Takahiro Nakayama

Involvement of microtubule integrity in memory impairment caused by colchicine.

In order to fully evaluate the effects of colchicine treatment on learning ability in rats, colchicine was administered, and both Morris water maze (MWM) and step-through type passive avoidance (PA) learning tests were conducted. In both learning tests, infusion of colchicine into the rat dentate gyrus, at two distinct bilateral rostrocaudal locations, potently impaired memory function in a dose-dependent manner (0.01-2.0 microg/site), whereas systemic injection of colchicine (50-300 microg/kg) did not. In the MWM test, memory impairment was observed even at doses where there was no evidence of any histological changes in the dentate granule cells. This suggests that functional deterioration, that is, learning impairment was induced by the dysfunction of microtubules and/or axons, was caused by colchicine. Moreover, ameliorated learning behavior was observed with chronic treatment of beta-estradiol 3-benzoate, which has been suggested to have an important role as an adjuvant treatment for younger Alzheimers disease (AD), immediately after colchicine infusion (0.3 microg). These results indicate that the animal model accompanying the colchicine-induced functional defect showing early tau pathology, but not neuronal cell degeneration, may well mimic comparatively early stage of AD.

Characterizing CGI-94 (comparative gene identification-94) which is down-regulated in the hippocampus of early stage Alzheimer's disease brain

The treatment of Alzheimers disease (AD) remains a major challenge because of the incomplete understanding of the triggering events that lead to the selective neurodegeneration characteristic of AD brains. Here we describe a new protein, CGI‐94, that is down‐regulated at the mRNA level in the hippocampus of early stage AD brain. Transfection experiments with CGI‐94 as a green fluorescent protein (GFP)‐fusion‐protein show that this protein is translocated into the nucleus of the cell. The finding that this protein, which has a bipartite nuclear localization signal, is also observed in the cytoplasm and extracellular space points to a multifunctional protein. Immunohistochemical analyses reveal that CGI‐94 is mainly expressed in neurons of the hippocampal formation and the cortex but not in the cerebellar nucleus. In conclusion, the expression of the nucleolar phosphoprotein CGI‐94 appears to be disturbed in early processes of neuronal degeneration.

Effect of TAK-147, a novel AChE inhibitor, on cerebral energy metabolism.

Effect of TAK-147, a novel acetylcholinesterase (AChE) inhibitor, on cerebral energy metabolism was investigated using an in vivo 31P-magnetic resonance spectroscopy (31P-MRS) technique and the autoradiographic 2-deoxy-[14C]-D-glucose method in aged Fischer 344 rats. We revealed that high-energy phosphate metabolites, phosphocreatine (PCr) and ATP, in the brain decreased gradually with aging and that significant decrement of cerebral PCr and ATP was observed from 13- and 8.5-month-old in comparison with those of 2.5-month-old rats, respectively. Daily oral administration of TAK-147 (1 mg/kg) for 40 days increased PCr and ATP levels in aged rats (29-month-old). To determine the site at which TAK-147 acts to increase high-energy phosphate metabolism, we investigated the rate of local cerebral glucose utilization (LCGU) in various brain regions. The rate of LCGU decreased in almost all brain regions in aged rats (28 months of age), and the decrease was significant in 29 out of the 35 regions. When TAK-147 was administered orally to the aged rats, the levels were dose dependently increased, especially in the auditory cortex. These results indicate that TAK-147 increases cerebral energy metabolism in aged rats.

Beneficial effects of TDN-345, a novel Ca2+ antagonist, on ischemic brain injury and cerebral glucose metabolism in experimental animal models with cerebrovascular lesions

The effects of TDN-345 on mortality and ischemic neurological deficit following transient global cerebral ischemia in Mongolian gerbils and also the rate of local cerebral glucose utilization (LCGU) in stroke-prone spontaneously hypertensive rats (SHRSP) with cerebrovascular lesions were investigated. In Mongolian gerbils, ischemia was produced by clamping the bilateral common carotid arteries for 15 min. TDN-345 (0.1-1.0 mg/kg) dose-dependently decreased the mortality and ischemic neurological deficit score when administered orally twice, 60 min before ischemia and 90 min after recirculation. Additionally, TDN-345 (0.2 or 1.0 mg/kg, p.o. once daily for 3 weeks after the onset of stroke) decreased the mortality and recurrence of stroke in SHRSP. To determine the site of action of TDN-345 in the brain, the rate of LCGU in various brain regions in SHRSP with stroke was examined using a [14C]2-deoxy-D-glucose method. The rate of LCGU decreased significantly in all the brain regions in SHRSP with stroke compared with Wistar-Kyoto (WKY) control rats, whereas the reduction in the rate of LCGU in SHRSP with stroke was prevented by TDN-345 treatment, especially in the sensorimotor cortex and locus coeruleus. These results suggest that TDN-345 has therapeutic efficacy in the treatment of cerebrovascular disease.

Effects of Thyrotrophin-releasing Hormone Tartrate and its Sustained Release Formulation on Cerebral Glucose Metabolism in Aged Rats

The effects of a sustained release formulation of thyrotrophin‐releasing hormone (TRH) over two weeks (TRH‐SR, 10 or 50 mg kg− equivalent to 0.56 or 2.80 mg kg− free TRH, respectively) and repeated treatment with TRH tartrate (TRH‐T, 0.3, 1.0 or 3.0 mg kg−, equivalent to 0.2, 0.7 or 2.0 mg kg− free TRH, respectively) on the rate of local cerebral glucose utilization (LCGU) were investigated using the quantitative autoradiographic 2‐deoxy‐[14C]d‐glucose method in various brain regions of aged rats.