Interactions between oxiracetam, aniracetam and scopolamine on behavior and brain acetylcholine

Spignoli, G.; Pepeu, Giancarlo

doi:10.1016/0091-3057(87)90353-4

Cited by 112 publications

(41 citation statements)

References 15 publications

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“…At lower doses, oxiracetam en hances neuronal transmission (in vitro dose: 10-6 -10-7 M) (6) and facilitates memory and learning in mice (in vivo dose: 10-50 mg/kg) (1). At higher doses, moderate and transient cerebral impairment is improved (in vivo dose: 50 300 mg/kg) (2,4). Furthermore, in the present study, we found that oxiracetam mini mized severe ischemic metabolic damage (in vivo dose: 400-800 mg/kg).…”

Section: Physiological Variablessupporting

confidence: 55%

The Effects of Oxiracetam (CT-848) on Local Cerebral Glucose Utilization after Focal Cerebral Ischemia in Rats.

et al. 1992

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-The effects of oxiracetam on the reduction of brain metabolism induced by focal cerebral ischemia were investigated by measuring local cerebral glucose uti lization (LCGU) in rats 24 hr after left middle cerebral artery occlusion. Focal cere bral ischemia reduced LCGU in the entire ipsilateral cortex, the greatest reduction being in the lateral parts of the frontoparietal cortex. LCGU was slightly reduced in the contralateral cortex; this reduction was considered to be caused by diaschisis. Ox iracetam was administered intraperitoneally for 3 days prior to middle cerebral artery occlusion. In the ipsilateral cortex, LCGU reduction was minimized in the ischemic center areas by oxiracetam at a dose of 400 mg/kg and in more extensive areas, by a dose of 800 mg/kg. Moreover, oxiracetam at a dose of 800 mg/kg enhanced metabo lism impaired by diaschisis in the caudal areas of the contralateral cortex. These find ings suggest that oxiracetam minimizes the reduction of brain function induced by ischemia and may therefore be useful in the treatment of cerebrovascular disease.The pharmacological actions of oxiracetam are similar to those of other pyrrolidone de rivatives, including piracetam, aniracetam and pramiracetam. Oxiracetam and other pyrroli done derivatives have been reported to im prove memory and learning ability in normal animals (1) and to prevent amnesia and the decrease in brain acetylcholine level induced by scopolamine and electroshock in rats (2 4). Oxiracetam and piracetam stimulate high affinity choline uptake in the rat hippocampus (5). Thus, the effects of pyrrolidone deriva tives may be related to the enhancement of brain cholinergic mechanisms. In addition, ox iracetam and other pyrrolidone derivatives have been shown to augment hippocampal long-term potentiation in rats (6) and guinea pigs (7,8). These investigations suggest that pyrrolidone derivatives enhance cerebral func tion in normal brain and protect it in impaired brain. Since we have recently found that ox iracetam protects rats and mice against cere bral hypoxia, we expected to find that ox iracetam had protective effects against cere bral ischemia in this experiment.Focal cerebral ischemia induced by middle cerebral artery (MCA) occlusion (9) is a use ful model (9, 10) for studying ischemic brain damage, as well as cerebral blood flow (11, 12), energy metabolism (13), and neurotrans mitters (14,15). Sokoloff (16) showed that cerebral functional activity was closely coupled to energy metabolism, especially glucose con sumption. In this study, we investigated

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Section: Physiological Variablessupporting

confidence: 55%

The Effects of Oxiracetam (CT-848) on Local Cerebral Glucose Utilization after Focal Cerebral Ischemia in Rats.

et al. 1992

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“…Recent work suggests an involvement of the histaminergic system in cognitive functions (De Almeida et al, 1989;Cacabelos & Alvarez, 1991;Kamei & Tasaka, 1991), but the mechanism is unknown. Object recognition and passive avoidance response may involve the cortical cholinergic system, since both tasks involve a form of memory (short term/ working memory) known to depend on the intact frontal cortex (Goldman-Rakic, 1987;Petrides, 1994), and are impaired by cholinoceptor antagonists (Spignoli & Pepeu, 1987;Ennaceur & Meliani, 1992). If cognitive deficits are related to reduced availability of ACh in the synaptic cleft (Quirion et al, 1995), and H3 receptor activation reduces ACh release, H3 receptor activation would be expected to impair learning and memory.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of cortical acetylcholine release and cognitive performance by histamine H₃ receptor activation in rats

