We studied the association of six common polymorphisms of four genes related to lipid metabolism with serum lipid levels. We selected single-nucleotide polymorphisms (SNPs) in the genes for cholesteryl ester transfer protein (CETP), lipoprotein lipase (LPL), hepatic lipase (LIPC), and apolipoprotein CIII (APOC3), and studied 2267 individuals randomly selected from the participants of Serum Lipid Survey 2000. There was a significant association of CETP polymorphism (D442G, Int14 +1 G --> A, and TaqIB), LPL polymorphism (S447X), and LIPC polymorphism (-514 --> CT) with HDL-cholesterol levels. We also found a significant association of LPL polymorphism (S447X) and APOC3 polymorphism (SstI) with triglyceride levels. This is the largest database showing the association of common genetic variants in lipid metabolism with serum lipid levels in the general Japanese population. Further study is necessary to elucidate the role of these gene polymorphisms in cardiovascular events.
Title: [Effects of breeding conditions on neurochemical cholinergic and monoaminergic markers in aged rat brain] Egashira T Ref: Nihon Ronen Igakkai Zasshi, 37:233, 2000 : PubMed
We investigated the effects of breeding conditions on neurochemical markers, muscarinic receptor (mAChR), beta-adrenoreceptor (beta-AdrR), imipramine binding sites (IMBS), choline acetyltransferase (ChAT), acetylcholinesterase (AChE) and monoamine oxidase (MAO) activity in aged rat brains. An increase of affinity (Kd) and the decrease in the number (Vmax) of mAChR were found in the individual aged rats. Concerning IMBS, Kd and Vmax values increased in the individual aged rats. However, no significant changes were observed in the beta-AdrR. The increases of ChAT and MAO activity were found in the aggregated aged rats to compare with in the individual aged rats, while AChE activity decreased in the aggregated aged rats. These changes were also particularly seen in the forebrain of aged rats. These results indicate that the functions of the central nervous system may be reduced in the individual aged rats to compare with in the aggregated aged rats under the breeding conditions.
Title: [Alterrations in neurotransmitter, amino acid and free radical related substances in cerebrospinal fluid in patients with cerebrovascular diseases] Egashira T, Goto H, Takeda H, Takada K, Matsumiya T Ref: Nippon Ronen Igakkai Zasshi, 36:256, 1999 : PubMed
Acetylcholinesterase (AChE), choline, monoamine and its metabolite, amino acid and superoxide dismutase (SOD) levels were measured in cerebrospinal fluid (CSF) in patients with cerebrovascular diseases. Patients were classified into the following four groups; controls: normal subjects without neurological disease, group A: cerebral hemorrhage, group B: cerebral infarction, group C: patients with mental impairment, including those in groups A and B, and a low score on Hasegawa's Dementia Rating Scale. CSF AChE level of groups A, B and C was decreased significantly, while choline concentration from patients showed a increase compared with that of control cases. CSF alanine concentration showed a tendency to increase, while glycine and glutamate tended to decrease. CSF epinephrine, norepinephrine or 3-methoxy-4-hydroxyphenylethylen glycol concentrations of groups A, B and C did not exhibit a significant difference from that in control cases. Some cases with cerebrovascular diseases showed low concentrations of both CSF 5-hydroxyindole acetic acid and homovanillic acid. However, dihydroxyphenyl acetic acid concentration was higher than in control cases. The CSF SOD level was not significantly from that in control cases. The changes in neurochemical substances in the CSF support their use as markers of cerebrovascular disease-related change.
