The Effects of SB 206284A, a Novel Neuronal Calcium-Channel Antagonist, in Models of Cerebral Ischemia

Abstract

The effects of SB 206284A, 1-[7-(4-benzyloxyphenoxy)heptyl] piperidine hydrochloride, have been investigated in vitro on calcium and sodium currents in rat-cultured dorsal root ganglion (DRG) neurones and potassium-mediated calcium influx in rat synaptosomes. Cardiovascular hemodynamic effects in both anesthetized and conscious rats, and neuroprotective activity in in vivo cerebral ischemia models were also investigated. In the rat DRG cells, SB 206284A caused almost complete block of the sustained inward Ca2+ current (IC50 = 2.4 microM), suggesting that the compound is an effective blocker of slowly inactivating, high-voltage calcium current. SB 206284A reduced locomotor hyperactivity in the gerbil bilateral carotid artery occlusion model without affecting ischemia-induced damage in the hippocampal CA1 region. In the rat middle cerebral artery occlusion model, SB 206284A reduced lesion volume in the posterior forebrain, and in the rat photochemical cortical lesion model, lesion volume was reduced even when treatment was delayed until 4 hours after occlusion. At neuroprotective doses, SB 206284A had no cardiovascular effects. These findings show that SB 206284A is a novel calcium channel antagonist that shows neuroprotective properties.

Neuroprotective effects of a novel broad-spectrum cation channel blocker, LOE 908 MS, on experimental focal ischemia: A multispectral study

“…Therefore, therapeutic strategies against calcium influx are potentially neuroprotective. Many studies have demonstrated that calcium antagonists reduce ischemic lesion volume in experimental stroke models (2)(3)(4)(5)(6). A new compound, (RS)-(3,4-dihydro-6,7-dimethoxyisoquinoline-1-␥1)-2-phenyl-N,N-di-2-(2,3,4-trimethoxyphenyl)ethyl acetamide (LOE 908 MS), is a broad-spectrum cation channel blocker that fully blocks adenosine triphosphate (ATP)-or N-formyl-L-methionyl-L-leucyl-L-phenylalanine-stimulated cation currents at 3 µM (7).…”

Low adjusted serum ionized calcium concentration shortly after birth predicts poor outcome in neonatal hypoxic–ischemic encephalopathy

“…The time at which [Ca 2+ ] s(7.4) was determined was 3.2 ± 2.1 h in group 1 and 4.3 ± 1.8 h in group 2, representing an assessment of multiple organ damage very shortly after birth. The possibility of preventing neuronal injury by blocking the influx of Ca 2+ into neurons by administering a N ‐methyl‐D‐aspartate receptor/channel antagonist (MK‐801) 24,25 or a calcium channel antagonist has been reported 26–28 . Such agents might be required immediately after birth in neonatal HIE patients, because our data suggest a substantial [Ca 2+ ] s decrease almost immediately after hypoxic–ischemic reperfusion injury occurs.…”

LOE 908: A Specific Blocker of Nonselective Cation Channel

“…In this context, therapeutic strategies against Ca 2+ influx are considered to be potentially neuroprotective. Many studies have demonstrated that Ca 2+ antagonists reduce the size of ischemic lesions in experimental stroke models (2,3,15,37). LOE 908 was found to have neuroprotective effects on focal ischemic injury of rat brain induced by temporal (24) or permanent occlusion of middle cerebral artery (12).…”