Association of Acute, High-dose Cadmium Exposure with Alterations in Vascular Endothelial Barrier Antigen Expression and Astrocyte Morphology in the Developing Rat Central Nervous System.

Clinical and experimental studies have demonstrated the neurotoxic and behavioural effects of cadmium. However, the exact pathophysiological mechanism(s) of cadmium neurotoxicity on the human central nervous system (CNS) is not completely understood. A rat blood-brain barrier (BBB) endothelial marker, the endothelial barrier antigen (EBA), has been identified and we have shown previously that an anti-EBA IgG1 antibody exclusively recognizes barrier-competent microvessels in the rat CNS and peripheral nervous system (PNS). Endothelial cells of peripheral tissues or brain regions possessing fenestrated microvascular endothelia do not display immunoreactivity for EBA. Here, we describe the application of sequential indirect immunofluorescence with anti-EBA, and an antibody directed against glial fibrillary acidic protein (GFAP), to evaluate the immunoreactivity patterns and morphological alterations in BBB microvessels and astrocytes, following a single, high dose of cadmium in normal, term-delivered young rats. We detected a moderate reduction in immunoreactivity and number of microvessels labelled by the anti-EBA in the forebrain, cerebellum and midbrain in cadmium-exposed rats compared with normal controls. We observed weakly GFAP-reactive astrocytes displaying cell bodies with ill-defined borders and blurred cytoplasm within the white and grey matter of cadmium-exposed brains. The astrocyte nuclei were markedly enlarged, intensely hyperchromatic and exhibited chromatin condensation with nuclear fragmentation. This study indicates for the first time that EBA is involved in, and could serve as a potentially useful marker for studying, cadmium neurotoxicity in the rat model system.

Monoclonal antibodies against vascular endothelial antigens expressed in normal human brain.

A panel of monoclonal antibodies reactive with human-brain vessels was raised by immunizing BALB/c mice with homogenate of whole human brain, obtained from temporal lobectomies. Hybridoma supernates were screened by immunohistochemical methods on frozen sections of human brain, liver and spleen and 16 clones were isolated. The pattern of immunoreactivity varied with respect to the type of brain blood vessels predominantly labelled and to tissue specificity. Some antibodies cross-reacted with cow or squirrel monkey forebrain microvessels with an intensity equal to that shown by human brain. The immunoreactivity patterns reflected antigenic heterogeneity among different subsets of vascular endothelial cells in human brain.

Lipofuscin pigment in cerebellar Purkinje neurones and choroid plexus epithelial cells of macaque monkeys with Plasmodium knowlesi cerebral malaria: an electron microscopical observation.

Experimental infection of rhesus monkeys (Macaca mulatta) with a virulent (W1) strain of Plasmodium knowlesi resulted in cerebral malaria. Electron microscopical examination of the brain revealed large numbers of intracytoplasmic lipofuscin pigment deposits in cerebellar Purkinje neurones and choroid plexus epithelium of the lateral ventricle. This lesion may be part of the nervous system response to ischaemic hypoxia.

Immunocytochemical study of a vascular barrier antigen in the developing rat brain.

A rat-specific mouse monoclonal antibody, exclusively reacting with a blood-brain and blood-nerve barrier protein, was employed to assess the post-natal, age-related changes in morphology and intraparenchymal distribution of barrier competent microvessels in normal rat forebrain. Antibody binding first appeared in single cells over the external surfaces of the brain between days 3 and 6 post-partum and increased progressively with age. In mature rats, the cerebral grey matter showed higher vascularization by barrier competent microvessels than white matter. Microvessels in the hippocampus were immunocytochemically more avid but less "networked" than the rest of the neocortex. These features may be related to morphological, metabolic and haemodynamic changes associated with brain growth and development.

Cerebral malaria in the rhesus monkey (Macaca mulatta): observations on host pathology.

Infection was induced in five rhesus monkeys (Macaca mulatta) by intravenous inoculation with a virulent strain of Plasmodium knowlesi. Approximately one week after inoculation, four of the exposed animals developed acute malaria and died or were killed when moribund after varying periods of illness. Post-mortem and light microscopical examination showed marked cerebral vascular congestion and widespread plugging of the brain capillaries and venules (microvessels) by heavily parasitized erythrocytes mixed with uninfected erythrocytes. Electronmicroscopically, the major changes seen were adherence of large numbers of parasitized erythrocytes and macrophages to swollen microvascular endothelial cells; increased numbers of fibroblasts and deposition of collagen bundles in the extracellular matrix around damaged and parasite-packed microvessels were also found in many areas. This animal model may prove useful for further investigation of the pathogenesis of cerebral malaria.