Up-regulation of miRNA-151-3p enhanced the neuroprotective effect of dexmedetomidine against β-amyloid by targeting DAPK-1 and TP53

Alzheimer's disease (AD) is the most common cause of dementia and is the leading lethal disease among the elderly. Dexmedetomidine (Dex) has been reported to have multiple neuroprotective effects, but its effect against beta-amyloid (Aβ) has not been completely determined and understood. Dex can activate both α2 adrenoceptor/cAMP/PKA and imidazoline I receptors/ERK1/2 signals. To determine which signal is critical for the effect of Dex on Aβ toxicity, we treated SH-SY5Y and PC12 cells with inhibitors of α2 adrenoceptor and ERK1/2. Dex suppressed the apoptosis of neuronal cells and production of reactive oxygen species induced by Aβ. These suppressive effects were attenuated by both inhibitors. As indicated by western blot, Dex stimulates both pro-apoptosis (activating death-associated protein kinase 1 [DAPK-1] and p53) and anti-apoptotic (up-regulating bcl-2 and bcl-xL) signals in Aβ-treated neuronal cells. This effect is likely associated with ERK1/2 signaling because ERK1/2 inhibitor disrupts the effect of Dex on these signals. To eliminate the pro-apoptotic effect of Dex while retaining its anti-apoptosis action, we screened miRNA-151-3p to target DAPK-1 and p53. Transfection with miRNA-151-3p mimics suppressed DAPK-1 and TP53 expression induced by Dex and increased Nrf-2 and SOD expression. More importantly, increasing miRNA-151-3p enhanced the anti-apoptotic and antioxidative effects of Dex in Aβ-treated neuronal cells. Overall, this study revealed that Dex additionally stimulated pro-apoptosis signaling, although it suppressed Aβ-induced apoptosis of neuronal cells. miRNA-151-3p enhanced the neuroprotective effect of Dex against Aβ by targeting DAPK-1 and TP53.