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Vol. 301, Issue 3, 1067-1078, June 2002

SSR180575 (7-Chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide), a Peripheral Benzodiazepine Receptor Ligand, Promotes Neuronal Survival and Repair

Badia Ferzaz, Emmanuel Brault, Genevieve Bourliaud, Jean-Pierre Robert, Gilles Poughon, Yves Claustre, Franck Marguet, Philippe Liere, Michael Schumacher, Jean-Pierre Nowicki, Jacqueline Fournier, Benoit Marabout, Mireille Sevrin, Pascal George, Philippe Soubrie, Jesus Benavides and Bernard Scatton

Sanofi-Synthélabo Recherche, Discovery Research, Central Nervous System Research Department, Bagneux Cedex, France (B.F., E.B., G.B., J.P.R., G.P., Y.C., F.M., J.P.N., J.F., P.G., P.S., J.B., B.S.); and Institut National de la Santé et de la Recherche Médicale U488, Steroids and Nervous System Laboratory, Le Kremlin-Bicêtre Cedex, France (P.L., M.S.)

In the present study, we have investigated the potential neuroprotective effects of a novel peripheral benzodiazepine binding site (PBR) ligand, 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide (SSR180575), in models of central and peripheral neurodegeneration in vivo and its effect on steroid concentrations in plasma and nervous tissue. SSR180575 shows high affinity (IC50, 2.5-3.5 nM) and selectivity for the rat and human PBR and potently inhibits the in vivo binding of [3H]alpidem to PBR in the rat brain and spleen after oral or i.p. administration (ID50, 0.1-0.3 mg/kg). In an experimental model of motoneuron degeneration induced by facial nerve axotomy in the immature rat, SSR180575 given i.p. or orally for 8 days rescued facial motoneurons, increasing their survival by 40 to 72% at 6 and 10 mg/kg p.o. b.i.d. Moreover, in this model, SSR180575 (10 mg/kg p.o. b.i.d.) increased by 87% the number of motoneurons immunoreactive to peripherin, a type III intermediate filament, whose expression is up-regulated during nerve regeneration. SSR180575 also improved functional recovery in acrylamide-induced neuropathy in the rat when given therapeutically at 2.5 to 10 mg/kg/day p.o. Furthermore, SSR180575 (3 mg/kg i.p. b.i.d.) accelerated functional recovery of the blink reflex after local injury of the facial nerve in the rat. SSR180575 increased pregnenolone accumulation in the brain and sciatic nerve (+100% at 3 mg/kg i.p.), suggesting that its neuroprotective effects are steroid-mediated. These results indicate that PBR ligands (e.g., SSR180575) promote neuronal survival and repair in axotomy and neuropathy models and have potential for the treatment of neurodegenerative diseases (e.g., peripheral neuropathies or amyotrophic lateral sclerosis).

0022-3565/02/3013-1067$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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Copyright © 2002 by the American Society for Pharmacology and Experimental Therapeutics.