Safinamide protects against amyloid ß (Aß)-induced oxidative stress and cellular senescence in M17 neuronal cells.

Alzheimer's disease (AD) is a neurodegenerative disorder that is pathologically related to oxidative stress and cellular senescence. Safinamide is one of the clinically prescribed monoamine oxidase B (MAOB) inhibitors. It has been reported to possess therapeutic potential in neurological disorders. However, the therapeutic potential of safinamide in AD is still under investigation. In this study, we explored the effect of safinamide in amyloid (Aß)1-42 oligomers-stimulated M17 neuronal cells. We established the in vitro model with M17 cells by treating them with 1 µM Aß1-42 oligomers with or without safinamide (100 or 200 nM). The results show that safinamide ameliorated Aß1-42 oligomers-induced oxidative stress in M17 cells as revealed by the decreased reactive oxygen species (ROS) production and reduced glutathione (GSH) content. Safinamide treatment significantly ameliorated senescence-associated-ß-galactosidase (SA-ß-gal)-positive cells and telomerase activity. Further, we show that safinamide treatment resulted in decreased mRNA and protein expressions of p21 and plasminogen activator inhibitor-1 (PAI-1). Moreover, silencing of Sirtuin1 (SIRT1) abolished the effects of safinamide on the mRNA levels of p21 and PAI-1, as well as SA-ß-gal-positive cells in Aß1-42 oligomers-induced M17 cells. In conclusion, we reveal that safinamide exerted a protective function on M17 cells from Aß1-42 oligomers induction-caused oxidative stress and cellular senescence through SIRT1 signaling. These present results provide meaningful evidence that safinamide may be medically developed for the prevention and therapy of AD.

Transforming growth factor­ß1 functions as a competitive endogenous RNA that ameliorates intracranial hemorrhage injury by sponging microRNA­93­5p.

Intracerebral hemorrhage (ICH) has the highest mortality rate of all stroke subtypes but an effective treatment has yet to be clinically implemented. Transforming growth factor­ß1 (TGF­ß1) has been reported to modulate microglia­mediated neuroinflammation after ICH and promote functional recovery; however, the underlying mechanisms remain unclear. Non­coding RNAs such as microRNAs (miRNAs) and competitive endogenous RNAs (ceRNAs) have surfaced as critical regulators in human disease. A known miR­93 target, nuclear factor erythroid 2­related factor 2 (Nrf2), has been shown to be neuroprotective after ICH. It was hypothesized that TGF­ß1 functions as a ceRNA that sponges miR­93­5p and thereby ameliorates ICH injury in the brain. Short interfering RNA (siRNA) was used to knock down TGF­ß1 and miR­93 expression was also pharmacologically manipulated to elucidate the mechanistic association between miR­93­5p, Nrf2, and TGF­ß1 in an in vitro model of ICH (thrombin­treated human microglial HMO6 cells). Bioinformatics predictive analyses showed that miR­93­5p could bind to both TGF­ß1 and Nrf2. It was found that neuronal miR­93­5p was dramatically decreased in these HMO6 cells, and similar changes were observed in fresh brain tissue from patients with ICH. Most importantly, luciferase reporter assays were used to demonstrate that miR­93­5p directly targeted Nrf2 to inhibit its expression and the addition of the TGF­ß1 untranslated region restored the levels of Nrf2. Moreover, an miR­93­5p inhibitor increased the expression of TGF­ß1 and Nrf2 and decreased apoptosis. Collectively, these results identified a novel function of TGF­ß1 as a ceRNA that sponges miR­93­5p to increase the expression of neuroprotective Nrf2 and decrease cell death after ICH. The present findings provided evidence to support miR­93­5p as a potential therapeutic target for the treatment of ICH.