Daniel L. Small

Ion channels are membrane proteins that flicker open and shut to regulate the flow of ions down their electrochemical gradient across the membrane and consequently regulate cellular excitability. Every living cell expresses ion channels, as they are critical life-sustaining proteins. Ion channels are generally either activated by voltage or by ligand interaction. For each group of ion channels the channels’ molecular biology and biophysics will be introduced and the pharmacology of that group of channels will be reviewed. The in vitro and in vivo literature will be reviewed and, for ion channel groups in which clinical trials have been conducted, the efficacy and therapeutic potential of the neuroprotective compounds will be reviewed. A large part of this article will deal with glutamate receptors, focusing specifically on N-methyl-D-aspartate (NMDA) receptors. Although the outcome of clinical trials for NMDA receptor antagonists as therapeutics for acute stroke is disappointing, the culmination of these failed trials was preceded by a decade of efforts to develop these agents. Sodium and calcium channel antagonists will be reviewed and the newly emerging efforts to develop therapeutics targeting potassium channels will be discussed. The future development of stroke therapeutics targeting ion channels will be discussed in the context of the failures of the last decade in hopes that this decade will yield successful stroke therapeutics.

The MIN6 pancreatic ji-cell line responds to glutamate, tx-amino-3-hydroxy-5-methyl-4-isoxazoleproplonic acid (AMPA) and kainate, but not N-methyl-D-aspartate (NMDA) or 1 S,3R-trans-ACPD, with increases in [Ca²⁺]_i. This correlates with MIN6 expression of AMP A receptor subunits (CluRI-4) but only weak expression of NMDA NR2 receptor subunits, as determined by reverse transcriptase polymerase chain reaction (RT-PCR). Pharmacological characterization of the MIN6 AMPA receptors showed that AMPA- triggered [Ca²⁺], responses were blocked by GYKI 52466, 6-cyano-7-nitroquinoxallne-2,3-dione (CNQX) and pentobarbital. AMPA-triggered [Ca²⁺]_i responses were also blocked in Na+-free medium and by the voltage-sensitive Ca²⁺ channel antagonist La³⁺. Unlike cortical neuronal cultures, which show a loss of membrane-associated protein kinase C (PKC) activity and die in response to excitatory amino acid exposure, glutamate was not toxic to MIN6 cells and it did not decrease PKC activity. These studies indicate that MIN6 cells possess Ca²⁺-impermeable AMPA receptors that secondarily allow Ca²⁺ influx following AMPA-induced depolarization and that, despite elevating [Ca²⁺]_i, AMPA is not toxic to these cells. The effects of glutamate and glutamate receptor antagonists on pancreatic cells needs to be better understood if these compounds are to be used as therapeutic agents to treat stroke. [Neurol Res 2000; 22: 379-385]

Nippon Shinyaku is developing NS-7, a sodium and calcium channel blocker, as a neuroprotectant for use following cerebral infarction [249336]. It entered phase I trials for the treatment of acute stage cerebrovascular disorders in 1997 [271963]. As of November 1999, Nippon Shinyaku was preparing to start phase II studies in Japan [347972]. In November 1999, Nippon Shinyaku granted Schering exclusive developing and marketing rights to NS-7. Schering will conduct clinical trials in Europe and the US [347972].