Abstract
During ischemic stroke, neurons at risk are exposed to pathologically high levels of intracellular calcium (Ca++), initiating a fatal biochemical cascade. To protect these neurons, we have developed openers of large-conductance, Ca++-activated (maxi-K or BK) potassium channels, thereby augmenting an endogenous mechanism for regulating Ca++ entry and membrane potential. The novel fluoro-oxindoles BMS-204352 and racemic compound 1 are potent, effective and uniquely Ca++-sensitive openers of maxi-K channels. In rat models of permanent large-vessel stroke, BMS-204352 provided significant levels of cortical neuroprotection when administered two hours after the onset of occlusion, but had no effects on blood pressure or cerebral blood flow. This novel approach may restrict Ca++ entry in neurons at risk while having minimal side effects.
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References
Williams, G.R., Jiang, J.G., Matchar, D.B. & Samsa, G.P. Incidence and occurrence of total (first-ever and recurrent) stroke. Stroke 30, 2523–2528 (1999).
Fisher, M. Antithrombotic and thrombolytic therapy for ischemic stroke. J. Thromb. 7, 165–169 (1999).
Schlaug, G. et al., The ischemic penumbra: operationally defined by diffusion and perfusion MRI. Neurology 53, 1528–1537 (1999).
Dirnagl, U., Iadecola, C. & Moskowitz, M.A. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 22, 391–397 (1999).
Jain, K.K. Neuroprotection in cerebrovascular disease. Exp. Opin. Invest. Drugs 9, 695–711 (2000).
De Keyser, J., Sutter, G. & Luiten, P.G. Clinical trials with neuroprotective drugs in acute ischaemic stroke: are we doing the right thing? Trends Neurosci. 22, 535–540 (1999).
Choi, D.W. Excitotoxic cell death J. Neurobiol. 23, 1261–1276 (1992).
Choi, D.W. Calcium: still center-stage in hypoxic-ischemic neuronal death. Trends Neurosci. 18, 58–60 (1995).
Kristian, T. & Siesjo, B.K. Calcium in ischemic cell death. Stroke 29, 705–718 (1998).
Gribkoff, V.K., Starrett, J.E. Jr. & Dworetzky, S.I. The pharmacology and molecular biology of large-conductance calcium-activated (BK) potassium channels. Adv. Pharmacol. 37, 319–348 (1997).
Meera, P., Wallner, M., Song, M. & Toro, L. Large conductance voltage- and calcium-dependent K+ channel, a distinct member of voltage-dependent ion channels with seven N-terminal transmembrane segments (S0-S6), an extracellular N terminus, and an intracellular (S9-S10) C terminus. Proc. Natl. Acad. Sci. USA 94, 14066–14071 (1997).
Schreiber, M., Yuan, A. & Salkoff, L. Transplantable sites confer calcium sensitivity to BK channels. Nature Neurosci. 2, 416–421 (1999).
Dworetzky, S.I., Trojnacki, J.T. & Gribkoff, V.K. Cloning and expression of a human large-conductance calcium-activated potassium channel. Brain Res. Mol. Brain Res. 27, 189–193 (1994).
McCobb, D.P. et al. A human calcium-activated potassium channel gene expressed in vascular smooth muscle. Am. J. Physiol. 269, H767–H777 (1995).
Tseng-Crank, J. et al. Cloning, expression, and distribution of functionally distinct Ca(2+)-activated K+ channel isoforms from human brain. Neuron 13, 1315–1330 (1994).
Dworetzky, S.I. et al. Phenotypic alteration of a human BK (hSlo) channel by hSlo β subunit coexpression: changes in blocker sensitivity, activation/relaxation and inactivation kinetics, and protein kinase A modulation. J. Neurosci. 16, 4543–4550 (1996).
Brenner, R., Jegla, T.J., Wickenden, A., Liu, Y. & Aldrich, R.W. Cloning and functional characterization of novel large conductance calcium-activated potassium channel β subunits, hKCNMB3 and hKCNMB4. J. Biol. Chem. 275, 6453–6461 (2000).
Joiner, W. et al. Formation of intermediate-conductance calcium-activated potassium channels by interaction of Slack and Slo subunits. Nature Neurosci. 1, 462–469 (1998).
McManus, O. Calcium-activated potassium channels: regulation by calcium. J. Bioenerg. Biomembr. 23, 537–560 (1991).
Wann, K.T. & Richards, C.D. Properties of single calcium-activated potassium channels of large conductance in rat hippocampal neurons in culture. Eur. J. Neurosci. 6, 607–617 (1994).
