Effects of bifemelane hydrochloride on various cholinergic markers in cortical and subcortical regions of aged rats.

Egashira, Toru; Nagai, Takayuki; Kimba, Yoshihira; Takano, Ritsuko; Yamanaka, Yasumitsu

doi:10.1254/jjp.51.211

Cited by 9 publications

(2 citation statements)

References 22 publications

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“…Because it is well-known that the functioning cholinergic system can be damaged by cerebral ischemia (14), we compared various cholinergic biochemical markers (mAChR and ChAT activity) in the cortex, hippocampus and striatum of the brains of aged (24 month) and young (6 weeks) rats treated with permanent 2VO. We previously reported that the investigation of brain cholinergic systems in aged control rats could provide useful information pertaining to age and age-related disorders in humans (9,10). However, in this study, ChAT activity and the number of mAChR in aged 2VO rats decreased nearly 10-20% as compared with those in aged control rats.…”

Section: Choline Acetyltransferase Activity Assaycontrasting

confidence: 60%

“…We these data should aid in establishing a model of senile also investigated the effect of long-term administration dementia that could be used to investigate potentially of bifemelane on cholinergic markers in aged 2VO rats; therapeutic drugs (9,10). This model, however, employbifemelane is known to be an effective treatment for ed rats that were simply aged, not true models of senile cerebrovascular disease in clinical trials as well as in dementia.…”

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Effects of Bifemelane on Muscarinic Receptors and Choline Acetyltransferase in the Brains of Aged Rats Following Chronic Cerebral Hypoperfusion Induced by Permanent Occlusion of Bilateral Carotid Arteries

Egashira

Takayama

Yamanaka

1996

Japanese Journal of Pharmacology

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ABSTRACT-Cerebralhypoperfusion was chronically induced in aged rats via permanent bilateral occlusion of common carotid arteries (2VO). Marked reduction of the Bmax value of the muscarinic receptors (mAChR) in both the cortex and striatum and the Vma,, value of choline acetyltransferase (ChAT) activity in the cortex, hippocampus and striatum were observed as compared with those of control aged rats. No significant changes in mAChR and ChAT activity were observed between young control rats and young 2VO rats. One month post-surgery in aged rats, daily doses of bifemelane (10 mg/kg) or aniracetam (50 mg/kg) were administered orally over a 4-week period. Administration of bifemelane significantly increased Bmax values and decreased apparent Kd values for 3H-quinuclidinyl benzilate (QNB) in mAChR in the striatum. Chronic administration of bifemelane or aniracetam also enhanced ChAT activity in the cortex, hippocampus and striatum. In particular, administration of bifemelane resulted in a significant increase in Vma., values of ChAT in all three brain regions, while no significant change in Km values for ChAT was observed. These results suggest that bifemelane is responsible for this activity, thereby enhancing the functioning system of CNS cholinergic neurons of cerebral hypoperfused aged rats.Keywords: Aged rat, Permanent bilateral occlusion of common carotid arteries, Muscarinic receptor, Choline acetyltransferase, Bifemelane, Aniracetam A number of drugs and substances have been devedecreased in patients with senile dementia, such as in the loped as means to decrease the symptoms of memory imcase of Alzheimer's disease (11, 12). Senile dementia is pairment observed in patients with senile dementia, and characterized by marked cognitive impairments that their effects have been studied in animal models (1-5).parallel the progression of neuronal damage (13). PermaThe results of these experiments, however, have not yet nent bilateral occlusion of common carotid arteries (2VO) yielded sufficient data to be useful in the clinical setting. in rats is used as a model for brain ischemia (14). In adVarious kinds of animal models have been developed to dition, it is known that permanent 2VO induces chronic study human dementia; these include drug-(2), brain cerebral hypoperfusion (15). lesion-(6-8), or transient ischemia-(3) induced amnesiaIn the present study, we examined whether chronic in rodents.cerebral hypoperfusion induced by permanent 2VO in We previously reported that the investigation of brain aged rats would result in neuronal damage and observed cholinergic systems in aged rats could provide informathe subsequent muscarinic receptor (mAChR) concentration concerning age-related disorders in humans and that tion and choline acetyltransferase (ChAT) activity. We these data should aid in establishing a model of senile also investigated the effect of long-term administration dementia that could be used to investigate potentially of bifemelane on cholinergic markers in aged 2VO rats; therapeutic drugs (9, 10). This mo...

