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PD98059 protects the brain against mitochondrial-mediated apoptosis and autophagy in a cardiac arrest rat model

AIMS:

Mitochondrial dysfunction has been regarded as one of the hallmarks of cerebral ischemia-reperfusion injury. In previous studies, we have provided evidence that the extracellular signaling pathway (ERK) 1/2 inhibitor PD98059 improved the neurological deficits by modulating antioxidant and anti-apoptotic activities in rats subjected to cardiac arrest/cardiopulmonary resuscitation (CA/CPR). Since oxidative stress can activate mitochondria-dependent apoptosis and autophagy, we further explored the effects of PD98059 on mitochondria involved with apoptosis and autophagy in rat CA model.

MATERIALS AND METHODS:

We disposed PD98059 in CA/CPR rats, tested the mitochondrial-mediated apoptosis pathway in brain tissues at 24 h post-resuscitation by mitochondrial permeability transition pores (MPTP), cytochrome c (CytC), BCL-2, BAX, caspase-3, as well as autophagy by LC3, Beclin-1, and p62. Furthermore, we explored the relationship of dynamin-related protein 1 (Drp1) with apoptosis and autophagy.

KEY FINDINGS:

Our study showed that PD98059 decreased the openings of MPTP, CytC release, caspase3 activation, apoptotic indices, LC3-II, Beclin-1and increased P62. PD98059 also inhibited mitochondria-dependent apoptosis and the activity of autophagy in a dose-dependent manner in rat cerebral cortices at 24 h post-resuscitation. The generation of phosphorylated Drp1-616 was down-regulated accompanied by a decrease of TUNEL-positive cells and LC3 in dual immunostaining after PD98059 inhibited activation of ERK signaling pathway in a dose-dependent manner in rat cerebral cortices at 24 h post-resuscitation.

SIGNIFICANCE:

PD98059 protects the brain against mitochondrial-mediated apoptosis and autophagy at 24 h post-resuscitation in rats subjected to CA/CPR, which is linked with the downregulation of Drp1 expression.

Related Products

Cat.No. Product Name Information
S1177 PD98059 PD98059 is a non-ATP competitive MEK inhibitor with IC50 of 2 μM in a cell-free assay, specifically inhibits MEK-1-mediated activation of MAPK; does not directly inhibit ERK1 or ERK2. PD98059 is a ligand for the aryl hydrocarbon receptor (AHR) and functions as an AHR antagonist.

Related Targets

MEK