Large-conductance Ca2+-activated potassium channels are potently involved in the inverse neurovascular response to spreading depolarization

The impact of dihydropyridine derivatives on the cerebral blood flow response to somatosensory stimulation and spreading depolarization

“…In contrast to LA1011, nimodipine application reduced SD size, in agreement with previous reports applying nimodipine at the concentration used here (Menyhárt et al, 2018;Richter et al, 2002).…”

“…As such, topical application of the pro-inflammatory cytokine TNF-α, the inhibition of the P2X7/pannexin 1 pore by the drug A438079, the blockade of largeconductance Ca 2+ -activated potassium channels by paxilline, or the uncoupling of postsynaptic density protein 95 from NMDA receptors by were all found to reduce the amplitude of SD; TNF-α, and A438079 even in a dose-dependent manner (Chen et al, 2017;Kucharz, Søndergaard Rasmussen, Bach, Strømgaard, & Lauritzen, 2017;Menyhárt et al, 2018;Richter et al, 2014). Two of these studies have pointed out that the amplitude of SD stands in a strong, positive correlation with the extracellular concentration of potassium (Chen et al, 2017;Menyhárt et al, 2018), which would infer that treatment with LA1011, an Hsp co-inducer, may support cellular (possibly neuronal) potassium efflux with SD. Indeed, heat shock preconditioning preserved the diminishing potassium peak of recurrent depolarizations triggered by intermittent anoxia, and…”

“…The amplitude of SD appears to be fairly conserved, since neither ischaemia nor age can alter the SD-related DC potential amplitude (Menyhárt et al, 2015;Menyhárt et al, 2017). Two of these studies have pointed out that the amplitude of SD stands in a strong, positive correlation with the extracellular concentration of potassium (Chen et al, 2017;Menyhárt et al, 2018), which would infer that treatment with LA1011, an Hsp co-inducer, may support cellular (possibly neuronal) potassium efflux with SD. As such, topical application of the pro-inflammatory cytokine TNF-α, the inhibition of the P2X7/pannexin 1 pore by the drug A438079, the blockade of largeconductance Ca 2+ -activated potassium channels by paxilline, or the uncoupling of postsynaptic density protein 95 from NMDA receptors by were all found to reduce the amplitude of SD; TNF-α, and A438079 even in a dose-dependent manner (Chen et al, 2017;Kucharz, Søndergaard Rasmussen, Bach, Strømgaard, & Lauritzen, 2017;Menyhárt et al, 2018;Richter et al, 2014).…”

Susceptibility of the cerebral cortex to spreading depolarization in neurological disease states: The impact of aging

“…A number of experimental studies conducted to this end have presented evidence that NMDA receptor blockade (Sanchez-Porras et al, 2015;Reinhart and Shuttleworth, 2018), or the inhibition of P/Q type Ca 2+ channels potentially reduces SD susceptibility (Hoffmann et al, 2010). On the other hand, L-type voltage-gated Ca 2+ channel antagonism was shown to reverse spreading ischemia to hyperemia (Dreier et al, 1998), and lessen the weight of early hypoperfusion in the full cerebral blood flow response to SD (Menyhart et al, 2018). The first clinical trials to prevent repeated SD occurrence by the application of ketamine are promising (Carlson et al, 2018;Sakowitz et al, 2009).…”

“…The channels mediating K + efflux during depolarization are still to be explored, but it is reasonable to suggest that Kv channels must be involved, because the wide spectrum K + channel blocker tetraethylammonium (a drug that acts on inward rectifying and delayed outward rectifying K + channels) (Cook, 1990); and 4-aminopyridine (a blocker of inward rectifier and A-type K + channels) partially limited K + efflux with SD (Aitken et al, 1991;Somjen, 2001). Recent evidence indicates that large-conductance Ca 2+ -activated K + (BK) channels contribute to the K + surge with SD (Menyhart et al, 2018), and ATPsensitive K + channels that open under metabolic stress could also be involved (Somjen, 2001). Finally, it is suspected that during hypoxia/ ischemia, massive nonselective Na + (Ca 2+ )/K + conductances take place with SD, via a yet unidentified channel (Czeh et al, 1992(Czeh et al, , 1993Gagolewicz, 2017).…”