Toxicological studies on (2'R)-4'-O-tetrahydropyranyladriamycin, a new antitumor antibiotic. Its acute toxicity in rats

(2'R)-4'-O-Tetrahydropyranyladriamycin (THP), a new antitumor antibiotic of anthracycline derivative, was given to Jcl-SD strain rats through intravenous (i.v.), intraperitoneal (i.p.), subcutaneous (s.c.) or oral (p.o.) administration routes and the animals were observed in respect of mortality, clinical signs and body weight for 21 days. Autopsy was done and histopathology on the tissues showing macroscopic abnormality was performed. The results were summarized as follows. Values of LD50 were 18.09 mg/kg i.v., 22.58 mg/kg i.p., 25.39 mg/kg s.c. and above 1,013 mg/kg p.o. for males and 18.07 mg/kg i.v., 20.30 mg/kg i.p., 21.76 mg/kg s.c. and above 1,013 mg/kg p.o. for females. No significant difference was found in LD50 values of different sexes. When higher than lethal dose levels of THP was given to animals, their clinical signs grew worse and weight loss occurred in about 5 days after the administration of the drug. Thereafter, deaths were observed. Macroscopic and microscopic observations on dead and survived rats revealed atrophy of spleen and thymus, whity clouding of spleen capsule, hemorrhage in mucosa of glandular stomach and congestion and hemorrhage in testes. These results suggest that THP shows weaker acute toxicity to rats than doxorubicin does, but the toxic effect of THP is approximately the same as that of other anthracycline derivatives.     

An autopsy case of "progressive supranuclear palsy" without psychiatric or neurological signs]

We report an autopsy case of a Japanese man with "progressive supranuclear palsy (PSP)" who showed neither neurological nor psychiatric signs. Although he died by heart failure at the age of 84 years, he had neither neurological nor psychiatric signs throughout the clinical course. Neuropathological examination revealed neuronal loss of the substantia nigra and pallidum. Neurofibrillary tangles were observed in the caudate nucleus, subthalamic nucleus, pallidum, putamen, substantia nigra, locus ceruleus, pontine nucleus, inferior olivary nucleus, and dentate nucleus, compatible with the NINDS pathological diagnosis of PSP reported in 1994. Staining by Gallyas-Braak methods disclosed tuft-shaped astrocytes in the caudate nucleus, putamen, and thalamus. To our knowledge, this is the first report of "PSP" without psychiatric or neurological signs.     

Distribution of neuropeptide Y interneurons in the dorsal prefrontal cortex of schizophrenia

The distribution of neuropeptide Y (NPY) containing neurons was investigated in the dorsal prefrontal region in the brains of the schizophrenic patients and compared to those of normal control. Proportional comparison of NPY neurons in four compartments, upper cortical layers, lower cortical layers, subcortical white matter and deep white matter, demonstrated differential distribution between schizophrenic brains and controls. The proportion of NPY neurons in the upper cortical layers was low in disorganized form and subsequently in paranoid form in comparison to controls. The proportion of NPY neurons in the deep white matter was, conversely, high in the disorganized form and subsequently in the paranoid form. These results indicate that there may be a gamma-aminobutyric acid (GABA)-ergic deficit in schizophrenic patients, especially, in the disorganized form. These results also support the hypothesis of neurodevelopmental dysfunction of schizophrenia.     

Toxicological studies on a new macrolide antibiotic, midecamycin acetate (miokamycin). Part II-1. Subacute toxicity in rats

Miokamycin (MOM) is a derivative of midecamycin, a macrolide antibiotic isolated from a culture broth of Streptomyces mycarofaciens. The objective of this study was to determine the subacute toxicity in male and female rats (Wistar, SPF, 5-week-old) after repeated oral administration of MOM, non-crystalline solid, for 5 weeks at selected dosage levels of 1,000, 2,000 and 4,000 mg/kg/day. It is concluded that the maximum non-toxic dosage level of MOM, non-crystalline solid, was 1,000 mg/kg/day but without specific toxic effects with rats when it was orally administered once daily for 5 weeks.     

Phosphorylated TDP-43 in Alzheimer’s disease and dementia with Lewy bodies

Phosphorylated and proteolytically cleaved TDP-43 is a major component of the ubiquitin-positive inclusions in the most common pathological subtype of frontotemporal lobar degeneration (FTLD-U). Intracellular accumulation of TDP-43 is observed in a subpopulation of patients with other dementia disorders, including Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). However, the pathological significance of TDP-43 pathology in these disorders is unknown, since biochemical features of the TDP-43 accumulated in AD and DLB brains, especially its phosphorylation sites and pattern of fragmentation, are still unclear. To address these issues, we performed immunohistochemical and biochemical analyses of AD and DLB cases, using phosphorylation-dependent anti-TDP-43 antibodies. We found a higher frequency of pathological TDP-43 in AD (36–56%) and in DLB (53–60%) than previously reported. Of the TDP-43-positive cases, about 20–30% showed neocortical TDP-43 pathology resembling the FTLD-U subtype associated with progranulin gene (PGRN) mutations. Immunoblot analyses of the sarkosyl-insoluble fraction from cases with neocortical TDP-43 pathology showed intense staining of several low-molecular-weight bands, corresponding to C-terminal fragments of TDP-43. Interestingly, the band pattern of these C-terminal fragments in AD and DLB also corresponds to that previously observed in the FTLD-U subtype associated with PGRN mutations. These results suggest that the morphological and biochemical features of TDP-43 pathology are common between AD or DLB and a specific subtype of FTLD-U. There may be genetic factors, such as mutations or genetic variants of PGRN underlying the co-occurrence of abnormal deposition of TDP-43, tau and α-synuclein.     

An autopsy case of senile dementia with pathological features of Parkinson's disease]

We report an autopsy case of Parkinson's disease mimicking senile dementia of the Alzheimer type. A Japanese man developed memory disturbance and visual hallucination at age 70. Although he died from pneumonia at age of 74, he had no neurological signs throughout the clinical course. The weight of his brain was 1,420 g. Macroscopic examination of the brain revealed prominent depigmentation of the substantia nigra and locus ceruleus. Histological examination disclosed neuronal loss with astrocytosis and the appearance of the Lewy bodies in the nucleus basalis of Meynert, substantia nigra, locus ceruleus, and dorsal vagal nucleus. There were widespread senile plaques in the brain, including the precentral gyrus, which was compatible with Braak stage C. A small number of neurofibrillary changes were present in the limbic areas, consistent with Braak stage III. This case is consistent with brain stem dominance with the pathological diagnosis of the Consortium on Dementia with Lewy Bodies International Workshop. That is, it is compatible with Parkinson's disease. We postulate that the clinical features of Parkinson's disease are more widespread than previously considered.     

Toxicological studies on a new macrolide antibiotic, midecamycin acetate (miocamycin). Part IV-6. Toxicity of metabolites of miocamycin: subacute toxicity of Mb2 in rats

Miocamycin (MOM) is a derivative of midecamycin, a macrolide antibiotic and is metabolized into 4 main metabolites of Mb1, Mb2, Mb6 and Mb12. At previous study, the acute and subacute toxicity of Mb1 and acute toxicity of Mb2 were performed that those metabolites did not exhibit any lethal toxicity even at the maximum physically applicable dose. The object of this study was to examine subacute toxicity in male and female rats after repeated p.o. administration of Mb2 for 5 weeks at a daily dosage of 125, 250, 500 and 1,000 mg/kg. It is, therefore, concluded that Mb2 exerted no toxic effects in this subacute toxicity.