γ-Guanidinobutyric Acid as a Convulsive Substance

Jinnai, Dennosuke; Sawai, Aijiro; Mori, Akitane

doi:10.1038/212617a0

Cited by 85 publications

(28 citation statements)

References 3 publications

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“…Whereas methylguanidine (10 mM) reduced GABA responses 25.7 f 7.37% (n = 3) and guanidine (10 mM) reduced GABA responses 23.3 * 4.1% (n = 3), their Creatinine (20 mM) Creatinine (20 [38,41,44,451 through an interaction with the benzodiazepine receptor. Moreover, the convulsants bicuculline, picrotoxin, and pentylenetetrazole were previously reported to selectively antagonize GABAmediated postsynaptic inhibition in cultured mammalian neurons [37,39,41,451.…”

Section: Additive Ehects Of Guanidine and Metbylguanidine On Gaba Resmentioning

confidence: 99%

Guanidino compounds that are increased in cerebrospinal fluid and brain of uremic patients inhibit GABA and glycine responses on mouse neurons in cell culture

Deyn

Macdonald

1990

Annals of Neurology

118

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Four guanidino compounds that have been found to be markedly increased in cerebrospinal fluid and brain tissue of uremic patients, namely, guanidine, methylguanidine, creatinine, and guanidinosuccinic acid, were applied to mouse spinal cord neurons in primary dissociated cell culture to evaluate their effects on postsynaptic responses to gamma-aminobutyric acid (GABA) and glycine. Intracellular microelectrode recording techniques were used. Guanidine, methylguanidine, creatine, and guanidinosuccinic acid reversibly and in a dose-dependent manner inhibited both GABA and glycine responses. Guanidinosuccinic acid was the most potent inhibitor of the amino acid responses, followed in decreasing potency by methylguanidine, guanidine, and creatinine. Guanidinosuccinic acid inhibited responses to GABA and glycine, at concentrations similar to those found in cerebrospinal fluid and brain tissue of patients with terminal renal insufficiency. The other guanidino compounds tested exerted their effects only at concentrations higher than those found in uremic biological fluids and tissues. The inhibitory effect of guanidine and methylguanidine on responses to GABA was additive. The effect of the guanidino compounds on GABA responses was not antagonized by coapplication of the benzodiazepine-receptor antagonist CGS 9896. The results suggest that guanidine, methylguanidine, creatinine, and guanidinosuccinic acid inhibited responses to the inhibitory neurotransmitters GABA and glycine by blocking the chloride channel. The observed action of the studied guanidino compounds might contribute to the pathogenesis of the complex neurological symptomatology encountered in uremia.

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Section: Additive Ehects Of Guanidine and Metbylguanidine On Gaba Resmentioning

confidence: 99%

Guanidino compounds that are increased in cerebrospinal fluid and brain of uremic patients inhibit GABA and glycine responses on mouse neurons in cell culture

Deyn

Macdonald

1990

Annals of Neurology

118

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“…Gamma-guanidinobutyric acid was shown to induce tonic and clonic seizures following intracisternal injection in rabbits. 16) De Deyn et al reported that guanidino compounds were found to be increased in the serum and CSF of uremic patients 17) and guanidinosuccinic acid induced behavioral convulsions after intraperitoneal injection in mice. 18) In addition, four guanidino compounds (guanidinosuccinic acid, creatinine, guanidine, and methylguanidine) were shown to inhibit gamma-aminobutyric acid and glycine responses on mouse neurons in cell culture.…”

Section: Effect Of Renal Failure On the Concentrations Of Cfsl In Sermentioning

confidence: 99%

Effect of Experimental Renal Failure on the Pharmacodynamics of Cefoselis-Induced Seizures in Rats.