Blandina

Giorgetti

Bartolini

et al. 1996

British J Pharmacology

216

151

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1 The effects of histamine and agents acting at histamine receptors on spontaneous and 100 mM K+-evoked release of acetylcholine, measured by microdialysis from the cortex of freely moving rats, and on cognitive tests are described. 2 Local administration of histamine (0.1-100 pM) failed to affect spontaneous but inhibited 100 mM K+-stimulated release of acetylcholine up to about 50%. The H3 receptor agonists (R)-ca-methylhistamine (RAMH) (0.1-10 yM), imetit (0.01-10 yM) and immepip (0.01-10 yM) mimicked the effect of histamine.3 Neither 2-thiazolylethylamine (TEA), an agonist showing some selectivity for H, receptors, nor the H2 receptor agonist, dimaprit, modified 100 mM K+-evoked release of acetylcholine. 4 The inhibitory effect of 100 pM histamine was completely prevented by the highly selective histamine H3 receptor antagonist, clobenpropit but was resistant to antagonism by triprolidine and cimetidine, antagonists at histamine H, and H2 but not H3 receptors.5 The H3 receptor-induced inhibition of K+-evoked release of acetylcholine was fully sensitive to tetrodotoxin (TTX).6 The effects of intraperitoneal (i.p.) injection of imetit (5 mg kg-') and RAMH (5 mg kg-') were tested on acetylcholine release and short term memory paradigms. Both drugs reduced 100 mM K+-evoked release of cortical acetylcholine, and impaired object recognition and a passive avoidance response.7 These observations provide the first evidence of a regulatory role of histamine H3 receptors on cortical acetylcholine release in vivo. Moreover, they suggest a role for histamine in learning and memory and may have implications for the treatment of degenerative disorders associated with impaired cholinergic function.

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“…It has been speculated that the improvement of learning and memory by aniracetam is based on the activation of central cholinergic pathways [Nakajima et al, 1986;Spignoli and Pepeu, 1987;Giovannini et al, 1993;Egashira et al, 1996]. Concerning the interaction with cholinergic receptors, it has been reported that aniracetam and its metabolites produced no significant inhibition on nonselective muscarinic receptor bindings up to a concentration of 1 mM [Nakajima et al, 1986] and on nicotinic and muscarinic M 1 and M 2 receptor binding up to 10 µM [ Martin and Haefely, 1993].…”

Section: Improvement By Aniracetam and Its Metabolitesmentioning

confidence: 99%

Scopolamine model of delirium in rats and reversal of the performance impairment by aniracetam

Nakamura¹,

Kurasawa²,

Tanaka³

1998

Drug Dev. Res.

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Interactions between oxiracetam, aniracetam and scopolamine on behavior and brain acetylcholine

Cited by 112 publications

References 15 publications

The Effects of Oxiracetam (CT-848) on Local Cerebral Glucose Utilization after Focal Cerebral Ischemia in Rats.

The Effects of Oxiracetam (CT-848) on Local Cerebral Glucose Utilization after Focal Cerebral Ischemia in Rats.

Inhibition of cortical acetylcholine release and cognitive performance by histamine H₃ receptor activation in rats

Scopolamine model of delirium in rats and reversal of the performance impairment by aniracetam

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Interactions between oxiracetam, aniracetam and scopolamine on behavior and brain acetylcholine

Cited by 112 publications

References 15 publications

The Effects of Oxiracetam (CT-848) on Local Cerebral Glucose Utilization after Focal Cerebral Ischemia in Rats.

The Effects of Oxiracetam (CT-848) on Local Cerebral Glucose Utilization after Focal Cerebral Ischemia in Rats.

Inhibition of cortical acetylcholine release and cognitive performance by histamine H3 receptor activation in rats

Scopolamine model of delirium in rats and reversal of the performance impairment by aniracetam

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Inhibition of cortical acetylcholine release and cognitive performance by histamine H₃ receptor activation in rats