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Section: Choline Acetyltransferase Activity Assaycontrasting

confidence: 60%

mentioning

confidence: 99%

Effects of Bifemelane on Muscarinic Receptors and Choline Acetyltransferase in the Brains of Aged Rats Following Chronic Cerebral Hypoperfusion Induced by Permanent Occlusion of Bilateral Carotid Arteries

Egashira

Takayama

Yamanaka

1996

Japanese Journal of Pharmacology

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Testing Drugs for Impaired Brain Function in Old Age: On the Effects of a Single Dose of Bifemelane using Topographic Mapping of EEG and Event-Related Potentials (P300) and Psychometric Measurements in Healthy Elderly Subjects

Semlitsch

Saletu

Anderer

et al. 1996

Hum. Psychopharmacol. Clin. Exp.

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Clinical studies have demonstrated that bifemelane hydrochloride [4-(0-benzylphenoxy)-N-methylbutylamine hydrochloride] can improve cognitive functions in patients with various types of dementia. To elucidate specific mechanisms which may underlie the clinical benefit, the effects of bifemelane were investigated by means of computerized electroencephalography (EEG), event-related potentials (P300) and psychometry. Eighteen healthy elderly subjects, aged between 60 and 73 years, were included in a double-blind, placebo-controlled crossover study. Each subject received a single dose of 150 mg bifemelane or placebo with an interval of 1 week in between. EEG and psychometric investigations were carried out before and 2, 4, 6, and 8 h after drug administration, ERP investigations only before and 3 h after drug administration. Descriptive data analysis of the EEG showed that 150 mg bifemelane accelerated the centroid of the total frequency band, induced a significant reduction of the absolute delta + theta power and increased the absolute beta power most markedly 6 h after drug intake. Topographic analyses of ERP amplitudes showed that bifemelane did not effect ERP amplitudes. While N1, P2 and N2 latencies were not changed after bifemelane, P300 latency was shortened significantly. Psychometric investigations did not show significant or consistent effects on noopsychic and thymopsychic functions. In conclusion, bifemelane affected EEG in the sense of improved vigilance. The reduction of P300 latency may be interpreted as accelerated stimulus evaluation time, therefore indicating a beneficial effect of bifemelane on cognition at this stage of information processing. (Ogawa et al., 1992a). Moreover, bifemelane given before ischemia antagonizes learning deficits in rats (Tobe et al., 1986). Concerning bifemelane actions that may be related to cognition enhancing activity, electrophysiological studies support cholinomimetic activity (Tobe et a/., 1981;Egawa et al., 1987;Okuyama and Aihara, 1988 The authors speculated that bifemelane may act both as a metabolic activator and a vasodilator. In a study with 10 patients with Alzheimer-type dementia and 10 patients with multi-infarct dementia, eight subjects out of 20 were regarded as responders after a 3-month treatment period with a daily dosage of 150 mg bifemelane (Shigeta et al., 1993a,b). As the frequency of small rapid eye movements in the EOG increased significantly only in responders, and as only responders demonstrated a significant reduction in amplitude of the 6.0-8.0 Hz EEG frequency band, the authors concluded that part of the intellectual improvement in the patients resulted from an increased level of arousal. KEYWhile the ultimate goal in the evaluation of nootropic drugs lies in the demonstration of clinically relevant changes (Amaducci et al., 1990; Advisory Committees to the German Federal Health Office, 1992), computerized electrophysiological methods like topographic mapping of the electroencephalogram (EEG) may allow classification as well as the evaluati...

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Effect of vagal autotransplantation and bifemelane hydrochloride on cholinergic markers and event-related potentials in rats with lesions of the nucleus basalis magnocellularis

Ikeda¹,

Egashira²,

Yamashita³

et al. 1995

Brain Research

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Effects of bifemelane hydrochloride on various cholinergic markers in cortical and subcortical regions of aged rats.

Cited by 9 publications

References 22 publications

Effects of Bifemelane on Muscarinic Receptors and Choline Acetyltransferase in the Brains of Aged Rats Following Chronic Cerebral Hypoperfusion Induced by Permanent Occlusion of Bilateral Carotid Arteries

Effects of Bifemelane on Muscarinic Receptors and Choline Acetyltransferase in the Brains of Aged Rats Following Chronic Cerebral Hypoperfusion Induced by Permanent Occlusion of Bilateral Carotid Arteries

Testing Drugs for Impaired Brain Function in Old Age: On the Effects of a Single Dose of Bifemelane using Topographic Mapping of EEG and Event-Related Potentials (P300) and Psychometric Measurements in Healthy Elderly Subjects

Effect of vagal autotransplantation and bifemelane hydrochloride on cholinergic markers and event-related potentials in rats with lesions of the nucleus basalis magnocellularis

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