Nagata

Yasuhara

2001

Biological & Pharmaceutical Bulletin

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Cefoselis (CFSL), a fourth-generation parenteral cephalosporin, has been marketed in Japan since September 1998. In December 1998, warnings of central nervous system (CNS) adverse effects such as seizures and confusional states were added to the labeling of CFSL. In many cases, these adverse effects were observed in patients who were elderly and/or had renal failure. Therefore renal failure is considered as one of the risk factors for neurotoxicity of CFSL. Since CFSL is mainly eliminated by renal excretion, 1) renal failure would be associated with increased serum concentrations of CFSL. On the other hand, it is still unknown whether renal failure can alter the pharmacodynamics of CFSL-induced seizures.Drug administration can be divided into two phases: a pharmacokinetic phase in which dose, dosage form, frequency, and route of administration are related to drug concentration-time relationships in the body; and a pharmacodynamic phase in which the concentration of drug at the site(s) of action is related to the magnitudes of the effect(s) produced.2) The pathophysiologic status of patients can affect both the pharmacokinetics and the pharmacodynamics of a drug. Our knowledge of the effects of disease on the pharmacokinetics of a drug cannot be used to optimize the drug dosage of a patient without information on disease effects on the pharmacodynamics. 3) Therefore it is important to distinguish the effects of disease on the pharmacokinetics from those on the pharmacodynamics. Danhof and Levy 3) reported an experimental strategy to assess the effects of disease and other variables on the pharmacodynamics of drugs with CNS activity. The effects of experimental renal failure on the pharmacodynamics of CNS stimulant drugs such as theophylline, 4) pentylentetrazole, 5) and cimetidine 6) were investigated previously.There have been clinical case reports of seizures caused by various b-lactam antibiotics such as penicillin, 7) cefazoline, 8) ampicillin, 9) and imipenem. 10) However, to our knowledge, there have been no reports that clarified the effect of renal failure on the pharmacodynamics of b-lactam antibiotic-induced seizures. To assure safe and effective antibiotic drug therapy, it must be determined if renal failure can change the relationship between the concentration and intensity of pharmacologic activity of drugs.The present study was designed to determine: 1) the suitability of the rat as an animal model of CFSL-induced seizures; 2) the sampling site where CFSL concentrations reflect the drug concentration at the site of neurotoxic action; and 3) the effect of renal failure on the pharmacodynamics of CFSL-induced seizures. MATERIALS AND METHODS AnimalsMale Wistar rats weighing 240 to 300 g were used in this investigation. The rats had an indwelling cannula implanted in the left juglar vein under light ether anesthesia one day before the experiment and they were fasted until the CFSL infusion began.Chemicals CFSL sulfate (Wincef ® for infusion) used for animal experiments was obtained from Fujisawa Pharmac...

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“…While still controversial [13], guanidinosuccinic acid is believed to be related to the ure mic bleeding diathesis [14,15]. Methylguanidine could be related to the uremic polyneuropathy [16] and has been shown experimentally to induce a catabolic state, hemoly sis [ 16] and epilepsy [17], y-Guanidinobutyric acid, meth ylguanidine, homoarginine, creatine and creatinine were found to have a convulsive effect in animals when injected intracisternally [18][19][20][21]. Guanidinosuccinic acid, methylguanidine, guanidine and creatinine were suggest ed to be chloride channel blockers and were shown to induce myoclonic and generalized seizures after systemic and intracerebroventricular administration in mice [22,23], Moreover, guanidinosuccinic acid was shown to inhibit excitatory neurotransmission in rat hippocampal brain slices, an effect that hypothetically could contribute to the uremic encephalopathy [24].…”

Section: Introductionmentioning

confidence: 99%

Serum Guanidino Compound Levels in Uremic Pediatric Patients Treated with Hemodialysis or Continuous Cycle Peritoneal Dialysis

Deyn

Robitaille

Vanasse

et al. 1995

Nephron

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Serum levels of twelve guanidino compounds (GCs) and nerve conduction velocities were determined in a dialyzed renal insufficient pediatric population. Two dialytic groups were considered: one subjected to hemodialysis (HD, 11 patients) and one subjected to continuous cycle peritoneal dialysis (CCPD, 13 patients). Before HD, marked increases were found for guanidinosuccinic acid (207 times), methylguanidine ( > 67 times), argininic acid (24 times), creatinine and α-N-acetylarginine (18 times) and guanidine ( > 14 times) when compared to controls. Important significant increases were still present after an HD session for guanidinosuccinic acid (49 times), methylguanidine (34 times), creatinine (7 times) and α-N-acetylarginine and guanidine (6 times). After HD, creatine, arginine and homoarginine were lower than in controls. All GCs, with the exception of creatine, decreased significantly after a single HD session with percentage decrease ranging between 40% (for arginine) and 77% (for guanidinosuccinic acid). Creatine decreased in a statistically nonsignificant manner by 48%. Marked increases were found in the CCPD group for guanidinosuccinic acid (114 times), α-N-acetylarginine (12 times), argininic acid (15 times), creatinine (22 times), guanidine ( > 11 times) and methylguanidine ( ≥ 48 times). Concentrations of guanidinosuccinic acid before and after HD and in CCPD were comparable to those reported to be toxic in vitro and in vivo. No clinical or electrophysiological indications of polyneuropathy were observed in our population. Sensory and motor nerve conduction studies showed few abnormalities apart from a significant correlation between argininic acid concentration or guanidine levels and the peroneal nerve conduction velocity in the CCPD-treated group.

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γ-Guanidinobutyric Acid as a Convulsive Substance

Cited by 85 publications

References 3 publications

Guanidino compounds that are increased in cerebrospinal fluid and brain of uremic patients inhibit GABA and glycine responses on mouse neurons in cell culture

Guanidino compounds that are increased in cerebrospinal fluid and brain of uremic patients inhibit GABA and glycine responses on mouse neurons in cell culture

Effect of Experimental Renal Failure on the Pharmacodynamics of Cefoselis-Induced Seizures in Rats.

Serum Guanidino Compound Levels in Uremic Pediatric Patients Treated with Hemodialysis or Continuous Cycle Peritoneal Dialysis

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