SB 201823-A, a neuronal Ca2+ antagonist is neuroprotective in two models of cerebral ischaemia

Benham, C.D.; Brown, Tom H.; Cooper, David G.; Evans, Marcus; Harries, Mark H; Herdon, Hugh J.; Meakin, Jackie; Murkitt, K. L.; Patel, Sara; Roberts, Jennifer; Rothaul, Alan L.; Smith, S. J.; Wood, Nigel I.; Hunter, A. Jacqueline

doi:10.1016/0028-3908(93)90019-y

Cited by 48 publications

(8 citation statements)

References 16 publications

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“…These concentrations are lower than the IC50 values reported in the preceding paper (Fletcher et al, 1995) DeCoster et al, 1995) may reflect, at least in part, blockade of multiple subtypes of HVA Ca2" channels, particularly given recent reports that novel broad-spectrum Ca2" channel blockers possess neuroprotective properties (e.g. Benham et al, 1993). Carbetapentane, for example, attenuates glutamate-induced neurotoxicity in rat cultured cortical neurones with an EC50 value of 46.3 uM (DeCoster et al, 1995), similar to the IC50 value obtained in the present study for Ca2" channel blockade in voltage-clamped neurones (40.5 gM; Table 1).…”

Section: Electrophysiological Studiesmentioning

confidence: 65%

Blockade by sigma site ligands of high voltage‐activated Ca²⁺ channels in rat and mouse cultured hippocampal pyramidal neurones

Church

Fletcher

1995

British J Pharmacology

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1 The effects of a series of structurally-dissimilar ai site ligands were examined on high voltage-activated Ca2`channel activity in two preparations of cultured hippocampal pyramidal neurones. 2 In mouse hippocampal neurones under whole-cell voltage-clamp, voltage-activated Ca2`channel currents carried by barium ions (IB.) were reduced with the rank order (IC" values in (18)>opipramol (32)>carbetapentane (40) (42)>caramiphen (47)>dextromethorphan (73). At the highest concentrations tested, the compounds almost abolished IB. in the absence of any other pharmacological agent.3 The current-voltage characteristics of the whole-cell IB. were unaffected by the test compounds. The drug-induced block was rapid in onset and offset, with the exceptions of carbetapentane and caramiphen where full block was achieved only after two to three voltage-activated currents and was associated with an apparent increase in the rate of inactivation of IB.4 In rat hippocampal neurones loaded with the Ca2"-sensitive dye Fura-2, rises in intracellular free Ca2+ concentration evoked by transient exposure to 50 mM K+-containing medium, either in the absence or in the presence of 10 pM nifedipine (to block L-type high voltage-activated Ca2`channels), were also reversibly attenuated by the ai ligands. The rank order potencies for the compounds in these experimental paradigms were similar to that observed for blockade of IB, in the electrophysiological studies. 5These results indicate that, at micromolar concentrations, the compounds tested block multiple subtypes of high voltage-activated Ca2" channels. These actions, which do not appear to be mediated by high-affinity a binding sites, may play a role in some of the functional effects previously described for the compounds.

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Section: Electrophysiological Studiesmentioning

confidence: 65%

Blockade by sigma site ligands of high voltage‐activated Ca²⁺ channels in rat and mouse cultured hippocampal pyramidal neurones

Church

Fletcher

1995

British J Pharmacology

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“…However, several reports indicate that selective blockers of the N‐type Ca channels may protect against delayed neuronal death after global ischaemia (Valentino et al . 1993), and non‐specific Ca channel blockers have shown effect in various models of focal ischaemia (Benham et al . 1993; Møller et al .…”

Section: Discussionmentioning

confidence: 99%

CNTF inhibits high voltage activated Ca²⁺ currents in fetal mouse cortical neurones

Holm¹,

Christophersen²,

Hounsgaard³

et al. 2002

Journal of Neurochemistry

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Neurotrophic factors yield neuroprotection by mechanisms that may be related to their effects as inhibitors of apoptosis as well as their effects on ion channels. The effect of ciliary neurotrophic factor (CNTF) on high-threshold voltage-activated Ca channels in cultured fetal mouse brain cortical neurones was investigated. Addition of CNTF into serum-free growth medium resulted in delayed reduction of the Ca 2+ currents. The currents decreased to 50% after 4 h and stabilized at this level during incubation with CNTF for 48 h. Following removal of CNTF the inhibition was completely reversed after 18 h. CNTF reduced the current of all pharmacological subtypes of Ca channels as shown by use of selective blockers of L, N, and P/Q type Ca channels (nifedipine, x-conotoxin MVIIA, x-agatoxin IVA). The Ca channel depression was mediated via the CNTF receptor, because enzymatic cleavage of the a-subunit glycerophosphatidylinositol anchor of the receptor eliminated the response. The CNTF effect was not elicited through pertussis toxin-sensitive G proteins. Other neurotrophic factors like neurotrophin-3 and insulin-like growth factor-I had no effect on the Ca 2+ currents. These results may have important implications for the possible functions of CNTF in the nervous system, such as altered synaptic activity, neuronal excitability and susceptibility to brain ischaemia.

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“…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).…”

mentioning

confidence: 99%

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

Carano

Irie

et al. 1999

J. Magn. Reson. Imaging

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SB 201823-A, a neuronal Ca2+ antagonist is neuroprotective in two models of cerebral ischaemia

Cited by 48 publications

References 16 publications

Blockade by sigma site ligands of high voltage‐activated Ca²⁺ channels in rat and mouse cultured hippocampal pyramidal neurones

Blockade by sigma site ligands of high voltage‐activated Ca²⁺ channels in rat and mouse cultured hippocampal pyramidal neurones

CNTF inhibits high voltage activated Ca²⁺ currents in fetal mouse cortical neurones

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

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SB 201823-A, a neuronal Ca2+ antagonist is neuroprotective in two models of cerebral ischaemia

Cited by 48 publications

References 16 publications

Blockade by sigma site ligands of high voltage‐activated Ca2+ channels in rat and mouse cultured hippocampal pyramidal neurones

Blockade by sigma site ligands of high voltage‐activated Ca2+ channels in rat and mouse cultured hippocampal pyramidal neurones

CNTF inhibits high voltage activated Ca2+ currents in fetal mouse cortical neurones

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

Contact Info

Product

Resources

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Blockade by sigma site ligands of high voltage‐activated Ca²⁺ channels in rat and mouse cultured hippocampal pyramidal neurones

Blockade by sigma site ligands of high voltage‐activated Ca²⁺ channels in rat and mouse cultured hippocampal pyramidal neurones

CNTF inhibits high voltage activated Ca²⁺ currents in fetal mouse cortical neurones