Cyclic AMP and GMP

Thampi, Mader and Earley, Pharmacologist (1974),²¹⁰³ demonstrated that PHT (5-15 µg/ml) produces an increase in cyclic AMP and a corresponding decrease in cyclic GMP in rat brain synaptosomes.

2103. Thampi, N. S., Mader, M. M. and Earley, R. J., Effect of diphenythydantoin on levels of cyclic AMP and cyclic GMP in rat brain synaptasomes, Pharmacologist, 16: Abstr. 551, Fall, 1974.

Pull and McIlwain, Biochemical Pharmacology (1975),²⁰²⁷ observed that PHT (300 µM) decreased by 20% release of adenine derivatives, including adenosine, from electrically-stimulated guinea pig neo-cortical tissues. In unstimulated tissue, PHT increased the adenine derivative output. The authors suggest that PHT's inhibition of adenosine release reduces the rise in cyclic AMP caused by electric stimulation.

2027. Pull, I. and McIlwain, H., Centrally-acting drugs and related compounds examined for action on output of adenine derivatives from superfused tissues of the brain, Biochem. Pharmacol., 25: 293-7, 1976.

Lewin and Bleck, Epilepsia (1977), ¹⁹⁵⁸ noting that increased cyclic AMP may have a role in abnormal neuronal excitability, demonstrated that PHT (300 µM) reduced the increase in cyclic AMP produced by the depolarizing agent ouabain, in rat brain cortex slices. The authors suggest that PHT reduces the increase in cyclic AMP by inhibiting stimulated adenosine release.

1958. Lewin, E. and Bleck, V., Cyclic AMP accumulation in cerebral cortical slices: effect of carbamazepine, phenobarbital and phenytoin, Epilepsia, 18(2): 237-42, 1977.

Lewin, Epilepsia (1977),¹⁹⁵⁷ demonstrated that PHT significantly reduced the increase in release of adenine derivatives induced by depolarizing agents ouabain and veratridine in rat brain cortex slices, human astrocytoma cell cultures and mouse neuroblastoma cell cultures.

1957. Lewin, E., Effects of phenytoin on the release of ¹⁴C-Adenine derivatives, Epilepsia, 18(3): 349-55, 1977.

Ferrendelli and Kinscherf, Epilepsia (1977), ¹⁸³⁰ demonstrated, in mouse cerebral cortex and cerebellum slices, that PHT (10-25 µg/ml) inhibited both ouabain-and veratridine-induced increases in cyclic AMP and cyclic GMP. Resting levels of cyclic AMP and cyclic GMP were not affected.

1830. Ferrendelli, J. A. and Kinscherf, D. A., Phenytoin: effects on calcium flux and cyclic nucleotides, Epilepsia, 18(3): 331-6, 1977.

Dretchen, Standaert and Raines, Epilepsia (1977),¹⁸¹¹ evaluated the effects of PHT on the motor nerve terminal of an in vivo cat soleus nerve-muscle preparation. PHT, 10 mg/kg, reduced the repetitive afterdischarges in motor nerve endings due to tetanic conditioning. It also reduced the repetitive activity due to adenylate cyclase activation with sodium fluoride, or to exogenous dibutyryl cyclic AMP.

1811. Dretchen, K. L., Standaert, F. G. and Raines, A., Effects of phenytoin on the cyclic nucleotide system in the motor nerve terminal, Epilepsia, 18(3): 337-48, 1977.

Lust, Kupferberg, Yonekawa, Penry, Passonneau and Wheaton, Molecular Pharmacology (1978),¹⁹⁶⁹ demonstrated, in mice, that PHT (25 mg/kg) decreases the cerebellar cyclic AMP increase induced by electroshock.

1969. Lust, W. D., Kupferberg, H. J., Yonekawa, W. D., Penry, J. K., Passonneau, J. V. and Wheaton, A. B., Changes in brain metabolites induced by convulsants or electroshock: Effects of anticonvulsant agents, Molec. Pharmacol., 14: 347-56, 1978.

McCandless, Feusner, Lust and Passonneau, Journal of Neurochemistry (1979),²²²⁹ found that PHT (25 mg/kg), administered twenty-five minutes prior to electroshock, protected mouse cerebellum from seizure-induced decreases in energy compounds and increases in cyclic AMP and cyclic GMP.

2229. McCandless, D. W., Feussner, G. K., Lust, W. D. and Passonneau, J. V., Metabolite levels in brain following experimental seizures: the effects of maximal electroshock and phenytoin in cerebellar layers, J. Neurochem., 32: 743-53, 1979.

Palmer, Jones, Medina, Palmer and Stavinoha, Epilepsia (1979), ²⁰¹³ observed that pretreatment with PHT (75 mg/kg) prevents the rise in cyclic AMP in mouse cerebrum and cerebellum following injection with pentylenetetrazol. In mouse cerebral cortex slices, PHT reduced the increase in cyclic AMP induced by norepinephrine, adenosine and ouabain.

