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,N,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 (ϩ100% 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).

Therapeutic approaches to peripheral neuropathy based on neuroactive steroids

“…Indeed, it has been demonstrated that a PBR ligand, SSR180575, is able to increase the survival of facial nerve motoneurons after axotomy and the regeneration of peripheral nerves [18]. Another PBR ligand, Ro5-4864, increases concentrations of pregnenolone in the rat sciatic nerve and its expression is increased in Schwann cells and in dorsal root ganglion neurons after nerve lesions and return to normal levels when regeneration is complete.…”

Role of Peripheral Benzodiazepine Receptors in Mitochondrial, Cellular, and Cardiac Damage Induced by Oxidative Stress and Ischemia-Reperfusion

“…We have investigated these questions by studying the effects of the potent, new, selective PBR ligand SSR180575 (Ferzaz et al, 2002) in mitochondrial and cellular models of oxidative stress and in isolated tissue or in vivo cardiac ischemia-reperfusion models.…”

Current status and future perspectives: TSPO in steroid neuroendocrinology

“…Moreover, there is also no correlation between the levels of TSPO expression and neurosteroid production capability within different regions of the brain. In support, some studies using in vivo models indicate that despite neurosteroid induction in the CNS, TSPO-binding drugs failed to induce steroid synthesis in high TSPO-expressing organs like the adrenal , Ferzaz et al 2002, Verleye et al 2005. Therefore, the assumption that targeting TSPO could result in a robust cellular steroidogenic response might be a too simplistic view.…”