Apurinic/apyrimidinic endonuclease 1 is a key modulator of aluminum-induced neuroinflammation

Abstract

BackgroundChronic administration of Aluminum is proposed as an environmental factor that may affect several enzymes and other biomolecules related to neurotoxicity and Alzheimer's disease (AD). APE1 a multifunctional protein, functions in DNA repair and plays a key role in cell survival versus cell death upon stimulation with cytotoxic agent, making it an attractive emerging therapeutic target. The promising protective effect of resveratrol (resv), which is known to exert potent anti-inflammatory effects on neurotoxicity induced by aluminum chloride (AlCl3), may be derived from its own antioxidant properties. In the present work we investigated the modulation of APE1 expression during AlCl3-induced neuroinflammation (25 mg/Kg body weight by oral gavages) in experimental rats. We tested the hypothesis that a reactive oxygen species (ROS)-scavenger, resveratrol at 0.5 mg/kg bodyweight, which is known to exert potent anti-inflammatory effects, would attenuate central inflammation and modulate APE1 expression in AlCl3-fed rats. Neuroinflammation-induced genes including β-secretase (BACE), amyloid-β precursor protein (APP), presenilin 2 (PSEN-2) and sirt-2 were determined by RT-PCR. APE1 is determined at mRNA and protein levels and confirmed by immunohistochemistry. The expression of pro-inflammatory cytokines (TNF-α, IL6) and iNOS by the rat brain extract were measured by RT-PCR.ResultOur results indicate that resveratrol may attenuate AlCl3-induced direct neuroinflammation in rats, and its mechanisms are, at least partly, due to maintaining high APE1 level. Resveratrol co-administration with aluminum chloride exerted more protective effect than pre-administration or treatment of induced rats. A significant elevation of APE1 at both mRNA and protein levels was observed in addition to a marked reduction in β-secretase and amyloid-β. We found that AlCl3 stimulated the expression of TNF-α, IL-6, and iNOS in rat brain in which NF-κB was involved. Resveratrol inhibited AlCl3-induced expression and release of TNF-α, IL-6, and iNOS in rat brain.ConclusionsThese findings establish a role for APE1 as a master regulator of AlCl3 dependent inflammatory responses in rat brain. In addition, there was an ameliorative change with resveratrol against AlCl3-induced neurotoxicity. These results suggest that rat brain cells produce pro-inflammatory cytokines in response to AlCl3 in a similar pattern, and further suggest that resveratrol exerts anti-inflammatory effects in rat brain, at least partly, by inhibiting different pro-inflammatory cytokines and key signaling molecules. It might be a potential agent for treatment of neuroinflammation-related diseases, such as AD.

Role and potential targeting of hepatic apurinic/apyrimidinic endonuclease-1 and cyclin-dependent kinase-4 in hepatocellular carcinoma

“…Resveratrol (trans-3′,4′,5-trihydroxystilbene), an essential polyphenolic cancer prevention agent present in grapes and other dietary parts, shows antiproliferative action against growth cells in vitro studies (Wong et al 2011). Resveratrol additionally assumes a vital part in the counteractive action of anxiety by regulating APE/Ref-1 (Zaky et al 2013). In this, the antioxidant effect of LBC (Teng et al 2016) and FnC 60 (Andrievsky et al 2009) may be hidden mechanism by which both of these components diminished the expression of APE-1/Ref-1, which is principally invigorated by oxidative anxiety (Zaky et al 2013).…”

“…Past information has demonstrated the inclusion of APE1 adjustment in the pathogenesis of numerous disarranges, including liver fibrosis (Bassiouny et al 2011a), liver cirrhosis (Bassiouny et al 2011b) ,neuroinflammation (Zaky et al 2013) and different cancers (Chen et al 2013). The multiplication of eukaryotic cells regularly includes a methodical movement through four unmistakable periods of the cell-cycle: G1, S, G2, and M (Obaya and Sedivy 2002).…”

Ibuprofen targets neuronal pentraxins expresion and improves cognitive function in mouse model of AlCl3-induced neurotoxicity

“…Previous studies have demonstrated a role for Al in dementia (8), PD (9) and AD (10). Furthermore, an aluminum chloride (AlCl 3 )-induced model has previously been established for the investigation of neurotoxicity (11), AD (12), dementia (13), and neuroinflammation (14).…”

Neuroprotective effects of eugenol against aluminiuminduced toxicity in the rat brain

“…Reports have also defined it as an important etiological factor in the progression of several neurodegenerative disorders as it influences more than 200 biologically important reactions (6,7). Aluminium-induced brain toxicity was reported in rats by many authors, including administration of aluminium chloride hexahydrate (25 mg kg -1 day -1 ) for one month by oral gavage (8), daily oral treatment with aluminium chloride (100 mg kg ) orally for four consecutive weeks (9,10). The neurotoxicity of Al is likely to be the result of a combination of several mechanisms, including oxidative brain injury, induction of apoptosis and neuronal damage, neuroglia inflammatory reaction, and reduced neurotransmitter biosynthesis (6,11).…”