title: 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.
abstract: 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 (IC(50), 2.5-3.5 nM) and selectivity for the rat and human PBR and potently inhibits the in vivo binding of [(3)H]alpidem to PBR in the rat brain and spleen after oral or i.p. administration (ID(50), 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).
authors.affiliation: Discovery Research, Central Nervous System Research Department, Sanofi-Synthélabo Recherche, 31 avenue P. Vaillant-Couturier, 92225 Bagneux Cedex, France. badia.ferzaz@sanofi-synthelabo.com
authors.forename: Badia
authors.initials: B
authors.lastname: Ferzaz
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Brault
authors.forename: Genevieve
authors.initials: G
authors.lastname: Bourliaud
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Robert
authors.forename: Gilles
authors.initials: G
authors.lastname: Poughon
authors.forename: Yves
authors.initials: Y
authors.lastname: Claustre
authors.forename: Franck
authors.initials: F
authors.lastname: Marguet
authors.forename: Philippe
authors.initials: P
authors.lastname: Liere
authors.forename: Michael
authors.initials: M
authors.lastname: Schumacher
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Nowicki
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Fournier
authors.forename: Benoit
authors.initials: B
authors.lastname: Marabout
authors.forename: Mireille
authors.initials: M
authors.lastname: Sevrin
authors.forename: Pascal
authors.initials: P
authors.lastname: George
authors.forename: Philippe
authors.initials: P
authors.lastname: Soubrie
authors.forename: Jesus
authors.initials: J
authors.lastname: Benavides
authors.forename: Bernard
authors.initials: B
authors.lastname: Scatton
mesh_terms: D000081:Acetamides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D000375:Aging / Q000187:drug effects / Q000502:physiology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism; D019771:Axotomy; D001667:Binding, Competitive; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D005154:Facial Nerve / Q000187:drug effects / Q000378:metabolism; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D006801:Humans; D007093:Imidazoles / Q000378:metabolism; D007211:Indoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D009046:Motor Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011724:Pyridazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011725:Pyridines / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism
chemical_list: D000081:Acetamides; D014151:Anti-Anxiety Agents; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D007093:Imidazoles; D007211:Indoles; D008024:Ligands; D018696:Neuroprotective Agents; D011724:Pyridazines; D011725:Pyridines; D011963:Receptors, GABA-A; C456740:SSR180575; C052036:alpidem