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.
Highlights
Chronic 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)
These findings establish a role for apyrimidinic endonuclease1 (APE1) as a master regulator of AlCl3 dependent inflammatory responses in rat brain
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
Summary
Chronic 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). Amyloid beta (Aβ) deposition, and plaque formation in the brain of transgenic mice that overexpress amyloid beta (A4) precursor protein (APP) [1] Both Aβ and aluminum are able to potentiate reactive oxygen species (ROS) formation that will lead to genotoxicity and DNA damage. The mammalian ap-endonuclease, APE1/ref-1, is a ubiquitous and remarkably multifunctional protein It plays a central role in the base excision repair (BER) pathway for damaged bases and DNA single-strand breaks induced by ROS and alkylating agents [2]. Several studies showed that global cerebral ischemia or traumatic brain injury or cold injury-induced brain trauma [6] induced oxidative stress decreases APE1 expression in the hippocampus and is associated with neuronal apoptosis in rats [7,8]. A very recent study by Mantha et al, [10] indicated that APE1/Ref-1 exerts neuro-protective role via its association with different intracellular proteins in Aβ (25–35)-treated rat pheochromocytoma, PC12 and SH-SY5Y cell lines, which could modulate their cellular functions during Aβ-mediated neurotoxicity
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