Voltage-gated cation channel modulators for the treatment of stroke.
Neuronal voltage-gated cation channels regulate the transmembrane flux of calcium, sodium and potassium. Neuronal ischaemia occurring during acute ischaemic stroke results in the breakdown in the normal function of these ion channels, contributing to a series of pathological events leading to cell death. A dramatic increase in the intracellular concentration of calcium during neuronal ischaemia plays a particularly important role in the neurotoxic cascade resulting in stroke-related acute neurodegeneration. One approach to provide therapeutic benefit following ischaemic stroke has been to target neuronal voltage-gated cation channels, and particularly blockers of calcium and sodium channels, for post-stroke neuroprotection. A recent development has been the identification of openers of large-conductance calcium- and voltage-dependent potassium channels (maxi-K channels), which hyperpolarize ischaemic neurons, reduce excitatory amino acid release, and reduce ischaemic calcium entry. Thus far, targeting these voltage-gated cation channels has not yet yielded significant clinical benefit. The reasons for this may involve the lack of small-molecule blockers of many neuronal members of these ion channel families and the design of preclinical stroke models, which do not adequately emulate the clinical condition and hence lack sufficient rigor to predict efficacy in human stroke. Furthermore, there may be a need for changes in clinical trial designs to optimise the selection of patients and the course of drug treatment to protect neurons during all periods of potential neuronal sensitivity to neuro-protectants. Clinical trials may also have to be powered to detect small effect sizes or be focused on patients more likely to respond to a particular therapy. The development of future solutions to these problems should result in an improved probability of success for the treatment of stroke.
Gribkoff
Valentin K
VK
Department of Biology, Scion Pharmaceuticals, Inc., 200 Boston Avenue, Suite 3600, Medford, MA 02155, USA. Valentingribkoff@scionpharma.com
Winquist
Raymond J
RJ
D000818:Animals; D015220:Calcium Channels / Q000502:physiology*; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D024642:Potassium Channels, Voltage-Gated / Q000502:physiology*; D015222:Sodium Channels / Q000502:physiology*; D020521:Stroke / Q000097:blood / Q000188:drug therapy*
D015220:Calcium Channels; D018696:Neuroprotective Agents; D024642:Potassium Channels, Voltage-Gated; D015222:Sodium Channels