Juhng, K.N. et al. Induction of seizures by the potent K+ channel-blocking scorpion venom peptide toxins tityustoxin-K(α) and pandinustoxin-K(α). Epilepsy Res. 34, 177–186 (1999).
Gribkoff, V.K. et al. Effects of channel modulators on cloned large-conductance calcium-activated potassium channels. Mol. Pharmacol. 50, 206–217 (1996).
Starrett, J.E. Jr., Dworetzky, S.I. & Gribkoff, V.K. Modulators of large-conductance calcium-activated potassium (BK) channels as potential therapeutic targets. Curr. Pharm. Design 2, 413–428 (1996).
Hewawasam, P., Meanwell, N.A. & Gribkoff, V.K. 3-substituted oxindole derivatives as potassium channel modulators. US Patent #5,565,483 (1996).
Hewawasam, P., Meanwell, N.A. & Gribkoff, V.K. 3-substituted oxindole derivatives as potassium channel modulators. US Patent #5,602,169 (1997).
McKay, M.C. et al. Opening of large-conductance calcium-activated potassium channels by the substituted benzimidazolone NS004. J. Neurophysiol. 71, 1873–1882 (1994).
Strøbæk, D. et al. Modulation of the Ca2+-dependent K+ channel, hslo, by the substituted diphenylurea NS 1608, paxilline and internal Ca2+. Neuropharmacology 35, 903–914 (1996).
Knaus, H.-G. et al. Distribution of high-conductance Ca2+-activated K+ channels in rat brain: targeting to axons and nerve terminals. J. Neurosci. 16, 955–963 (1996).
Gribkoff, V.K. & Starrett, J.E., Jr. An assessment of the present and future roles of non-ligand gated ion channel modulators as CNS therapeutics. Exp. Opin. Pharmacother. 1, 61–70 (1999).
Vang, C., Dunbabin, D. & Kilpatrick, D. Effects of spontaneous recanalization on functional and electrophysiological recovery in acute ischemic stroke. Stroke 30, 2119–2125 (1999).
Bowler, J.V., Wade, J.P., Jones, B.E., Nijran, K.S. & Steiner, T.J. Natural history of the spontaneous reperfusion of human cerebral infarcts as assessed by 99mTc HMPAO SPECT. J. Neurol. Neurosurg. Psychiatry 64, 90–97 (1998).
Gillard, J.H., Oliverio, P.J., Barker, P.B., Oppenheimer, S.M. & Bryan, R.N. MR angiography in acute cerebral ischemia of the anterior circulation: a preliminary report. Am. J. Neuroradiol. 18, 343–50 (1997)
Fisher, M. for the Stroke Therapy Academic Industry Roundtable. Special report: Recommendations for standards regarding preclinical neuroprotective and resorative drug treatment. Stroke 30, 2752–2758 (1999).
Penner, R. A practical guide to patch clamping. In Single Channel Recording 2nd Ed. (eds. Sakmann, B. & Neher, E.) 3–30 (Plenum, New York, 1995).
Butler, A., Tsunoda, S., McCobb, D.P., Wei, A. & Salkoff, L. mSlo, a complex mouse gene encoding “maxi” calcium-activated potassium channels. Science 261, 221–224 (1993).
Willette, R.N., Sauermelch, C., Ezekiel, M., Feuerstein, G. & Ohlstein, E.H. Effect of endothelin on cortical microvascular perfusion in rats. Stroke 21, 451–458 (1990).
Tamura, A., Graham, D.I., McCulloch, J. & Teasdale, G.M. Focal cerebral ischaemia in the rat: 1. Description of technique and early neuropathological consequences following middle cerebral artery occlusion. J. Cerebr. Blood Flow Metab. 1, 53–60 (1981).
Brint, S., Jacewicz, M., Kiessling, M., Tanabe, J. & Pulsinelli, W. Focal brain ischemia in the rat: Methods for reproducible neocortical infarction using tandem occlusion of the distal middle cerebral and ipsilateral common carotid arteries. J. Cerebr. Blood Flow Metab. 8, 474–485 (1988).
Li, F., Sotak, C.H. & Fisher, M. Temporal evolution of ischemic injury evaluated with diffusion-, perfusion-, and T2-weighted MRI. Neurology 54, 689–696 (2000).
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Gribkoff, V., Starrett, J., Dworetzky, S. et al. Targeting acute ischemic stroke with a calcium-sensitive opener of maxi-K potassium channels. Nat Med 7, 471–477 (2001). https://doi.org/10.1038/86546
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DOI: https://doi.org/10.1038/86546
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