Occurrence of ‘natural’ diazepam in human brain

Unseld, E.; Fischer, Christine; Rothemund, Elisabeth; Klotz, Ulrich

doi:10.1016/0006-2952(90)90668-b

Cited by 31 publications

(9 citation statements)

References 5 publications

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“…In contrast, the concentrations of diazepam and N-desmethyldiazepam were increased 2-to 9-fold in brain extracts from rats with HE. The variability in the concentrations of these substances in HE may reflect, in part, the wide range of BZ concentrations in control brains, a phenomenon that has been observed previously (18,20). In addition to the elevated concentrations of diazepam and N-desmethyldiazepam present in brain extracts of rats with HE, the overall concentration of HPLC-purified substances inhibiting radioligand binding to BZ receptors (expressed in diazepam equivalents) was elevated 4-to 6-fold compared to controls ( Table 1, Fig.…”

Section: Discussionmentioning

confidence: 83%

Brain concentrations of benzodiazepines are elevated in an animal model of hepatic encephalopathy.

Basile

Pannell

Jaouni

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

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Brain extracts from rats with hepatic encephalopathy due to thioacetamide-induced fulminant hepatic failure contained 4-to 6-fold higher concentrations of substances that inhibit radioligand binding to benzodiazepine receptors than corresponding control rat extracts. Both isocratic and gradient-elution HPLC indicated that this inhibitory activity was localized in 3-8 peaks with retention times corresponding to deschlorodiazepam, deschlorolorazepam, lorazepam, oxazepam, diazepam, and N-desmethyldiazepam. The presence of diazepam and N-desmethyldiazepam was confirmed by mass spectroscopy. Both mass spectroscopic and radiometric techniques indicated that the concentrations of N-desmethyldiazepam and diazepam in brain extracts from encephalopathic rats were 2-9 and 5-7 times higher, respectively, than in control brain extracts. While benzodiazepines have been identified previously in mammalian and plant tissues, this report demonstrates that concentrations of these substances are increased in a pathophysiological condition. These findings provide a rational basis for the use of benzodiazepine receptor antagonists in the management of hepatic encephalopathy in humans.Hepatic encephalopathy (HE) is a complex neuropsychiatric disorder arising from the metabolic abnormalities associated with acute or chronic liver failure (1). It has been proposed that an increase in the activity of y-aminobutyric acid (GABA)-containing pathways contributes to the manifestations of this disorder (2). Studies of visual evoked responses in the galactosamine-treated rabbit model of HE due to fulminant hepatic failure (FHF) (3) and in rats with HE due to thioacetamide (TAA)-induced FHF (4) indicate that central nervous system (CNS) GABAergic tone is increased in these models of HE. Electrophysiologic studies of single cerebellar Purkinje neurons in the rabbit model of HE further support this hypothesis. These neurons are hypersensitive to depression by the GABA receptor agonist muscimol and the benzodiazepine (BZ) receptor agonist flunitrazepam, but not to the a-adrenergic receptor agonist phenylephrine (5). In contrast, BZ receptor antagonists increase the spontaneous firing rate of these neurons and reverse their hypersensitivity to muscimol at concentrations that do not affect the firing rates of control neurons (5). Furthermore, BZ receptor antagonists correct the abnormalities in visual evoked responses associated with HE while transiently reversing the behavioral manifestations of this syndrome in both the rabbit and rat models of this disorder (3, 4).These observations indicate that the increase in "GABAergic tone" found in HE may be mediated by the BZ receptor, possibly as a consequence of an increase in the concentration or availability of a BZ receptor ligand with agonist (BZ-like) properties (6, 7). Elevated concentrations of substances that competitively and reversibly inhibit radioligand binding to BZ receptors have recently been found in extracts of brain and peripheral tissues from the TAA-treated rat model of HE (8)....

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Section: Discussionmentioning

confidence: 83%

Brain concentrations of benzodiazepines are elevated in an animal model of hepatic encephalopathy.

Basile

Pannell

Jaouni

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

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“…such as diazepam, are the product of industrial synthesis. However, some investigators have found very small amounts of diazepam, its methylated derivative desmethyldiazepam and several other related halogenated benzodiazepines in human and animal tissue, plants and other foodstuffs (24)(25)(26)(27)(28)(29)(30)(31)(32)(33). Fungi and plants have synthetic pathways for the formation of distantly related benzodiazepines (341, but these are not halogenated benzodiazepines, and the fungal benzodiazepines appear to have a low potency for the benzodiazepine receptor (35).…”

mentioning

confidence: 99%

Benzodiazepine-receptor ligands and hepatic encephalopathy: A causal relationship?

Rothstein

1994

Hepatology

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“…The presence of an endogenous BZD ligand in the mammalian brain has been suggested (Mohler, 1980;DeBlass and Sangameswaran, 1986;Unseld et al, 1990). The actions of this putative ligand would be mediated via the BZD receptor, and thus it might play a role in mediating behaviors such as anxiety, sedation, and hypnosis.…”

Section: Discussionmentioning

confidence: 99%

Chronic brief restraint decreases in vivo binding of benzodiazepine receptor ligand to mouse brain

Mosaddeghi

Burke

Moerschbaecher

1993

Molecular and Chemical Neuropathology

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This study examines the effects of chronic brief restraint on in vivo benzodiazepine (BZD) receptor binding in mouse brain. Three groups of mice were used. Mice in group 1 were neither restrained nor injected (ACUTE control). Mice in group 2 were restrained for 5-6 s by grabbing the back skin and holding the subject upside-down at a 45 degrees angle as if to be injected (CHRONIC SHAM control) for 7 d. Mice in group 3 (CHRONIC SALINE) received daily single intraperitoneal (ip) injections of saline (5 mL/kg) for 7 d. On d 8 BZD receptors were labeled in vivo by administration of 3 microCi [3H]flumazenil (ip). The levels of ligand bound in vivo to cerebral cortex (CX), cerebellum (CB), brain stem (BS), striatum (ST), hippocampus (HP), and hypothalamus (HY) were determined. Results indicated that the level of binding was significantly (p < 0.01) lower by 30-50% (depending on the brain region) in saline-injected or sham control groups compared to acute control animals. Furthermore, the values for sham control were similar to the saline-treated group. Our data suggest that exposure to chronic mild restraint produces a decrease in in vivo binding of [3H]flumazenil in mouse brain and supports the hypothesis that chronic mild stress produces a decrease in BZD receptor binding sites.

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Occurrence of ‘natural’ diazepam in human brain

Cited by 31 publications

References 5 publications

Brain concentrations of benzodiazepines are elevated in an animal model of hepatic encephalopathy.

Brain concentrations of benzodiazepines are elevated in an animal model of hepatic encephalopathy.

Benzodiazepine-receptor ligands and hepatic encephalopathy: A causal relationship?

Chronic brief restraint decreases in vivo binding of benzodiazepine receptor ligand to mouse brain

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