute thiamine-deficient encephalopathy was produced in adult male Wistar rats. Twenty-four hours before the onset of neurological signs the brain showed no morphological abnormalities. Encephalopathic rats had symmetrical lesions of edematous necrosis localized in the thalamus, mammillary body, and pontine tegmentum. Biochemically, encephalopathic rats had brain thiamine levels less than 20% of controls. For the assay of the concentrations of adenosine triphosphate (ATP) and phosphocreatine, the brains were fixed using 5 KW microwave irradiation and were divided into four parts: cerebral cortex, diencephalon, lower brainstem, and cerebellum. In the lower brainstem of the encephalopathic rats ATP concentrations were 89.5% of normal controls. Phosphocreatine levels were lowered to 70% of controls in the diencephalon and to 75% in the lower brainstem. Total high energy phosphate levels were decreased to 89% of controls in the diencephalon and 91% in the lower brainstem before the onset of neurological signs and to 76% and 79%, respectively, after the onset. In the cerebral cortex and cerebellum high energy phosphates were not significantly reduced. Lower high energy phosphate levels and the distribution of edematous lesions were coincident in the brain. These findings suggest that a low energy state is closely related to the formation of edematous lesions in thiamine-deficient encephalopathy.

Hemorrhage of thiamine-deficient encephalopathy

Hemorrhagic lesions of pyrithiamine-induced acute thiamine-deficient encephalopathy of the mouse (PIATDEM) consisted of petechiae, which often coalesced to form small hematomas. Electron microscopy showed the typical petechial lesion to be composed of a perivascular necrotic zone containing fibrin-platelet clot surrounded by a ring of erythrocytes. Endothelial cells were intact and tight junctions were closed. A study of permeability to horseradish peroxidase (HRP) revealed only a slight increase in the number of transport vesicles in the endothelial cells. A large amount of HRP present in the lesions seemed to have entered the brain by a hemorrhagic route which remains unclarified. Spherical latex particles, 0.23 μm in diameter, were injected intravenously into encephalopathic mice at a time when intracerebral hemorrhages frequently occurred. Two to 24 hours after the injection, a large number of latex particles penetrated the blood vessels at sites of hemorrhage. There were many particles in the phagosomes of the endothelial cells, which suggested transendothelial transport by the organelle. The possibility of endothelial phagocytic transport of erythrocytes as a main route of diapedesis is discussed.

Enteric gliopathy in niacin-deficiency induced by CNS glio-toxin

6-Aminonicotinamide (6-AN), an antagonist of niacin and a potent CNS glio-toxin, selectively caused degeneration of glial cells in the central nervous system (CNS) of rodents. Suckling mice treated with 6-AN developed diarrhea clinically and displayed vacuolated degenerating glial cells in the myenteric plexus as well as in the CNS. Myenteric neurons were well preserved. These findings provide further evidence for possible functional similarities between the glial cells in the central and enteric nervous systems.

6-Aminonicotinamide-Induced Hydrocephalus in Suckling Mice

Following a single intraperitoneal injection of 6-aminonicotinamide (6-AN, 50 mg/kg of body weight) into newborn mice of the Institute of Cancer Research strain, hydrocephalus consistently developed nine days after injection, with rapid progression. All of these mice died before reaching adulthood. The most striking early histologic change in these mice was cytoplasmic vacuolation of ependymal cells, which was observed as early as 24 hours after injection. Vacuolation of subependymal astrocytes appeared during the next few days. After day seven, the aqueduct was obliterated by swollen vacuolated ependymal cells and subependymal astrocytes. The aqueduct remained obliterated even after the vacuolation of the ependymal cells subsided after day nine, when vacuolation of subependymal astrocytes was still pronounced. These morphological observations reveal that, in newborn mice, the ependymal cells are the most sensitive to the toxic action of 6-AN and suggest that the pathogenesis of 6-AN-induced hydrocephalus is likely to be due to the combination of ependymal cell damage and compression of the lumen by the edematous periaqueductal gray matter. This is a highly reproducible animal model of drug-induced hydrocephalus.

Experimental Chronic Subdural Hematoma in Mice: Gross morphology and light microscopic observations

A new experimental model of chronic subdural hematoma in mice is described. A single intraperitoneal injection of 6-aminonicotinamide (25 mg/kg body weight) on the 5th postnatal day induced hydrocephalus in mice with almost 100% success. Approximately 60% of the mice spontaneously developed intracranial hemorrhage 20 days after the injection. About 1 week after the hemorrhage, a lens-shaped or spherical subdural hematoma was observed, accompanied by marked dilatation of the lateral ventricles and intraventricular hemorrhage. Histological examination revealed that the hematoma contained well-organized outer and inner membranes. Fresh hemorrhage surrounded by many hemosiderin-laden macrophages was seen at the margin of the hematoma adjacent to the organizing outer membrane, in which many fibroblasts and blood vessels were noted. The inner membrane of the hematoma was made up of several tiers of flattened cells with thin-walled blood vessels. The gross morphology and histology of these hematomas closely resembled those of human chronic subdural hematoma.

Internodal microvillus-like Schwann cell fingers in myelinated fibres in mouse spinal roots

SummaryCollections of microvillus-like Schwann cell fingers identical to those described previously in the nodal gap substance were commonly found along the internodes of large myelinated fibres in the spinal roots of adult mice. They were covered by Schwann cell basal lamina and focally protruded from the outer cytoplasmic Schwann cell compartment. Unlike nodal Schwann cell fingers, these internodal fingers had no contact with the axolemma, but were directed toward the endoneurium. These were not recognized in the distal peripheral nerves. The frequent occurrence of internodal Schwann cell fingers in the spinal root fibres suggests that these structures may be involved in some electrophysiological regulatory mechanism in this particular region of the nervous system.

Aqueduct stenosis induced by a single injection of antivitamin

Hydrocephalus with aqueduct stenosis was a consistent feature in mice which received a single intraperitoneal injection of 6-aminonicotinamide (6-AN) on day 5 postnatal. Chronological investigation revealed that 6-AN-treated mice had aqueductal obstruction with edematously swollen ependymal cells and spongy changes in the periaqueductal gray matter in the early stage (on days 5 and 7 postinjection). However, these cytoplasmic edema of the ependymal and glial cells totally subsided by day 30 postinjection, leaving an obliterated aqueduct with a few remnants of ependymal cells without reactive gliosis. This abnormality of aqueductal lesions in the chronic stage was similar to those of human congenital hydrocephalus. These findings raise the possibility that some form of human congenital hydrocephalus may result from ependymal cell degeneration due to exposure to certain noxious substances in the perinatal period.

Neurotoxic Effects of 6-Aminonicotinamide, Mouse

Suckling mice injected intraperitoneally with 6-aminonicotinamide (6-AN) in one dose of 25 mg/kg body weight consistently develop enlargement of the head 7–9 days after injection (Aikawa and Suzuki 1985a, 1986). In coronal sections of the cerebrum, marked hydrocephalus is evident due to dilatation of the lateral ventricles (Fig. 57). The fourth ventricle is not dilated and the aqueduct is always narrowed and obliterated (Aikawa et al. 1984). No hydrocephalus is seen in adult mice treated with 6-AN.