Protective Role of K_v7 Channels in Oxygen and Glucose Deprivation-Induced Damage in Rat Caudate Brain Slices

Abstract

Ischemic stroke can cause striatal dopamine efflux that contributes to cell death. Since K v 7 potassium channels regulate dopamine release, we investigated the effects of their pharmacological modulation on dopamine efflux, measured by fast cyclic voltammetry (FCV), and neurotoxicity, in Wistar rat caudate brain slices undergoing oxygen and glucose deprivation (OGD). The K v 7 activators retigabine and ICA27243 delayed the onset, and decreased the peak level of dopamine efflux induced by OGD; and also decreased OGD-induced damage measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Retigabine also reduced OGD-induced necrotic cell death evaluated by lactate dehydrogenase activity assay. The K v 7 blocker linopirdine increased OGD-evoked dopamine efflux and OGD-induced damage, and attenuated the effects of retigabine. Quantitative-PCR experiments showed that OGD caused an~6-fold decrease in K v 7.2 transcript, while levels of mRNAs encoding for other K v 7 subunits were unaffected; western blot experiments showed a parallel reduction in K v 7.2 protein levels. Retigabine also decreased the peak level of dopamine efflux induced by L-glutamate, and attenuated the loss of TTC staining induced by the excitotoxin. These results suggest a role for K v 7.2 in modulating ischemia-evoked caudate damage.

The anticonvulsant retigabine suppresses neuronal KV2-mediated currents

“…In addition, we found that the addition of the auxiliary subunit KCNE2 decreased the retigabine sensitivity of heterotetrameric K V 7.2-K V 7.3, but not of K V 2.1, channels. These findings identify K V 2.1 as an important molecular target for the action of retigabine and, due to K V 2.1’s key role in apoptosis, could help explain the previously reported neuroprotective properties 24 25 26 .…”

“…Therefore, retigabine might prevent apoptosis through inhibition of K V 2.1 currents, thus promoting cell survival. However, retigabine was found to promote neuroprotection by diminishing excitotoxicity through suppression of hyperexcitability by K V 7 channel activation 24 25 26 . Thus, retigabine might promote neuroprotection in neurons through its concerted action on K V 2 and K V 7 channels.…”

“…This general mechanism for suppression of neuronal excitability additionally makes retigabine and other K V 7 activators interesting compounds for several other hyperexcitability-related disorders such as migraine, chronic pain, tinnitus, and even Huntington’s disease 20 21 22 23 . In addition, it has been shown that retigabine has neuroprotective properties 24 25 26 . However, not all of retigabine’s effects are necessarily due to its action on K V 7 channels since it also modulates GABA A receptors in a similar concentration range 27 .…”

Kcnq2/Kv7.2 controls the threshold and bihemispheric symmetry of cortical spreading depolarization

“…Fluctuations of this current under pathological states [49][50][51] may contribute to SD susceptibility, and serve as a therapeutic target in epilepsy and other neurological disorders…”

Effect of Comprehensive Cerebral Protection Program on Cerebral Oxygen Metabolism and Vascular Endothelial Function in Elderly Patients with Acute Cerebral Infarction

“…Brain tissue hypoxia, ischemia, and metabolic disorders not only directly participate in the process of brain injury, but also work together with other secondary injury mechanisms to aggravate brain tissue damage. (2). And NO, ET and ICP also play an important biological activity in acute cerebral ischemia, and participate in the occurrence and development of cerebral infarction.…”