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To elucidate the biological significance of fibroblast growth factor-2 (FGF-2) expression in epilepsy-associated malformations of cortical development, immunohistochemical expression of FGF-2 was investigated in the developing human cerebral mantles obtained from 30 autopsy cases of fetuses, stillborn infants and children ranging from 12 weeks gestation to 15 years old, and 70 surgically-resected corticectomy specimens from patients with medically intractable epilepsy, including: group I, 12 tubers of tuberous sclerosis; group II, 24 cases of focal cortical dysplasia (FCD) with balloon cells (BC); group III, 11 FCD without BC; group IV, 23 histologically normal-appearing neocortices from patients with Rasmussen encephalitis, cystic-gliotic encephalopathy, temporal lobe epilepsy; and group V, 14 normal-appearing neocortices adjacent to dysplastic lesions from groups I and II. FGF-2 expression was detected in a population of matrix cells and/or neuroblasts within the ventricular zone in fetuses younger than 19 weeks gestation. Nuclei of glioblasts and immature astrocytes were also positive for FGF-2 in cases older than 18 weeks gestation. FGF-2 expression was not detected in immature cortical plate neurons. Astrocytes and ependymal cells were positive for FGF-2 in the postnatal brains. Choroid plexus epithelium was strongly positive for FGF-2 in all cases examined. Among the corticectomy specimens, the cytoplasms and/or nuclei of dysmorphic neurons (DNs) and BCs in groups I and II were variably positive for FGF-2. The proportions of FGF-2 immunoreactive cells (FGF-2-IR%) was significantly higher in groups I (36.9 ± 9.6) and II (45.1 ± 7.0) than in groups III (21.0 ± 5.7), IV (14.4 ± 4.7) and V (24.3 ± 10.3), and that in group V was higher than in group IV (P

Neuroprotective effects of 6-formylpterin (6FP) on transient retinal ischemia-reperfusion injury were evaluated in rats by means of counting the number of retinal ganglion cells, measuring the thicknesses of the inner plexiform and inner nuclear layers, and by immunohistochemical detection of apoptotic cells in the retina. Sixty-one Sprague-Dawley rats (12 weeks, male, 295-330 g) were subjected to transient retinal ischemia-reperfusion by elevated intra-ocular pressure (80 mmHg for 60 min). Intraperitoneal injection of 6FP (3.8 mg/kg) was performed before or after ischemia. The retina was histologically better preserved in rats with 6FP treatment than without 6FP treatment. 6FP showed more strong neuroprotective effects when it was administered before ischemia. The number of single-stranded DNA-positive cells in the retina also decreased remarkably in rats with 6FP treatment, especially when administered before ischemia. These results suggest that 6FP protects retinal neurons from transient ischemia-reperfusion injury, at least in part by inhibiting apoptotic cell death.

Neuronal Lewy body-like hyaline inclusions (LBHI) and astrocytic hyaline inclusions (Ast-HI) are morphological hallmarks of certain familial amyotrophic lateral sclerosis (FALS) patients with superoxide dismutase-1 (SOD1) gene mutations, and transgenic mice expressing the human SOD1 gene mutation. The ultrastructure of inclusions in both diseases is identical: the essential common constituents are granule-coated fibrils approximately 15-25nm in diameter and granular materials. Detailed immunohistochemical analyses have shown that the essential common protein of the inclusions in both diseases is an SOD1 protein. This finding, together with the immunoelectron microscopy finding that the abnormal granule-coated fibrils comprising the inclusions are positive for SOD1, indicates that these granule-coated fibrils containing SOD1 are important evidence for mutant SOD1-linked disease in human and mouse. For immunoelectron microscopy, the granule-coated fibrils are modified by advanced glycation endproducts (AGE) such as N(epsilon)-carboxymethyl lysine, pyrraline and pentosidine (Maillard reaction). Based on the fact that AGE themselves are insoluble molecules with direct cytotoxic effects, the granule-coated fibrils and granular materials are not digested by the lysosomal and ubiquitin systems. The neurons and astrocytes of the normal individuals and non-transgenic mice show no significant immunoreactivity for AGE. Considered with the mutant-SOD1 aggregation toxicity, a portion of the SOD1 comprising both types of the inclusion is modified by the AGE, and the formation of the AGE-modified SOD1 (probably AGE-modified mutant SOD1) is one of the mechanisms responsible for the aggregation (i.e. granule-coated fibril formation).

We report a Japanese case of sporadic Creutzfeldt-Jakob disease (CJD) with particular clinical course and neuropathological findings. A 74-year-old female exhibited parkinsonism and later, dementia, myoclonus as well as visual hallucinations, lacking periodic synchronous discharges in the electroencephalogram. The duration of her illness was 2 years, longer than typical CJD cases which average 8 months’ duration. Gray matter was severely affected, the Ammon’s horn and subicular cortex were well preserved and many kuru plaques were observed in the cerebellum using routine histological stainings. Immunohistochemistry for prion protein (PrP) using both formic acid and hydrolytic autoclaving pretreatment revealed numerous prion plaques throughout the brain together with intense synaptic-type deposition of PrPCJD (abnormal isoform of PrP) in all gray matter examined, particularly in the Ammon’s horn and subicular cortex. The definite combination of these two types of stain has never been reported previously in Japan other than in Gerstmann-Straussler– Scheinker syndrome. Relative resistance of the Ammon’s horn and subicular cortex to the PrPCJD deposition is also discussed.