Title: [Study on the anti-dementia therapies for rats with a unilateral basal forebrain lesion--serial changes of the cholinergic markers' activities and event-related potentials after the administration of bifemelane hydrochloride or autotransplantation of the vagal nodosal ganglion]. [Japanese] Ikeda K, Yamashita J, Egashira T, Takayama F, Yamanaka Y Ref: No to Shinkei Brain & Nerve, 47:455, 1995 : PubMed
Using rats with a unilateral lesion in the nucleus basalis magnocellularis (NBM), we examined electrophysiologically the therapeutic effects of bifemelane (BIF) and autotransplantation of the vagal nodosal ganglion (X) on the event-related potential (P300) serially for 4 weeks, and also neurochemically their effects on cholinergic markers--the specific binding of 3H-QNB (quinuclidinyl benzilate) on muscarinic acetyl-choline receptor (mAChR) and the activities of acetylcholinesterase (AChE) and choline acetyltransferase (CAT). The latency of P300 was continuously delayed and its amplitude remained low voltage until 4 weeks in the NBM-lesioned rats (No-Tx group). Whereas the latency and amplitude returned to normal after 2-3 weeks in the rats given daily intraperitoneal injection of 15 mg/kg BIF (BIF group) and autotransplanted ones (X group). The cortical CAT and AChE levels on the lesion side did not recover until 4 weeks in No-Tx group, but the CAT levels recovered after 3 weeks in both BIF and X group; the AChE levels, after 1 week in BIF group and after 3 weeks in X group. The cortical mAChR on the lesion side was within or more than normal range in all rats. These results might indicate as follows: 1) Compensatory postsynaptic process such as cortical mAChR increase and AChE decrease occurred after acute cholinergic depletion. 2) Administration of BIF and X autotransplantation recovered cortical CAT and AChE levels and normalized cholinergic neuronal activity of P300.
Title: [Experimental techniques for developing new drugs acting on dementia (4)--Aged rats]. [Japanese] Egashira T Ref: Yakubutsu, Seishin, Kodo [Japanese Journal of Psychopharmacology], 14:245, 1994 : PubMed
We have devised a method for the procurement and breeding of aged rats used for aiding in the development of drugs for disease, involving Alzheimer's disease and cerebrovascular dementia. The changes in choline acetyltransferase (ChAT), acetylcholinesterase (AChE), muscarinic receptor binding (mAChR) and Na(+)-dependent high affinity choline uptake (HACU) are generally consistent with age-dependent declines in cholinergic neurotransmission, although these decreases may include differences in strain/species, sex, tissue sampling and assay procedures. So, the choice of time points during the life cycle selected for comparison between young and aged rats is particularly important when using laboratory animals. These observations support the utility of the senescent rat model in studying aging and development of nootropic drugs.
Title: Age-related changes of cholinergic markers in the rat brain Yufu F, Egashira T, Yamanaka Y Ref: Japanese Journal of Pharmacology, 66:247, 1994 : PubMed
To evaluate whether any degenerative changes affect the brain cholinergic systems during natural aging, we compared various cholinergic biochemical markers (number of muscarinic receptors, mAChR; choline acetyltransferase activity, ChAT; acetylcholinesterase activity, AChE; and sodium-dependent high affinity choline uptake) in the cortical (CR) and subcortical (SS) regions of the brains of aged (24 month) and young (2 month) rats. Using [3H]-quinuclidinyl benzilate ([3H]-QNB) as the ligand of muscarinic receptor binding, the numbers of mAChR decreased about 30% in both the CR and the SS of aged rats compared with those in young rats, while a significant age-related increase in the affinity of mAChR was observed. [3H]-QNB binding in both the young and aged rat brain was displaced markedly by pirenzepine, while [3H]-QNB binding in the SS of the aged rat brain was displaced at low concentrations of atropine. The Vmax values of ChAT and AChE also decreased about 20-30% compared with those of young rats. The sodium-dependent high affinity choline uptake was lower in the crude synaptosomal fraction prepared from aged rat brain than in young brain. Hemicholinium-3 inhibited the choline uptake in young rat brain at a concentration range of 1 microM-10 nM, but choline uptake in aged brain was insensitive to hemicholinium-3. These results indicate that natural aging brings about a diffuse and multiple depletion of various biochemical markers in cholinergic neurons.
