K_ATP channel openers protect mesencephalic neurons against MPP⁺‐induced cytotoxicity via inhibition of ROS production

Abstract

Opening of ATP-sensitive potassium (K(ATP)) channels has been demonstrated to exert significant neuroprotection in in vivo and in vitro models of Parkinson's disease (PD), but the exact mechanism remains unclear. In the present study, various K(ATP) channel openers (KCOs) sensitive to diverse K(ATP) subunits were used to clarify the protective role of K(ATP) channel opening in 1-methyl-4-phenylpyridinium (MPP(+))-induced oxidative stress injury in mouse primary cultured mesencephalic neurons. The results showed that pretreatment with nonselective KCO pinacidil (Pin) or diazoxide (Dia), a KCO sensitive to Kir6.2/SUR1 K(ATP) channels, protected mesencephalic neurons, especially dopaminergic neurons, against MPP(+)-induced injury in a concentration-dependent manner. However, cromakalim (Cro), an opener of Kir6.1/SUR2 but not Kir6.2/SUR1 K(ATP) channels, failed to protect against MPP(+)-induced cytotoxicity. Furthermore, Pin and Dia but not Cro significantly suppressed the elevation of reactive oxygen species (ROS) triggered by MPP(+) and prevented the loss of mitochondrial member potential (Delta Psi m) and the release of mitochondrial cytochrome c. Consequently, opening of K(ATP) channels expressed in neurons could protect primary mesencephalic neurons against MPP(+)-induced cytotoxicity via inhibiting ROS overproduction and subsequently ameliorating mitochondrial function.

Subcellular expression and neuroprotective effects of SK channels in human dopaminergic neurons

“…It has also been demonstrated that activation of potassium K ATP channels mediate protection in cortical and dopaminergic neurons. 34, 35 Interestingly, activation of mitochondrial calcium-induced calcium release 36 depends on the rate at which Ca 2+ is provided to mitochondria. 37 On the other hand, Ca 2+ accumulation in mitochondria via the uniporter is dependent on the external Ca 2+ concentration and the transmembrane potential.…”

Bax Inhibitor-1-Mediated Inhibition of Mitochondrial Ca2+ Intake Regulates Mitochondrial Permeability Transition Pore Opening and Cell Death

“…It has been suggested that the highly activated K + channel is a protective mechanism against ischemia/hypoxic stress-induced intracellular Ca 2+ overloading495051. Activation of other K + channels also contributes to the stably maintained and resistant Δψm against cell-death stimuli5253.…”

Novel Mitochondrial Targets for Neuroprotection

“…While there are numerous examples of neuroprotection by either activation or overexpression of UCP2 (Paradis et al, 2003), the mechanism of protection by uncoupling and inhibition of mitochondrial superoxide production is not uniformly accepted (Cannon et al, 2006). The same lack of consensus applies to the mild uncoupling mechanism by which activators of the mitochondrial ATP-regulated potassium channel, e.g., diazoxide, provide neuroprotection (Xie et al, 2010).…”