A 57-year-old woman with chronic myelogenous leukemia developed neurological abnormalities. Brain biopsy revealed enlarged and basophilic nuclear cells with bizarre astrocytes on the background of demyelination, which are the characteristic histological findings of progressive multifocal leukoencephalopathy (PML). Immuno-histochemical analysis confirmed JC virus infection. Analysis of the viral regulatory regions demonstrated two different clones. DNA sequences of both clones showed a constant rearrangement of duplication and deletion, which was characteristic of the PML type of JC virus.

Immunohistochemical localization of cathepsin B (CB) in the hippocampal nerve cells was examined in patients ranging from age 18 days to 82 years to examine the change of proteolytic activity of nerve cells with aging through the CB immunoreactivity. Although it varied from case to case, region to region, and to some degree cell to cell, generally, CB immunoreactivity in the nerve cells was weak in the newborn, strong from age 7 to about 60, and decreased in most nerve cells, or the number of nerve cells with impaired CB immunoreactivity increased, after about 60 years of age. This suggests impairment of protein metabolism and/or dysfunction of lysosomal proteolysis in the nerve cells with aging. The last finding may be important as a background or preceding phenomenon that may cause abnormal protein metabolism relating to the formation of neurofibrillary tangles and/or senile plaques with aging and in Alzheimer's disease (AD). The involvement of CB in the metabolism of Aβ-amyloid protein precursors (APP) and the possible close relation of presenilins to APP should also be considered.

Three autopsied cases of pallidonigroluysian atrophy (PNLA) were studied clinicopathologically and 11 previously reported cases were reviewed for the purpose of clarifying the clinicopathological characteristics of the disease. The main clinical symptoms are parkinsonism, predominantly akinesia or pure akinesia with or without effective levodopa therapy. Major lesions approximately were confined to the globus pallidus, subthalamic nucleus and substantia nigra. Gallyas-Braak method and immunohistochemistry with a monoclonal antibody (mAb) to tau-2 protein (tau-2) revealed a small number of neurofibrillary tangles (NFT) and argyrophilic and tau-2 positive structures within the cytoplasms of the glial cells in the major lesions. Immunohistochemistry with a mAb to Alzheimer NFT (Ab39) demonstrated only a few classical tangles in the globus pallidus in one case. These findings suggest that PNLA can be pathologically differentiated from progressive supranuclear palsy.

Experimental allergic encephalomyelitis (EAE) is an organspecific, cell-mediated inflammatory autoimmune disease and is regarded as a model of multiple sclerosis (MS). Relapsing EAE was induced in Lewis rats and the effect of mizoribine on the relapsing EAE was examined clinically, histologically and immunohistochemically. Mizoribine (4-carbamoyl-1-β-D-ribofuranosyl-imidazolium-5-olate), an immunosuppresive agent, is an imidazole nucleotide isolated from a culture infiltrate of Eupenicillium brefeldianum M-2166. Most control and treated rats suffered two attacks. Treated rats at a dose of 10mg/kg per day showed clinically significant delay of the disease attacks and histologically reduction of infiltrating cell number. Treated rats at a dose of 20 mg/kg per day showed a further delay in the attacks and attenuation of clinical signs, and a smaller number of inflammatory cells and Ia positive cells were revealed at the first attack. This study suggests that mizoribine suppresses the clinical severity and inflammation in relapsing EAE.

Immunohistochemical investigations were carried out on cerebellar Purkinje cells of eight patients with Menkes' kinky hair disease (MD) using an antibody against the inositol 1, 4, 5-triphosphate receptor which is identical to the cerebellar Purkinje cell glycoprotein P400 (P400/IP3R). In normal cerebellar Purkinje cells, the cell bodies, axons and dendrites including spiny branchlets were specifically stained by the antibody. By comparison, the immunoreactivity of the MD Purkinje cells ranged from negative to positive. The most frequent staining pattern in the MD Purkinje cells was that of cell bodies and proximal portions of the dendrites expressing P400/IP3R in varying degrees, with the peripheral dendrites including spiny branchlets not being stained. The Purkinje cells of the eight patients were also analyzed for expression of phosphorylated neurofilament proteins (pNFP), αB-crystallin, stress-response protein (srp) 72, srp 27 and ubiquitin. Most MD Purkinje cell bodies reacted with the antibody against pNFP. Although the proportion of stained Purkinje cells was less, a positive reaction was also observed with the antibodies to αB-crystallin, srp 72 and srp 27. By contrast, no normal Purkinje cell was stained by these antibodies. Our results suggest that the function of P400/IP3R in the Purkinje cells of MD patients is impaired, that these cells have an aberrant phosphorylation of NFP and that some of the imparied Purkinje cells synthesize specific sets of stress-related proteins.