Abstract
Recent experimental evidence has suggested that peripheral benzodiazepine receptors (PBR) may play a role in epilepsy and antiepileptic drug action. Since PBR are also present in circulating lymphocytes, and may interact with anticonvulsant drugs, this study was designed to look for possible modifications of these receptors and their endogenous ligand diazepam binding inhibitor (DBI) in the lymphocytes of epileptic patients treated with various drugs. PBR levels were 50% to 80% higher in patients treated with carbamazepine, phenobarbital and valproic acid than in controls and untreated epileptics. DBI levels were significantly increased in the lymphocytes of untreated patients, and showed only a slight further increase after anticonvulsant therapy.
The possibility that PBR and DBI modifications in the lymphocytes of epileptic patients may be linked to the immunological alterations reported in these patients and/or may represent possible markers of neurochemical modifications in the central nervous system is discussed.
Sommario
Recenti dati sperimentali hanno evidenziato che i recettori periferici delle benzodiazepine (PBR) possono ricoprire un ruolo nell'epilessia e nell'azione dei farmaci antiepilettici. Poiché i PBR sono presenti anche sui linfociti in circolo, dove è stato dimostrato che possono interagire con i farmaci antiepilettici, abbiamo ricercato le possibili modificazioni di questi recettori e del loro ligando endogeno diazepam binding inhibitor (DBI) in linfociti di pazienti epilettici trattati con farmaci diversi. La densità recettoriale dei PBR risultava aumentata del 50–80% in pazienti trattati con carbamazepina, fenobarbital, ed acido valproico, rispetto ai controlli ed ai pazienti epilettici non trattati. Le concentrazioni di DBI risultavano significativamente aumentate nei linfociti di pazienti epilettici non trattati e, mostravano solo un limitato aumento dopo terapia.
È tutt'ora in discussione la possibilità che le modificazioni di PBR e DBI nei linfociti di pazienti epilettici possano essere correlate alle alterazioni immunologiche segnalate in questi pazienti e/o possano essere considerate come possibili indicatori di modificazioni neurochimiche presenti nel sistema nervoso centrale.
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References
Benavides J., Guillox F., Allam D.E. et al.:Opposite effects of an agonist, RO 5-4864, and an antagonist, PK 11185, of the peripheral type benzodiazepine binding sites on audiogenic seizures in DBA/2J mice. Life, Sci. 34: 2613–2620, 1984.
Berkovich A., Ferrarese C., Cavaletti G., Alho H., Marzorati C., Bianchi G., Guidotti A., Costa E.:Topology of two DBI receptors in human lymphocytes. Life Sciences, 52: 1265–1277, 1993.
Besman M.J., Yanagibashi L., Lee T.D., Kawamura M., Hall P.F., Shively J.E.:Identification of des-(Gly-Ile)-endozepine as an effector of corticotropin-dependent adrenal steroidogenesis: stimulation of cholesterol delivery is mediated by the peripheral benzodiazepine receptor. Proc. Natl. Acad. Sci. (U.S.A.), 86: 4897–4901, 1989.
Bessler H., Weizman R., Gavish M., Notti I., Djaldetti M.:Immunomodulatory effect of peripheral benzodiazepine receptor ligands on human mononuclear cells. J. Neuroimmunol., 38: 19–26, 1992.
Boyum A.:Separation of white blood cells. Nature, 204: 793–828, 1964.
Commission on Classification and Terminology of the International League Against Epilepsy.Proposal for Revised Classification of Epilepsies and Epileptic Syndromes. Epilepsia 30(4): 389–399, 1989.
Dosch H.M., Jason J., Gelfand E.W.:Transient antibody deficiency and abnormal T-suppressor cell induced by phenytoin. N. Engl. J. Med. 306: 406, 1982.
Eeg-Olofsson O., Prchal J.F., Andermann F.:Abnormalities of T-lymphocyte subsets in epileptic patients. Acta Neurol. Scand. 72: 140–144, 1985.
Ferrarese C., Alho H., Guidotti A., Costa E.:Colocatization and co-release of GABA and putative allosteric modulators of GABA receptors. Neuropharmacology 26: 1011–1018, 1987.
Ferrarese C., Appollonio I., Bianchi G., Frigo M., Marzorati C., Pecora N., Perego M., Pierpaoli C., Frattola L.:Benzodiazepine receptors and diazepam binding inhibitor: a possible link between stress, anxiety and the immune system. Psychoneuroendocrinology 18: 3–22, 1993.
Ferrarese C., Appollonio I., Frigo M., Perego M., Piolti R., Trabucchi M., Frattola L.:Decreased density of benzodiazepine receptors in lymphocytes of anxious patients: reversal after chronic diazepam treatment. Acta Psychiatr. Scand. 82: 169–173, 1990.
Ferrarese C., Appollonio I., Frigo M., Piloti R., Tamma F., Frattola L.:Distribution of a putative endogenous modulator of the GABAergic system in human brain. Neurology. 39: 443–445, 1989.
