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.
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).
Ferzaz
Badia
B
Discovery Research, Central Nervous System Research Department, Sanofi-Synthélabo Recherche, 31 avenue P. Vaillant-Couturier, 92225 Bagneux Cedex, France. badia.ferzaz@sanofi-synthelabo.com
Brault
Emmanuel
E
Bourliaud
Genevieve
G
Robert
Jean-Pierre
JP
Poughon
Gilles
G
Claustre
Yves
Y
Marguet
Franck
F
Liere
Philippe
P
Schumacher
Michael
M
Nowicki
Jean-Pierre
JP
Fournier
Jacqueline
J
Marabout
Benoit
B
Sevrin
Mireille
M
George
Pascal
P
Soubrie
Philippe
P
Benavides
Jesus
J
Scatton
Bernard
B
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
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