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Brain Concentrations of Benzodiazepines Are Elevated in An Proc. Natl. Acad. Sci. USA Vol. 87, pp. 5263-5267, July 1990 Neurobiology Brain concentrations of benzodiazepines are elevated in an animal model of hepatic encephalopathy (benzodiazepine receptors/fulminant hepatic failure/diazepam/N-desmethyldiazepam/mass spectroscopy) ANTHONY S. BASILE*t, LEWIS PANNELLt, TAYSIR JAOUNI§, SERGIO H. GAMMAL¶, HENRY M. FALES§, E. ANTHONY JONES¶, AND PHIL SKOLNICK* *Laboratory of Neuroscience, tLaboratory of Bioorganic Chemistry, $Liver Diseases Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, and §Laboratory of Biophysical Chemistry, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892 Communicated by Joseph E. Rall, April 20, 1990 ABSTRACT Brain extracts from rats with hepatic enceph- or availability of a BZ receptor ligand with agonist (BZ-like) alopathy due to thioacetamide-induced fulminant hepatic fail- properties (6, 7). Elevated concentrations of substances that ure contained 4- to 6-fold higher concentrations of substances competitively and reversibly inhibit radioligand binding to that inhibit radioligand binding to benzodiazepine receptors BZ receptors have recently been found in extracts of brain than corresponding control rat extracts. Both isocratic and and peripheral tissues from the TAA-treated rat model of HE gradient-elution HPLC indicated that this inhibitory activity (8). We have further purified the brain extracts from this was localized in 3-8 peaks with retention times corresponding model and now report that the substances which inhibit to deschlorodiazepam, deschlorolorazepam, lorazepam, ox- radioligand binding to BZ receptors exhibit chromatographic azepam, diazepam, and N-desmethyldiazepam. The presence properties characteristic of BZs. Diazepam and N-desmeth- of diazepam and N-desmethyldiazepam was confirmed by mass yldiazepam were chemically identified in these extracts by spectroscopy. Both mass spectroscopic and radiometric tech- mass spectroscopy and were present in significantly elevated niques indicated that the concentrations of N-desmethyldiaz- concentrations in the brains of rats with HE. epam 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 iden- METHODS tified previously in mammalian and plant tissues, this report Animals. The rat model of HE due to TAA-induced FHF demonstrates that concentrations of these substances are in- was used throughout this study (4). Adult (180-225 g) male creased in a pathophysiological condition. These findings pro- Sprague-Dawley rats (Taconic Farms) were maintained in a vide a rational basis for the use of benzodiazepine receptor 12-hr light/dark cycle (lights on at 0700) with free access to antagonists in the management of hepatic encephalopathy in rat chow (National Institutes ofHealth open formula no. 1 rat humans. chow) and water. FHF was induced by the daily intraperi- toneal injection of TAA (600 mg/kg in 0.9% NaCl, 5 ml/kg) Hepatic encephalopathy (HE) is a complex neuropsychiatric for 3 consecutive days, along with supportive therapy. Ve- disorder arising from the metabolic abnormalities associated hicle-treated controls and rats in stage III-IV HE were used with acute or chronic liver failure (1). It has been proposed in these studies. that an increase in the activity of y-aminobutyric acid Extraction Procedure. Rats were decapitated according to (GABA)-containing pathways contributes to the manifesta- guidelines of the American Association for the Accreditation tions of this disorder (2). Studies of visual evoked responses ofLaboratory Animal Care. The brains were rapidly removed in the galactosamine-treated rabbit model of HE due to and placed in ice-cold isotonic sucrose. Brains were ex- fulminant hepatic failure (FHF) (3) and in rats with HE due tracted by a modification of the techniques of Osselton (9) to thioacetamide (TAA)-induced FHF (4) indicate that cen- and Foerster et al. (10). Tissues were homogenized in 4 tral nervous system (CNS) GABAergic tone is increased in volumes (vol/wt) of 1 M Tris base (pH 10.9) with alkaline these models of HE. Electrophysiologic studies of single protease (1 mg/g of tissue) by using a Brinkmann Polytron cerebellar Purkinje neurons in the rabbit model of HE further (setting 6.5, 30 sec). Internal standards for monitoring the support this hypothesis. These neurons are hypersensitive to extraction efficiency of BZs were then added to the homog- depression by the GABA receptor agonist muscimol and the enate: prazepam (100 ng) was the internal standard for the benzodiazepine (BZ) receptor agonist flunitrazepam, but not quantitation of materials by HPLC/radioreceptor assay; di- to the a-adrenergic receptor agonist phenylephrine (5). In azepam-d5 and N-desmethyldiazepam-d5 (50, 100, or 200 ng) contrast, BZ receptor antagonists increase the spontaneous were used for quantitation by HPLC/mass spectroscopy. firing rate ofthese neurons and reverse their