title: Apurinic/apyrimidinic endonuclease 1 is a key modulator of aluminum-induced neuroinflammation.
abstract: BACKGROUND
  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). 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.
  
  
  RESULTS
  Our 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.
  
  
  CONCLUSIONS
  These 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.
authors.affiliation: Department of Biochemistry, Faculty of Science, Alexandria University, Alexandria, Egypt. amzakyha@yahoo.com
authors.forename: Amira
authors.initials: A
authors.lastname: Zaky
authors.forename: Bassma
authors.initials: B
authors.lastname: Mohammad
authors.forename: Marie
authors.initials: M
authors.lastname: Moftah
authors.forename: Kamal M
authors.initials: KM
authors.lastname: Kandeel
authors.forename: Ahmad R
authors.initials: AR
authors.lastname: Bassiouny
mesh_terms: D000077410:Aluminum Chloride; D017607:Aluminum Compounds / Q000633:toxicity*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D002712:Chlorides / Q000633:toxicity*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000139:chemically induced* / Q000201:enzymology*; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D017607:Aluminum Compounds; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002712:Chlorides; D015850:Interleukin-6; D010446:Peptide Fragments; D053764:Presenilin-1; C078592:amyloid beta-protein (1-40); D000077410:Aluminum Chloride; D002374:Catalase; D052247:Nitric Oxide Synthase Type II; D005982:Glutathione Transferase; D001219:Aspartate Aminotransferases; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D005978:Glutathione