The role of K _ATP channel blockade and activation in the protection against neurodegeneration in the rotenone model of Parkinson's disease

Aims: Several studies suggested that ATP-sensitive potassium channels (K_ATP) are potential therapeutic targets for protection against various neurodegenerative disorders, yet, there is an ongoing controversy regarding their role in Parkinson's disease (PD). Thus, the aim of the current study is to investigate the protective effect of K_ATP blockade and activation in the mice rotenone model of PD.

Main methods: PD has been induced by 9 subcutaneous injections of rotenone (1.5 mg/kg; 3 times/week) in adult male Swiss albino mice. For 3 consecutive weeks, parkinsonian mice were either untreated or treated with L-dopa (25 mg/kg), the K_ATP channel blocker glibenclamide (3 mg/kg) or the K_ATP channel opener nicorandil (6 mg/kg).

Key findings: Glibenclamide significantly improved motor performance in the wire hanging and stair tests and halted the decline in striatal dopamine content as well as dopaminergic neurons' density. In addition, it reduced the rotenone-induced apoptosis as portrayed in the immunohistopathological examination via increasing Bcl-2 and decreasing caspases-3, -8, -9 contents. Furthermore, through its anti-inflammatory potential, glibenclamide reduced tumor necrosis factor-alpha level. On the other hand, nicorandil failed to mitigate the rotenone-induced neurodegenerative consequences.

Significance: K_ATP channel blockade by glibenclamide has neuroprotective effect against rotenone-induced neurotoxicity, that was mediated by its anti-inflammatory effect along with hindering apoptosis through extrinsic and intrinsic pathways.

Keywords: Caspases; Glibenclamide; Inflammation; K(ATP) channels; Nicorandil; Rotenone.