2013. Palmer, G. C., ]ones, D. J., Medina, M. A. and Stavinoha, W. B., Anticonvulsant drug actions on in vitro and in vivo levels of cyclic AMP in the mouse brain, Epilepsia, 20: 95-104, 1979.

Ferrendelli, Antiepileptic Drugs: Mechanisms of Action (1980),¹⁸²⁸ reported that, in mouse cerebral cortex slices, PHT prevented cyclic AMP and cyclic GMP increases induced by ouabain or veratridine depolarization, but not potassium- or glutamate-induced depolarization. This inhibitory effect of PHT was dose-dependent, significant at 10 µg/ml. In in vivo studies, PHT (25 mg/kg) produced a 50% reduction of basal cyclic GMP levels, but not cyclic AMP levels, in mouse cerebellum. In the cerebral cortex, striatum, thalamus and hippocampus, cyclic GMP and cyclic AMP were unchanged. The authors suggest that these cyclic nucleotide changes produced by PHT relate to its regulatory effect on sodium channels.

1828. Ferrendelli, J. A., Phenytoin: cyclic nucleotide regulation in the brain, Antiepileptic Drugs: Mechanisms of Action, 429-33, Glaser, G. H., Penry, J. K. and Woodbury, D. M., Eds., Raven Press, New York, 1980.

Folbergrova, Neuroscience Letters (1980),²⁵⁰² reported that the administration of PHT (30 mg/kg) intraperitoneally, thirty minutes prior to seizure induction, markedly reduced the rise in cyclic AMP, but not cyclic GMP, in the cerebral cortex of mice during seizures induced by 3-mercaptopropionic acid.

2502. Folbergrova, J., Cyclic GMP and cyclic AMP in the cerebral cortex of mice during seizures induced by 3-mercaptopropionic acid: effect of anticonvulsant agents, Neurosci. Lett., 16: 291-6, 1980.

Study, The Journal of Pharmacology and Experimental Therapeutics (1980),²⁰⁹³ demonstrated that PHT (3-300 µM, half-maximal effect at 40 µM) inhibited calcium-dependent increases in cyclic GMP produced by potassium depolarization or muscarinic receptor activation in NIE-115 neuroblastoma cells. These results suggest that PHT inhibited the cyclic GMP increase by blocking calcium influx.

See also Refs. 1829, 1831, 2236, 2341, 2627, 2628, 2743, 2834.

2093. Study, R. E., Phenytoin inhibition of cyclic guanosine 3’:5’-monophosphate (cGMP) accumulation in neuroblastoma cells by calcium channel blockade, J. Pharmacol. Exp. Ther., 215(3): 575-81, 1980.
1829. Ferrendelli, J. A. and Kinscherf, D. A., Inhibitory effects of anticonvulsant drugs on cyclic nucleotide accumulation in brain, Ann. Neurol., 5: 533-8, 1979.
1831. Ferrendelli, J. A. and Kinscherf, D. A., Similar effects of phenytoin and tetrodotoxin on cyclic nucleotide regulation in depolarized brain tissue, J. Pharm. Exp. Ther., 207(3): 787-93, 1978.
c2236. Palmer, G. C., Palmer, S. J. and Legendre, J. L., Guanylate cyclase-cyclic GMP in mouse cerebral cortex and cerebellum: modification by anticonvulsants, Exp. Neurol., 71: 601-14, 1981.
2341. Bittar, E. E., Nwoga, J., Some further observations on the stimulation by high external potassium of the sodium efflux in barnacle muscle fibers, Pflugers Arch., 395: 318-25, 1982.
2627. Johnson, S. W., Riker, W. K., Relationships between the antagonism of electrically-induced maximal seizures by phenytoin (PHT) and central nervous system (CNS) levels of adenosine 3’,5-monophosphate (cAMP) and guanosine 3’,5monophosphate (cGMP) in frogs and mice, Soc. Neurosci. Abstr., 7, 1981.
2628. Johnson, S. W., Riker, W. K., Phenytoin antagonism of electrically induced maximal seizure in frogs and mice and effects on central nervous system levels of adenosine 3’,5’monophosphate and guanosine 3’,5’-monophosphate, J. Pharmacol. Exp. Ther., 221(l): 139-45, 1982.
2743. Lust, W. D., Fuessner, G. K., Passonneau, J. V., McCandless, D. W., Biochemical mechanisms of anticonvulsants: studies on cyclic neucleotide systems in brain, Neuropharmacology of Central Nervous System and Behavioral Disorders, Palmer, G. C., Ed., Academic Press, New York, 407-31, 1980.
2834. Nosek, T. M., The effects of valproate and phenytoin on the cAMP and cGMP levels in nervous tissue, Proc. Soc. Exp. Biol. Med., 178(2): 196-9, 1985.

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