ns-309 and Brain-Ischemia

Exacerbated activation of glutamate receptor-coupled calcium channels and subsequent increase in intracellular calcium ([Ca2+]i) are established hallmarks of neuronal cell death in acute and chronic neurological diseases. Here we show that pathological [Ca2+]i deregulation occurring after glutamate receptor stimulation is effectively modulated by small conductance calcium-activated potassium (KCa2) channels. We found that neuronal excitotoxicity was associated with a rapid downregulation of KCa2.2 channels within 3 h after the onset of glutamate exposure. Activation of KCa2 channels preserved KCa2 expression and significantly reduced pathological increases in [Ca2+]i providing robust neuroprotection in vitro and in vivo. These data suggest a critical role for KCa2 channels in excitotoxic neuronal cell death and propose their activation as potential therapeutic strategy for the treatment of acute and chronic neurodegenerative disorders.

Topics: Animals; Brain Ischemia; Calcium Signaling; Cell Culture Techniques; Cell Death; Cells, Cultured; Excitatory Amino Acid Agonists; Glutamic Acid; Indoles; Infarction, Middle Cerebral Artery; Male; Mice; Mice, Inbred C57BL; N-Methylaspartate; Neurons; Neuroprotective Agents; Oximes; Small-Conductance Calcium-Activated Potassium Channels; Transcription, Genetic