Effects of BMY-21502 on Anoxia in Mice

Amano, Minoru; Goto, Arata; Takahashi, Norimitsu; Hasegawa, Takaaki; Nabeshima, Toshitaka

doi:10.1254/jjp.61.157

Cited by 6 publications

(7 citation statements)

References 17 publications

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“…24,25) The presynaptic terminals of the cholinergic neuron are vulnerable to ischemic insult, and cholinergic dysfunction precedes postsynaptic CA1 pyramidal cell death in the hippocampus. 16) Consequently, in order to confirm whether sinapic acid directly modulates the cholinergic function, its effect on scopolamine-induced amnesia was examined.…”

Section: Discussionmentioning

confidence: 99%

Cerebral Protective and Cognition-Improving Effects of Sinapic Acid in Rodents

Karakida

Ikeya

Tsunakawa

et al. 2007

Biological & Pharmaceutical Bulletin

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Senile dementia of Alzheimer type and multi-infarct dementia are considered to be major problems of contemporary societies. Recently, Kami-kihi-to, Ninjin-yoei-to and Kamiuntan-to, which are traditional Japanese herbal medicines (Kampo medicines) have been reported to improve memory disturbance and the related behaviors.1-4) Because these Kampo Medicines contain Polygalae Radix (Onji in Japanese), the root of Polygala tenuifolia WILLDENOW as a common herb, it is suggested that the constituent herb may possess the activity to improve memory disturbance. Polygalae Radix itself has been utilized empirically in Chinese medicine, works to relieve amnesia, neurasthenia, palpitations, nocturnal emission, and insomnia. 5) Recently, evidence of the memoryenhancing effects of Polygalae Radix has been accumulated by several in vivo and in vitro studies; it was reported that a water extract of Polygalae Radix improved scopolamine-induced memory impairment in mice, 6) and that DX-9368 belong to the group of Polygalae Radix agents ameliorated ethanol-and scopolamine-induced memory impairment in mice.7) Yabe et al. 8) reported that the water extract up-regulated choline acetyltransferase (ChAT) activity and increased nerve growth factor (NGF) secretion in vitro. However, the pharmacological effects of the ingredients in Polygalae Radix have been little investigated. In these background, more recently, we demonstrated that tenuifoliside B [6Ј-(phydroxybenzoyl)-3-sinapoylsucrose] and 3,6Ј-disinapoylsucrose among the components isolated from Polygalae Radix inhibited potassium cyanide (KCN)-induced hypoxia and scopolamine-induced memory impairment.9) From these results, we suggested that the two ingredients were instrumental in the cerebral protective and cognition-improving effects of Polygalae Radix. More interestingly, both ingredients have a common sinapoyl moiety in their chemical structures. These suggest that sinapic acid might be not only a main active structure in the pharmacological effects of tenuifoliside B and 3,6Ј-disinapoylsucrose but also a candidate for cerebral protective and cognition-improving medicine.In the present study, in order to ascertain the hypothesis, we examined whether sinapic acid possesses cerebral protective and cognition-improving effects in various animal models of hypoxia and amnesia. MATERIALS AND METHODS Drug and ReagentsSodium sinapate (Fig. 1), which is the water-soluble form of sinapic acid, was used in the following experiments. Sodium sinapate (4.92 g) was obtained by lyophilizing a solution of sinapic acid (4.48 g) purchased from Wako Pure Chemical Industries Ltd. (Osaka, Japan) in 200 ml of 0.1 M sodium hydroxide. Ethylhomocholine iodide (EHC), an internal standard for determination of acetylcholine (ACh), was synthesized from 3-dimethylamino-1-propanol and iodoethane purchased from Sigma-Aldrich Fine Chemicals Japan Co., Ltd. (Tokyo, Japan). Other reagents used for analysis were the highest purity commercially available.Animals Male ICR mice (7 weeks old) to evaluate KCN-induced c...

