Reduction of glutamate release and protection against ischemic brain damage by BW 1003C87

Meldrum, Brian S.; Swan, Jeanette H.; Leach, Michael J.; Millan, M.H.; Gwinn, Ryder P.; Kadota, Koki; Graham, Steven H.; Chen, J.; Simon, Roger P.

doi:10.1016/0006-8993(92)91254-c

Cited by 109 publications

(29 citation statements)

References 23 publications

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“…The assay was performed as previously described (20,21). Crosschopped slices, 0.2 mm thick, from rat brain cortex or striatum of Wistar rats (Boehringer Ingelheim) were randomly distributed into microcentrifuge tubes (equivalent to about 430 g of protein) and incubated for 15 min with or without veratridine (3 M) from Research Biochemicals (Natick, MA) with an Eppendorf model 5437 Thermomixer.…”

Section: Methodsmentioning

confidence: 99%

Potent blockade of sodium channels and protection of brain tissue from ischemia by BIII 890 CL

Carter

Grauert

Pschorn

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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We have synthesized a new benzomorphan derivative, 2R-[2␣,3(S*),6␣]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-3-[2-(phenylmethoxy)propyl]-2,6-methano-3-benzazocin-10-ol hydrochloride (BIII 890 CL), which displaced [ 3 H]batrachotoxinin A-20␣-benzoate from neurotoxin receptor site 2 of the Na ؉ channel in rat brain synaptosomes (IC50 ‫؍‬ 49 nM), but exhibited only low affinity for 65 other receptors and ion channels. BIII 890 CL inhibited Na ؉ channels in cells transfected with type IIA Na ؉ channel ␣ subunits and shifted steadystate inactivation curves to more negative potentials. The IC 50 value for the inactivated Na ؉ channel was much lower (77 nM) than for Na ؉ channels in the resting state (18 M). Point mutations F1764A and Y1771A in transmembrane segment S6 in domain IV of the ␣ subunit reduced the voltage-and frequency-dependent block, findings which suggest that BIII 890 CL binds to the local anesthetic receptor site in the pore. BIII 890 CL inhibited veratridine-induced glutamate release in brain slices, as well as glutamate release and neurotoxicity in cultured cortical neurons. BIII 890 CL (3-30 mg͞kg s.c.) reduced lesion size in mice and rats when administered 5 min after permanent focal cerebral ischemia at doses that did not impair motor coordination. In contrast to many other agents, BIII 890 CL was neuroprotective in both cortical and subcortical regions of the rat brain. Our results demonstrate that BIII 890 CL is a potent, selective, and highly usedependent Na ؉ channel blocker that protects brain tissue from the deleterious effects of focal cerebral ischemia in rodents.

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Section: Methodsmentioning

confidence: 99%

Potent blockade of sodium channels and protection of brain tissue from ischemia by BIII 890 CL

Carter

Grauert

Pschorn

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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“…As lamotrigine, BW1003C87, BW619C89 and riluzole consistently attenuate ischaemia-induced efflux of glutamate (and aspartate in some studies), it is often proposed that inhibition of glutamate exocytosis is the primary action underlying the cerebroprotective effects of these drugs (Meldrum et al, 1992;Graham et al, 1993;Lekieffre and Meldrum, 1993;Chen et al, 1995;Shuaib et al, 1995;Tsuchida et al, 1996;unpublished observations of Plotkine et al, cited by Doble, 1996;Bacher and Zornow, 1997). However, this hypothesis conflicts with two relevant features, in addition to the considerations detailed in the above sections.…”

Section: Are Cerebroprotective Effects Of Use-dependent Na÷-channel Bmentioning

confidence: 77%

Glutamate release inhibitors: A critical assessment of their action mechanism

Obrenovitch¹,

Urenjak

1998

Amino Acids

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A number of important experimental data do not support the widespread hypothesis that Na(+)-channels block is cerebroprotective, essentially because it reduces presynaptic glutamate release: (i) the inhibition of exocytosis by these compounds is not specific to glutamate; (ii) aspartate efflux produced by various stimuli was also reduced, but aspartate cannot be released by exocytosis because it is not concentrated within presynaptic vesicles; and (iii) glutamate accumulated extracellularly during ischaemic or traumatic insult to the CNS is mainly of cytosolic origin. As an alternative, we propose that use-dependent Na(+)-channel blockers enhance the resistance of nerve cells to insults, primarily by decreasing their energy demand, and that reduced efflux of glutamate and other compounds is a consequence of attenuated cellular stress.

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“…BW1003C87 [5-(2,3,5-trichlorophenyl)-2,4-diaminopyrimidine ethane sulphonate] and BW619C89 [4-amino-2-(4-methyl-l-piperazinyl)-5-(2,3,5-trichlorophenyl pyrimidine)], structurally related to lamotrigine, potently reduced tissue injury subsequent to global and focal ischaemia (Meldrum et al, 1992;Leach et al, 1993;Lekieffre and Meldrum, 1993;Smith et al, 1993;Graham et al, 1993Graham et al, , 1994Gilland et al, 1994) and both analogues appear more potent neuroprotectors than lamotrigine. Besides their "anti-ischaemic" effects, BW1003C87 and BW619C89 protected against brain injury induced in rats by lateral fluid percussion, reducing regional edema, astrocytic activation, neuronal loss and neurological deficit (Sun and Faden, 1995;Okiyama et al, 1995).…”

Section: "Novel" Neuroprotective Drugs Acting On Voltage-gated Na÷-cmentioning

confidence: 98%

“…Although these compounds are often referred to as (presynaptic) glutamate release inhibitors (Leach et al, 1986;1993;Meldrum et al, 1992;Graham et al, 1993;Schulz et al, 1996), ligand-binding experiments with rat brain synaptosomes (Cheung et al, 1992) and voltage-clamp recordings with cultured neurons and recombinant rat brain type IIa Na +-channels expressed in CHO cells (Cheung et al, 1992;Lang et al, 1993;Lees and Leach, 1993;Xie et al, 1995;Xie and Garthwaite, 1996) show that their actions actually originates from use-dependent inhibition of Na + conductance, presumably by stabilization of the Na+-channel in its inactivation state.…”

Section: "Novel" Neuroprotective Drugs Acting On Voltage-gated Na÷-cmentioning

confidence: 99%

Neuroprotection ? rationale for pharmacological modulation of Na+-channels

Urenjak

Obrenovitch²

1998

Amino Acids

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The primary factor detrimental to neurons in neurological disorders associated with deficient oxygen supply or mitochondrial dysfunction is insufficient ATP production relative to their requirement. As a large part of the energy consumed by brain cells is used for maintenance of the Na+ gradient across the cellular membrane, reduction of energy demand by down-modulation of voltage-gated Na(+)-channels is a rational strategy for neuroprotection. In addition, preservation of the inward Na+ gradient may be beneficial because it is an essential driving force for vital ion exchanges and transport mechanisms such as Ca2+ homeostasis and neurotransmitter uptake.

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Reduction of glutamate release and protection against ischemic brain damage by BW 1003C87

Cited by 109 publications

References 23 publications

Potent blockade of sodium channels and protection of brain tissue from ischemia by BIII 890 CL

Potent blockade of sodium channels and protection of brain tissue from ischemia by BIII 890 CL

Glutamate release inhibitors: A critical assessment of their action mechanism

Neuroprotection ? rationale for pharmacological modulation of Na+-channels

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