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P.6.046 Pharmacology of some new DL-aspartic acid derivatives
P.6 Other topics
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Inhibitory effects of caffeine on cerebral blood flow. Evaluation by means of neurospect
A. Ruiz, I. Mena, S. Neubauer, J. Cornejo, C. Thomas, T. Strickland.
Dept. of Psychiatry and Mental Health, School of Medicine, University of Chile; Dept. of Nuclear Medicine, Clinica Las Condes, Chile. Di~: of Nuclear Medicine, Harbor UCLA Med. Ctr., Torrance, CA; Depart. of Psychiatr); Drew Univ. Medicine and Science, Los Angeles, CA. USA Objective: The increased use of SPECT for clinical evaluation and measurement of cerebral blood flow (CBF) for assessment of neuropsychiatric disorders must consider that caffeine may produce a diminution of CBE The purpose of this paper is the demonstration of this hypothesis and quantification and localization of inhibitory effects of caffeine on CBE Method: A comparative study was performed in two samples, before and 30 minutes after oral administration of 250 mg of caffeine: 1). In 20 young normal volunteers, CBF was measured using Xenon-133 inhalation technique. 2). In 7 other young volunteers, CBF measurements were obtained by means of SPECT with ECD Tc-99m (Neurolite TM). Results: Sample 1: Administration of caffeine produced 30 minutes afterwards, a significant reduction of CBF, 8.5 ml/min/100 g (p < 0.0001) and 9.5 ml/min/100 g (p < 0.0001) at 2 cm and 6 cm above the orbitomeatal line respectively. This corresponds to a diminution of 25% and 23% respectively. There is no effect of lateralization. Sample 2: Results demonstrated that the distribution of CBF after ingestion of caffeine was homogeneous and there were no regional effects on CBE Conclusions: The inhibitory effects of caffeine on CBF are demonstrated throughout all the cerebral cortex. Caffeine ingestion (coffee, tea, chocolate) should be discontinued before NeuroSPECT.
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Pharmacology of some new DL-aspartic acid derivatives
N.S. Sapronov, M. Kamri, L.B. Piotrovsky. Institute for Experimental Medicine of the Russian Academy of Medical Sciences, Department of Neuropharmacolog),; St. Petersburg 197376, Russia It is widely accepted that excitatory amino acids (EAA) transmission system takes part in the regulation of different biochemical processes and physiological function of mammalian brain sensory information, learning, memory, behavior and convulsive reactions (Nakanishi, 1992; Lipton & Rosenberg, 1994). However the critical use of EAA-ergic compounds, especially full agonists and antagonists of NMDA receptors is quite confined because of their neurotoxicity and expressed side effects (Danysz et at., 1994). That is why the attempt was made to design the partial agonists of NMDA receptors. For the purpose in the department of neuropharmacology there was synthesized a number of derivatives of DL-aspartic acid: N-allyl-(I), N-n-butyl- (II), N-n-pentyl(III), N-cyclohexyl-(IV) and N-benzyl (V) analogues. In vivo experiments have been carried out in mice, rats and rabbits. The convulsive and anticonvulsive properties, behavioral effects in "open field" and the influence of these substances on bioelectric activity in brain structures have been studied. The size enlargement of alkyl chain in alpha-amino group leads to decrease of convulsive activity of aspartic acid derivatives as compared with NMDLA: allyl- >butyl- >benxyl- >pentyl- >cyclohexyl-. The substitution of alkyl-radical to aralkyl-radical increases the ability of drug to penetrate blood-brain barrier. All compounds potentiated the seizures induced by NMDLA. Only N-n-butyl-DL-aspartic acid had duel effect: in low dose (subconvulsive) it prevented the NMDLA induced seizures and in high doses it potentiated these convulsions. In electrophysiological experiments this substance (10 mcrnol, intracerebrovenricularly~ can diminish the duration of afterdischarge seizures by hippocampal stimulation as well as NMDLA induced seizures. In high doses N-DL-aspartic acid derivatives suppress the behavior of rats in "open field" especially locomotor activity. The results of experiments show that between new synthesized analogues of N-DL-aspartic acid there is the derivative (N-n-butyl-DLaspartic acid) possessing with properties of partial agonist of NMDA receptors.