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Section: Discussionmentioning

confidence: 99%

Cerebral Protective and Cognition-Improving Effects of Sinapic Acid in Rodents

Karakida

Ikeya

Tsunakawa

et al. 2007

Biological & Pharmaceutical Bulletin

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“…These two experimental models are generally used to screen drugs for cerebrovasucular diseases; such drugs include activators of cerebral energy metabolism (14,15), cerebral vasodilators (15 -17), CNS depressants (18,19) and activators of the CNS cholinergic system (20) or acetylcholine esterase inhibitors (21,22). In the two models, BHB significantly prolonged the survival time at the dose of 50 mg·kg -1 ·h -1 or more, while glycerin failed in all models.…”

Section: Discussionmentioning

confidence: 99%

Effect of β-Hydroxybutyrate, a Cerebral Function Improving Agent, on Cerebral Hypoxia, Anoxia and Ischemia in Mice and Rats

Suzuki

Sato

et al. 2001

Japanese Journal of Pharmacology

146

116

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ABSTRACT-Although improving energy metabolism in ischemic brain has been accepted for the treatment of cerebrovascular diseases, administration of glucose, as an energy substrate, would aggravate ischemic brain damage via activating anaerobic glycolysis, which leads to lactate accumulation. b-hydroxybutyrate (BHB) is one of the ketone bodies that can be utilized as an energy source during starvation. The purpose of our study was to define the protective effects of BHB on brain damage induced by hypoxia, anoxia and ischemia. The isotonic solution of BHB administered 30 min before the induction of ischemia at doses over 50 mg · kg -1 ·h -1 showed remarkable protective effects against hypoxia and anoxia. BHB administered immediately after a bilateral carotid artery ligation at a dose of 30 mg·kg -1 ·h -1 significantly suppressed the elevation of cerebral water and sodium contents as well as maintaining high ATP and low lactate levels. In contrast, glycerin, a hypertonic agent, substantially reduced the water content but did not show any significant effect on other parameters. We demonstrated that BHB, unlike glycerin, when used as an energy substrate in ischemic brain, has protective effects on cerebral hypoxia, anoxia and ischemia-induced metabolic change.Keywords: b -Hydroxybutyrate, Glycerin, Anti-anoxic effect, Cerebral ischemia, Cerebral energy metabolism The brain is a surprisingly active tissue in terms of glucose metabolism; almost all the energy supplied to maintain its vital functions are derived from glucose oxidation. Restriction of the glucose supply and metabolism under such conditions as hypoxia and ischemia would result in brain damages (cerebral edema and infarct). However, epidemiological data have shown that hyperglycemia was associated with higher risks of strokes and that ischemic cerebral injury was, at least partly, attributed to hyperglycemia as well (1 -3). Furthermore, it has been verified in several animal models that glucose administration accelerated brain damage caused by cerebral ischemia (4 -6). The elevated glucose anaerobic metabolism under hypoxia and ischemia conditions (6 -9) causes tissue lactate accumulation which subsequently leads to an increased H + intracellular concentration level. It is thus conclusive to state that glucose containing solutions have or might have harmful effects in an ischemic brain.Ketone bodies are known for their energy source uses in states of starvation (10). b-Hydroxybutyrate (BHB, Fig. 1), a representative type of ketone body, is produced by degradation of fatty acids in the liver. Recent studies have reported the utilization of BHB as an energy substrate in head trauma patients (11) and hemorrhage shock rats (12). Go et al. reported that fasting, characterized by features like hypoglycemia and ketosis, protected rats from developing brain infarction following hypoxia-ischemia (13). The rats were found to have an increased level of BHB in their blood compared with rats that had a normal *Corresponding author. FAX: +81-543-35-4858 E-mail: motohisa-...

