PI3K/AKT signaling activation by roflumilast ameliorates rotenone-induced Parkinson's disease in rats.

Parkinson's disease (PD) is the second most common progressive age-related neurodegenerative disorder. Paramount evidence shed light on the role of PI3K/AKT signaling activation in the treatment of neurodegenerative disorders. PI3K/AKT signaling can be activated via cAMP-dependent pathways achieved by phosphodiesterase 4 (PDE4) inhibition. Roflumilast is a well-known PDE4 inhibitor that is currently used in the treatment of chronic obstructive pulmonary disease. Furthermore, roflumilast has been proposed as a favorable candidate for the treatment of neurological disorders. The current study aimed to unravel the neuroprotective role of roflumilast in the rotenone model of PD in rats. Ninety male rats were allocated into six groups as follows: control, rotenone (1.5 mg/kg/48 h, s.c.), L-dopa (22.5 mg/kg, p.o), and roflumilast (0.2, 0.4 or 0.8 mg/kg, p.o). All treatments were administrated for 21 days 1 h after rotenone injection. Rats treated with roflumilast showed an improvement in motor activity and coordination as well as preservation of dopaminergic neurons in the striatum. Moreover, roflumilast increased cAMP level and activated the PI3K/AKT axis via stimulation of CREB/BDNF/TrkB and SIRT1/PTP1B/IGF1 signaling cascades. Roflumilast also caused an upsurge in mTOR and Nrf2, halted GSK-3ß and NF-ĸB, and suppressed FoxO1 and caspase-3. Our study revealed that roflumilast exerted neuroprotective effects in rotenone-induced neurotoxicity in rats. These neuroprotective effects were mediated via the crosstalk between CREB/BDNF/TrkB and SIRT1/PTP1B/IGF1 signaling pathways which activates PI3K/AKT trajectory. Therefore, PDE4 inhibition is likely to offer a reliable persuasive avenue in curing PD via PI3K/AKT signaling activation.

The role of KATP 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 (KATP) 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 KATP 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 KATP channel blocker glibenclamide (3 mg/kg) or the KATP 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: KATP 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.