Ischemic stroke causes the activation of multiple processes, including ionic imbalance, depolarization and excessive neurotransmitter release (Doyle et al., 2008). Although glutamate release has been viewed as a main cause of neuronal damage, massive release of dopamine (DA) also occurs, directly contributing to cell death (Lieb et al., 1995). The voltage-gated Kv7 potassium channel family comprises five members (Kv7.1- Kv7.5) that have been demonstrated to regulate DA release in the caudate, a region rich in DA and frequently damaged in ischemic stroke (Martire et al., 2007). In this study we investigated the potential neuroprotective role of Kv7 channels in an in vitro model of ischemia, namely rat brain slices undergoing oxygen- and glucose- deprivation (OGD). In particular, we evaluated the effects of different Kv7-acting drugs on: 1) OGD-induced DA release, measured by fast cyclic voltammetry (Davidson et al., 2011); 2) OGD-induced damage, assessed by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Values are means ± S.E.M., expressed as percentage of controls. The Kv7 activator retigabine (RT) 1μM increased time to onset (T-on) of OGD-induced DA release (131±7, and also reduced DA peak (DApeak) and rate of change of DA efflux (DA/Tpeak) when compared to vehicle-treated slices (DApeak 57±12; DA/Tpeak 40±9) (n=7). RT (0.3 to 10μM) dose-dependently reduced the loss of TTC staining induced by OGD (n=5 for each experimental point). The Kv7.2/Kv7.3-preferring activator ICA27243 1μM decreased DA peak (42±10) while it did not significantly affect T-on (102±19) and DA/Tpeak (121±35) (n=6). ICA27243 (0.1 to 10μM) also prevented dose-dependently the loss of TTC staining in brain slices exposed to OGD (n=5 for each experimental point). The new Kv7.2/Kv7.4 activator NS15370 0.1μM doubled time to reach DA peak (200±34), but had no significant effects on other parameters (n=4). The Kv7 blocker linopiridine 10μM increased DApeak (417±85) and DA/Tpeak (436±75) (n=7), and prevented RT-induced changes in voltammetric parameters. Linopiridine (3 to 30μM) enhanced OGD-induced loss of TTC staining and prevented RT-mediated loss attenuation of TTC-staining. Quantitative-PCR experiments showed a 6-fold decrease in Kv7.2 transcript, while levels of mRNAs encoding for other Kv7 subunits were unaffected (n=5); western blot experiments showed a parallel reduction in Kv7.2 protein levels (n=5). Taken together, these results suggest a main role for Kv7.2 also in the modulation of DA release induced by an ischemic insult and highlight pharmacological activation of Kv7 channels as a possible strategy for the treatment of brain ischemia.