References [1] Danysz W., Essman V., Bresink 1., Wilke R. Glutamate antagonists aave different effects on spontaneouslocomotoractivity in rats.//Pharmacol. Biochem. Behav. - 1994, v.48, p. 111-118. [2] Lipton S.A., RosenbergEA. Mechanismsof disease: Excitatory amine, acids as a final common pathway for neurologic disorders.//New England J. ldedicine - 1994, v. 330, p. 613~522. [3] Nakanishi S. Molecular diversity of glutamate receptors and implications for brain functions.//Science. - 1992, v. 258, p. 597-603.
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Regulatory system of brain chromatin in nootropic action
O.G. Kulikova, B.A. Reikhardt, N.S. Sapronov. Institute for Experimental Medicine of the Russian Academy of Medical Sciences, Department of Neuropharmacology, St. Petersburg 197376, Russia It is widely accepted the apply of nootropic drugs for correction of age related cognitive disorders. Now believed that decline in gene expression and chromatin compactization is the basic mechanism of aging. Our studies concentrated on regulation of gene expression in brain. This topic includes molecular mechanisms of memory and memory disorder as well as effects of nootropic drugs. Feature of system of trans,:fiption regulation in old animals along with the possibility of their pharmacological correction was studied. Male white rats 20-month-old were used for behavioral and biochemical tests. Protein kineses of ch:omatin including both cAMP-independent casein kinase I and II in brain cortex and hippocampus were measured. Phosphorylation of chromosomal protein substrates by both type of CKs and neuronal transcriptic,n were studied in old rats and at the action of nootropic. Ethylnorantifein (4.5 dimethylcarbamoyl-l-ethyl-imidazole) was chosen because this one stimulated neuronal transcription and memory. Piracetam (2-oxo-1-pyrrolidon acetamide) was used as reference nootropic. Old rats have the disorders in learning and progressing amnesia in test of passive avoidance in one-trial. Significant decrease in activity of CK type II in rat brain cortex and hippocampus was observed in old animals (20-months) in comparison with adult (7-months). So, as CK I, no changes were found. Besides, the phosphorylation of chromatin proteins was decreased in old rats. Chromatin proteins were analyzed by electrophoresis and use of antibodies. In particular, the phosphorylation of nonhistone high mobility ~oup (HMO) 14 protein was occurred. HMG14 is physiological substrate of CK It and it was proved, its role in regulation transcription in neurons. Decline of neuronal transcription in old rats was shown. Ethylnorantifein in vivo (3 mg/kg i.p.) and in vitro stimulated the activity of CK II in cortex and hippocampus in adult rats. In old rats ethylnorantifein reduced the CK II up to level of adult rats. Herewith, the raise in HMGI4 phosphorylation by CK II was found. Attract altention that ethylnorantifein increased both the neuronal transcription and cognitive function in old rats or its well matiamnestic effect. It is important that piracetam in vivo (250 mg/kg i.p.) like ethylnorantifein increased the CK II in old rats, however direct action on CK II was not found. The present data demonstrated the role of regulatory system of chTomatin (CKII-HMGI4) in both mechanisms of aging and antianmestic action; this may contribute to the mechanisms underlying memory improvement produced by notropic.
References [l] O.G. Kulikova and B.A. Reikhardt. HMGI4 - a physiological subs:rate for casein kinase NII of neuronal chromatin. Biochemistry (Moscow), 1996, 61, 6, 750-756. [2] O.G. Kutikova et al. The modern aspects of search on the effective nootropic drugs. Vestnik Akad.med.nauk SSSR, 1992, 8, 56450.