Ferrarese C., Marzorati C., Perego M., Bianchi G., Cavarretta R., Pierpaoli C., Moretti G., Frattola L.:Effect of anticonvulsant drugs on peripheral benzodiazepine receptors of human lymphocytes. Neuropharmacology, 34: 427–431, 1995.
Ferrarese C., Vaccarino F., Alho H., Mellstrom B., Costa E., Guidotti A.:Subcellular location and neuronal release of diazepam binding inhibitor (DBI). J. Neurochem. 48: 1093–1102, 1987.
Ferrero P., Costa E., Conti-Tronconi B., Guidotti A.:A diazepam binding inhibitor (DBI)-like neuropeptide is detected in human brain. Brain Res. 399: 136–142, 1986.
File S.E.:Pro- and anti-convulsant properties of PK 11195, a ligand for benzodiazepine binding sites: development of tolerance. Br. J. Pharmacol. 83: 471–476, 1984.
Gilhus N.E., Matre R.:Carbamazepine effects on mononuclear blood cells in epileptic patients. Acta Neurol. Scand. 74: 181–185, 1986.
Guidotti A., Berkovitch A., Ferrarese C., Santi M.R., Costa E.:Neuronal- glial differential processing of DBI to yield ligands to central or peripheral benzodiazepine recognition sites. In: Sauvanet P., Langer S.Z., Morselli P.L. (Eds.), Imidazopyridines in Sleep Disorders. Raven Press, New York, pp. 25–38, 1988.
Johnson E.W., de Lanerolle N.C., Lim J.H., Sundersan S., Spencer D.D., Mattson R.H., Zoghbi S.S., Baldwin R.M., Hoffer P.B., Seibyl J.P., Innis R.B.:Central and peripheral benzodiazepine receptors: opposite changes in human epileptogenic tissue. Neurology 42: 811–815, 1992.
Larkin J.G., McKee P.J., Thompson G.G., Brodie M.J.:Peripheral benzodiazepine receptors in platelets of epileptic patients. Br. J. Clin. Pharmacol. 36(1): 71–74, 1993.
Liederman D.B., Csernansky J.G., Moses J.A. Jr.:Neuroendocrinology and limbic epilepsy: relationship to psychopathology, seizure variables, and neuropsychological function. Epilepsia 31: 270–274, 1990.
Pacifici R., Paris L., Di Carlo S., Pichini S., Zuccaro P.:Immunologic aspects of carbamazepine treatment in epileptic patients. Epilepsia 32: 122–127, 1991.
Papadopulos V., Guarneri P., Krueger K.E., Guidotti A., Costa E.:Pregnenolone biosynthesis in C6-2B glioma cell mitochondria: regulation by a mitochondrial diazepam binding inhibitor receptor. Proc. Natl. Acad. Sci. (USA), 89: 5113–5117, 1992.
Rocca P., Ferrero P., Gualerzi A., Zanalda E., Maina G., Bergamasco B., Ravizza L.:Peripheral-type benzodiazepine receptors in anxiety disorders. Acta Psychiatr. Scand. 84: 537–544, 1991.
Ruff M.R., Pert C.B., Weber R.J., Wahl L.M., Wahl S.M., Paul S.M.:Benzodiazepine receptor-mediated chemotaxis of human monocytes. Science 229: 1281–1283, 1985.
Strandjord R.E., Johannessen S.I., Aarli J.A.:Serum concentrations of immunoglobulins in patients with epilepsy treated with carbamazepine. Acta Neurol. Scand. 61: 260–263, 1980.
Taupin V., Herbelin A., Descamps-Latscha B., Zavala F.:Endogenous anxiogenic peptide, ODN-diazepam- binding inhibitor, and benzodiazepines enhance the production of interleukin-1 and tumor necrosis factor by human monocytes. Lymphokine and Cytokine Research 10: 7–13, 1991.
Vezzani A., Serafini R., Stasi M.A., Samanin R., Ferrarese C.:Epileptogenic activity of two peptides derived from diazepam binding inhibitor after intrahippocampal injection in rats. Epilepsia 32(5): 597–603, 1991.
Weiss S.R.B., Post R.M.:Contingent tolerance to carbamazepine: a peripheral-type benzodiazepine mechanisms. Eur. J. Pharmacol. 193: 159–163, 1991.
Weiss S.R.B., Post R.M., Patel J., Marangos P.J.:Differential mediation of the anticonvulsant effects of carbamazepine and diazepam. Life Sci. 36: 2413, 1985.
Weizman A., Tanne Z., Karp L., Martfeld Y., Tyano S., Gavish M.:Carbamazepine up-regulates the binding of [3H]PK 11195 to platelets of epileptic patients. Eur. J. Pharmacol. 141: 471–474, 1987.
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Supported by the Italian Ministry of Health (Ricerca Finalizzata 1989 of Scientific Institute “E. Medea”, performed, 1991–1994).
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Ferrarese, C., Perego, M., Marzorati, C. et al. Modifications of diazepam binding inhibitor and peripheral benzodiazepine receptors in the lymphocytes of epileptic patients. Ital J Neuro Sci 17, 141–145 (1996). https://doi.org/10.1007/BF02000845
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DOI: https://doi.org/10.1007/BF02000845