title: Angiotensin Receptor Blockade Modulates NFκB and STAT3 Signaling and Inhibits Glial Activation and Neuroinflammation Better than Angiotensin-Converting Enzyme Inhibition.
abstract: Neuroinflammation, sustained by astroglial and microglial activation, is the preceding event in neurodegeneration. Various clinical reports showed better neuroprotection by AT1 receptor blockade (ARB) than angiotensin-converting enzyme inhibition (ACEi), but experimental evidences and associated mechanism for this observation are lacking. Therefore, we investigated the effect of ARB, using Candesartan, and ACEi, using Perindopril, in equimolar concentrations in astroglial (C6) and microglial (BV2) cells employing lipopolysaccharide (LPS) to induce neuroinflammation. Further, Candesartan (0.1 mg/kg) and Perindopril (0.1 mg/kg) were orally administered in male SD rats for five consecutive days, and on the fifth day, rats were challenged with LPS (i.p.; 250 μg/kg) and sacrificed after 24 h. LPS-induced neuroinflammation (increased astroglial and microglial activation, IκBα degradation, NFкB nuclear translocation, STAT3 activation, and TNF-α release) was more efficiently prevented by Candesartan (even at lower concentration of 1 nM) than by Perindopril (1 μM) in both the cell types and in rat model of neuroinflammation. In addition, increased AT1 receptor (AT1R) and decreased AT2 receptor (AT2R) expression was observed in LPS-induced neuroinflammation in both in vitro and in vivo studies. Candesartan, as compared to Perindopril, increased the expression of AT2R in both the experimental conditions. Interestingly, concomitant blockade of AT2R by PD123319 significantly reversed the beneficial effects of Candesartan in both the cell types and in rat model of neuroinflammation. Finally, our data emphasize that superiority of Candesartan as compared to Perindopril is due to better activation of AT2R which results in PP2A activation, IκBα stabilization, and suppression of NFкB and STAT3 inflammatory signaling.
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, Uttar Pradesh, India.
authors.forename: Shahnawaz Ali
authors.initials: SA
authors.lastname: Bhat
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, Uttar Pradesh, India.
authors.forename: Ruby
authors.initials: R
authors.lastname: Goel
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, Uttar Pradesh, India.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Shukla
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, Uttar Pradesh, India. k_hanif@cdri.res.in.|National Institute of Pharmaceutical Education and Research, Rae Bareli, India. k_hanif@cdri.res.in.
authors.forename: Kashif
authors.initials: K
authors.lastname: Hanif
mesh_terms: D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005911:Gliosis / Q000188:drug therapy / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D000072000:NF-KappaB Inhibitor alpha / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D011945:Receptors, Angiotensin / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009573:Nitrites; D017382:Reactive Oxygen Species; D011945:Receptors, Angiotensin; D050796:STAT3 Transcription Factor; D000072000:NF-KappaB Inhibitor alpha; D054648:Protein Phosphatase 2
keywords: AT1 receptor; AT2 receptor; Angiotensin converting enzyme; Astroglia; Microglia; Neuroinflammation