$278
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Inhibitory effects of caffeine on cerebral blood flow. Evaluation by means of neurospect
A. Ruiz, I. Mena, S. Neubauer, J. Cornejo, C. Thomas, T. Strickland.
Dept. of Psychiatry and Mental Health, School of Medicine, University of Chile; Dept. of Nuclear Medicine, Clinica Las Condes, Chile. Di~: of Nuclear Medicine, Harbor UCLA Med. Ctr., Torrance, CA; Depart. of Psychiatr); Drew Univ. Medicine and Science, Los Angeles, CA. USA Objective: The increased use of SPECT for clinical evaluation and measurement of cerebral blood flow (CBF) for assessment of neuropsychiatric disorders must consider that caffeine may produce a diminution of CBE The purpose of this paper is the demonstration of this hypothesis and quantification and localization of inhibitory effects of caffeine on CBE Method: A comparative study was performed in two samples, before and 30 minutes after oral administration of 250 mg of caffeine: 1). In 20 young normal volunteers, CBF was measured using Xenon-133 inhalation technique. 2). In 7 other young volunteers, CBF measurements were obtained by means of SPECT with ECD Tc-99m (Neurolite TM). Results: Sample 1: Administration of caffeine produced 30 minutes afterwards, a significant reduction of CBF, 8.5 ml/min/100 g (p < 0.0001) and 9.5 ml/min/100 g (p < 0.0001) at 2 cm and 6 cm above the orbitomeatal line respectively. This corresponds to a diminution of 25% and 23% respectively. There is no effect of lateralization. Sample 2: Results demonstrated that the distribution of CBF after ingestion of caffeine was homogeneous and there were no regional effects on CBE Conclusions: The inhibitory effects of caffeine on CBF are demonstrated throughout all the cerebral cortex. Caffeine ingestion (coffee, tea, chocolate) should be discontinued before NeuroSPECT.
•
Pharmacology of some new DL-aspartic acid derivatives
N.S. Sapronov, M. Kamri, L.B. Piotrovsky. Institute for Experimental Medicine of the Russian Academy of Medical Sciences, Department of Neuropharmacolog),; St. Petersburg 197376, Russia It is widely accepted that excitatory amino acids (EAA) transmission system takes part in the regulation of different biochemical processes and physiological function of mammalian brain sensory information, learning, memory, behavior and convulsive reactions (Nakanishi, 1992; Lipton & Rosenberg, 1994). However the critical use of EAA-ergic compounds, especially full agonists and antagonists of NMDA receptors is quite confined because of their neurotoxicity and expressed side effects (Danysz et at., 1994). That is why the attempt was made to design the partial agonists of NMDA receptors. For the purpose in the department of neuropharmacology there was synthesized a number of derivatives of DL-aspartic acid: N-allyl-(I), N-n-butyl- (II), N-n-pentyl(III), N-cyclohexyl-(IV) and N-benzyl (V) analogues. In vivo experiments have been carried out in mice, rats and rabbits. The convulsive and anticonvulsive properties, behavioral effects in "open field" and the influence of these substances on bioelectric activity in brain structures have been studied. The size enlargement of alkyl chain in alpha-amino group leads to decrease of convulsive activity of aspartic acid derivatives as compared with NMDLA: allyl- >butyl- >benxyl- >pentyl- >cyclohexyl-. The substitution of alkyl-radical to aralkyl-radical increases the ability of drug to penetrate blood-brain barrier. All compounds potentiated the seizures induced by NMDLA. Only N-n-butyl-DL-aspartic acid had duel effect: in low dose (subconvulsive) it prevented the NMDLA induced seizures and in high doses it potentiated these convulsions. In electrophysiological experiments this substance (10 mcrnol, intracerebrovenricularly~ can diminish the duration of afterdischarge seizures by hippocampal stimulation as well as NMDLA induced seizures. In high doses N-DL-aspartic acid derivatives suppress the behavior of rats in "open field" especially locomotor activity. The results of experiments show that between new synthesized analogues of N-DL-aspartic acid there is the derivative (N-n-butyl-DLaspartic acid) possessing with properties of partial agonist of NMDA receptors.