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“…16) Our data show that compound 1 suppresses the breakdown of cellular metabolism induced by the inhibition of cytochrome oxidase. Gibson et al reported that KCN reduced potassium-stimulated synaptosomal acetylcholine release.…”

Section: Discussionmentioning

confidence: 65%

Cognitive Improving and Cerebral Protective Effects of Acylated Oligosaccharides in Polygala tenuifolia

Ikeya

Takeda

Tunakawa

et al. 2004

Biological & Pharmaceutical Bulletin

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Senile dementia of the Alzheimer type and multi-infarct dementia are considered to be major problems of contemporary societies. In traditional Chinese medicine, Polygalae Radix (Japanese name: Onji), the root of Polygala tenuifolia WILLDENOW (Polygalaceae), is prescribed for amnesia, neurasthenia, palpitation, noctural emission and insomnia. 1) According to the Chinese Materia Medica, the root is guessed to have a special effect upon the will and mental powers, improving understanding and strengthening the memory.There have been numerous studies regarding the reputed memory-enhancing potential of the roots of P. tenuifolia. DX-9368, which is composed of four herbs (Panax ginseng, P. tenuifolia, Acorus gramineus and Poria cocos), ameliorated the ethanol-and scopolamine-induced memory impairment in mice.2) It is reported by Yabe et al. that the water extract of this plant up-regulates choline acetyltransferase (ChAT) activity and increases NGF secretion in vitro.3) Recently, Egashira et al. reported that the water extract improved the scopolamine-induced impairment of passive avoidance response and enhanced oxotremorine-induced tremors in mice.4) There are few reports, however, on the active constituents involved in the reputed memory-enhancing potential of the roots of P. tenuifolia, and we therefore studied these cognitive improving constituents. In this paper, we report that tenuifoliside B (1) 5) showed a cerebral protective effect on potassium cyanide (KCN)-induced anoxia and an ameliorative effect on the scopolamine-induced impairment of passive avoidance response in rats.It is well known that a decrease in oxygen supply to the brain (hypoxia) depresses cerebral function in experimental animals and humans 6,7) and that memory and learning are impaired by hypoxia in animals and humans. 8,9) The KCN anoxia model is widely used in preclinical evaluations of drugs for the treatment of cerebrovascular disorders. 6,10,11) Therefore, we used this model in addition to the scopolamine-induced impairment of passive avoidance performance as screening method. MATERIALS AND METHODSExtraction and Fractionation of P. tenuifolia As shown in Fig 1, the dried roots (9.4 kg) of P. tenuifolia from Shanxi Province in China (purchased from Yamamoto Yakuhin Kogyo Co., Ltd., Tokyo) were pulverized and extracted twice with boiling MeOH (50 l) for 2 h. The concentrated MeOH extract (PM) (2.21 kg) was dissolved in H 2 O and successively extracted with ether and n-BuOH. These layers were concentrated to give an ethereal soluble fraction (PE, xanthone-containing fraction) (398 g), an n-BuOH soluble fraction (902 g), and a water soluble fraction (PW) (609 g), respectively. The n-BuOH soluble fraction was chromatographed on silica gel [Kieselgel 60, 230-400 mesh (Merck)] (5 kg) with EtOAc-MeOH (4 : 1) and then with MeOH. Concentration of elutions with EtOAc-MeOH (4 : 1) and MeOH afforded the acylated oligosaccharide-containing fraction (PA) (468 g) and saponin-containing fraction (PS) Research Division, Tsumura & Co.; 3586 Yoshiwara Ami-...

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Effects of BMY-21502 on Anoxia in Mice

Cited by 6 publications

References 17 publications

Cerebral Protective and Cognition-Improving Effects of Sinapic Acid in Rodents

Cerebral Protective and Cognition-Improving Effects of Sinapic Acid in Rodents

Effect of β-Hydroxybutyrate, a Cerebral Function Improving Agent, on Cerebral Hypoxia, Anoxia and Ischemia in Mice and Rats

Cognitive Improving and Cerebral Protective Effects of Acylated Oligosaccharides in Polygala tenuifolia

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