SSR180575 (7-Chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4 H-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…
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From Pharmacological modulation of TSPO in microglia/macrophages and neurons in a chronic neurodegenerative model of prion disease (2023) · cites this paper as [53]
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Self-citation
- Authors
- Ferzaz, B., Brault, E., Bourliaud, G., Robert, J.-P., Poughon, G., Claustre, Y., Marguet, F., Liere, P., Schumacher, M., Nowicki, J.-P., Fournier, J., Marabout, B., Sevrin, M., George, P., Soubrie, P., Benavides, J., & Scatton, B.
- Affiliations
- Sanofi (France) (FR)
- ORCID
- Scatton, Bernard
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2002-06
- Volume
- 301
- Issue
- 3
- Pages
- 1067-1078
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2155301275
- Cited by
- 126
- References
- 41
- Citations by year
- 2024: 5 · 2023: 2 · 2022: 5 · 2021: 2 · 2020: 5 · 2019: 4 · 2017: 7 · 2016: 11 · 2015: 3 · 2014: 4 · 2013: 6 · 2012: 3
- FWCI
- 5.38
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pharmacological Receptor Mechanisms and Effects
- Keywords
- translocator protein (TSPO), neuroprotection, motor neuron degeneration, facial nerve axotomy, pregnenolone, peripherin, nerve regeneration, functional recovery, blink reflex
- MeSH terms
- Acetamides, Aging, Animals, Binding, Competitive, Cell Survival, Facial Nerve, Humans, Imidazoles, Indoles, Ligands, Male, Motor Neurons, Pyridazines, Pyridines, Receptors, GABA-A, Anti-Anxiety Agents, Rats, Sprague-Dawley, Neuroprotective Agents, Axotomy, Rats, GABA-A Receptor Agonists, GABA-A Receptor Antagonists
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