References [1] Danysz W., Essman V., Bresink 1., Wilke R. Glutamate antagonists aave different effects on spontaneouslocomotoractivity in rats.//Pharmacol. Biochem. Behav. - 1994, v.48, p. 111-118. [2] Lipton S.A., RosenbergEA. Mechanismsof disease: Excitatory amine, acids as a final common pathway for neurologic disorders.//New England J. ldedicine - 1994, v. 330, p. 613~522. [3] Nakanishi S. Molecular diversity of glutamate receptors and implications for brain functions.//Science. - 1992, v. 258, p. 597-603.
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Regulatory system of brain chromatin in nootropic action
O.G. Kulikova, B.A. Reikhardt, N.S. Sapronov. Institute for Experimental Medicine of the Russian Academy of Medical Sciences, Department of Neuropharmacology, St. Petersburg 197376, Russia It is widely accepted the apply of nootropic drugs for correction of age related cognitive disorders. Now believed that decline in gene expression and chromatin compactization is the basic mechanism of aging. Our studies concentrated on regulation of gene expression in brain. This topic includes molecular mechanisms of memory and memory disorder as well as effects of nootropic drugs. Feature of system of trans,:fiption regulation in old animals along with the possibility of their pharmacological correction was studied. Male white rats 20-month-old were used for behavioral and biochemical tests. Protein kineses of ch:omatin including both cAMP-independent casein kinase I and II in brain cortex and hippocampus were measured. Phosphorylation of chromosomal protein substrates by both type of CKs and neuronal transcriptic,n were studied in old rats and at the action of nootropic. Ethylnorantifein (4.5 dimethylcarbamoyl-l-ethyl-imidazole) was chosen because this one stimulated neuronal transcription and memory. Piracetam (2-oxo-1-pyrrolidon acetamide) was used as reference nootropic. Old rats have the disorders in learning and progressing amnesia in test of passive avoidance in one-trial. Significant decrease in activity of CK type II in rat brain cortex and hippocampus was observed in old animals (20-months) in comparison with adult (7-months). So, as CK I, no changes were found. Besides, the phosphorylation of chromatin proteins was decreased in old rats. Chromatin proteins were analyzed by electrophoresis and use of antibodies. In particular, the phosphorylation of nonhistone high mobility ~oup (HMO) 14 protein was occurred. HMG14 is physiological substrate of CK It and it was proved, its role in regulation transcription in neurons. Decline of neuronal transcription in old rats was shown. Ethylnorantifein in vivo (3 mg/kg i.p.) and in vitro stimulated the activity of CK II in cortex and hippocampus in adult rats. In old rats ethylnorantifein reduced the CK II up to level of adult rats. Herewith, the raise in HMGI4 phosphorylation by CK II was found. Attract altention that ethylnorantifein increased both the neuronal transcription and cognitive function in old rats or its well matiamnestic effect. It is important that piracetam in vivo (250 mg/kg i.p.) like ethylnorantifein increased the CK II in old rats, however direct action on CK II was not found. The present data demonstrated the role of regulatory system of chTomatin (CKII-HMGI4) in both mechanisms of aging and antianmestic action; this may contribute to the mechanisms underlying memory improvement produced by notropic.
References [l] O.G. Kulikova and B.A. Reikhardt. HMGI4 - a physiological subs:rate for casein kinase NII of neuronal chromatin. Biochemistry (Moscow), 1996, 61, 6, 750-756. [2] O.G. Kutikova et al. The modern aspects of search on the effective nootropic drugs. Vestnik Akad.med.nauk SSSR, 1992, 8, 56450.