hypersensitivity The homogenate was then incubated in a water bath with to muscimol at concentrations that do not affect the firing continuous shaking for 1 hr at 55-60°C. At the end of the rates of control neurons (5). Furthermore, BZ receptor incubation, the pH was adjusted to 9 with 1 volume of antagonists correct the abnormalities in visual evoked re- saturated Na2CO3. The homogenate was extracted by stirring sponses associated with HE while transiently reversing the with 8 volumes of 1-chlorobutane for 20 min, after which the behavioral manifestations of this syndrome in both the rabbit samples were centrifuged (15,000 x g, 10 min, 0-4°C) and the and rat models of this disorder (3, 4). organic layer was removed. This step, as well as all subse- These observations indicate that the increase in "GABAer- quent steps, was repeated once. The 1-chlorobutane was then gic tone" found in HE may be mediated by the BZ receptor, extracted by stirring with 4 volumes of 1 M HCI for 20 min possibly as a consequence of an increase in the concentration Abbreviations: BZ, benzodiazepine; FHF, fulminant hepatic failure; The publication costs of this article were defrayed in part by page charge GABA, 'y-aminobutyric acid; HE, hepatic encephalopathy; TAA, payment. This article must therefore be hereby marked "advertisement" thioacetamide; TFA, trifluoroacetic acid. in accordance with 18 U.S.C. §1734 solely to indicate this fact. tTo whom reprint requests should be addressed. 5263 Downloaded by guest on September 25, 2021 5264 Neurobiology: Basile et al. Proc. Natl. Acad. Sci. USA 87 (1990) to remove basic compounds. The aqueous layer was retained RESULTS and washed once against 8 volumes of 1-chlorobutane. The pH of the aqueous phase was then adjusted to 9 with Several fractions obtained from reversed-phase HPLC of concentrated ammonium hydroxide to free the bases, then control extracts inhibited [3H}Ro 15-1788 binding (Figs. 1A extracted against 8 volumes of 1-chlorobutane. The organic and 2). Fractions eluted with the TFA/acetonitrile gradient layer was retained, and the 1-chlorobutane was evaporated contained low levels of inhibitory activity, which had reten- under vacuum at 50TC. Three to five grams of tissue was A. CTRL nR 2 routinely extracted for quantitation by radioreceptor assay, o'°o6 -I ~ ~ ~ ~ whereas 19-30 g of brain was extracted for mass spectral analysis. All glassware was siliconized and was either dis- carded or acid-washed after use. Chromatography. Extracts were purified using two HPLC techniques. Samples were applied to either a Novapak C18 reverse-phase cartridge in a RCM-100 radial compression u.02 module or a gBondapak C18 (7.8 x 300 mm) reverse-phase column (Waters/Millipore). Samples applied to the Novapak column were eluted isocratically with 40% 10 mM NH4- CO2H/60% methanol (pH 4) at a rate of 2 ml/min for 30 min. 0.00 - Fractions were collected every 18 sec. Absorbance was monitored at 229 nm. The column was then washed with 30 0 20 40 60 80 ml of 100% methanol and reequilibrated with 30 ml of the mobile phase. The second elution technique used the 1LBondapak column and a gradient of 90% trifluoroacetic acid B. ~~~~~~~~~HE ~ 20o L. (TFA, 0.143% vol/vol)/10% acetonitrile (solution A) and 10% TFA/90% acetonitrile (solution B), developed at a rate of 0-60% solution B over 120 min at a flow rate of 1 ml/min. Fractions were collected every minute. At the end of each D I15 run, the column was washed with 120 ml of 10% TFA/90%o 0 acetonitrile and reequilibrated with 60 ml of 90% TFA/10% cl, I ~~~~~~~~~~~~A.IJ. 1 acetonitrile. All fractions were dried under vacuum at 450C 'I and stored at -20°C until assayed. Quantitative Analysis. Extracts were analyzed by a radio- receptor assay or by mass spectroscopy. Radioreceptor analysis was performed on each dried fraction by using 0 20 40 60 s0 [3H]Ro 15-1788 as a ligand (8). The retention times of frac- tions that inhibited radioligand binding by 10-90% under C. STDS these standard assay conditions were compared to those of diazepam and N-desmethyldiazepam standards. The amount 0.061 of inhibitory material in each fraction was quantitated by constructing competition curves for known concentrations of 0.04 if these standards assayed under identical conditions. The minimum quantity of diazepam and N-desmethyldiazepam reliably detected by this radioreceptor assay was 0.3 and 0.9 0.02 - DuD ng per assay, respectively. The recovery was determined Ii using the ratio of the known extraction efficiency of the particular BZ to the observed efficiency of the prazepam 0.00 internal standard. The concentration of material determined by the radioreceptor assay was then corrected for this recovery. The mean extraction efficiency for 10-100 ng of 0 20 40 60 R0 diazepam, N-desmethyldiazepam, and prazepam from 1-2 g TIME Inlij of control rat brain was 68 ± 7.2% (n = 13), 68 ± 4.8% (n = 13), and 16 ± 5.3% (n = 11), respectively.
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