Molecular Neurobiology

, Volume 55, Issue 2, pp 1725–1739 | Cite as

Angiotensin II Receptor Blockers Attenuate Lipopolysaccharide-Induced Memory Impairment by Modulation of NF-κB-Mediated BDNF/CREB Expression and Apoptosis in Spontaneously Hypertensive Rats

  • Ruby Goel
  • Shahnawaz Ali Bhat
  • Kashif Hanif
  • Chandishwar Nath
  • Rakesh ShuklaEmail author


Clinical studies demonstrated a positive correlation between hypertension and cognitive decline. Beneficial effects of angiotensin II receptor blockers on cognitive functions have also been reported earlier; however, its role in chronic neuroinflammation-induced memory impairment in the hypertensive state is not well understood. Therefore, in the present study, we investigated the effect of angiotensin II receptor blockers on memory impairment induced by lipopolysaccharide (LPS) in spontaneously hypertensive rats (SHRs). Our data provides the strong evidence that intracerebroventricular (ICV) administration of LPS (25 μg) on the 1st, 4th, 7th, and 10th days leads to sustained neuroinflammation (as indicated by increased TNF-α, GFAP, COX-2, and NF-κB) and oxidative stress (increased reactive oxygen species (ROS) and nitrite levels) resulting in amyloid beta (Aβ1–42) deposition, apoptosis (increased Bax and decreased Bcl-2 expression as well as increased caspase-3 activity and TUNEL-positive cells), and memory impairment. Further, we found that exaggerated inflammatory response and oxidative stress were associated with RAS over-activation (as evident from the increased ACE expression, angiotensin II (Ang II) level, and angiotensin type 1 receptor (AT1R) expression) and decreased BDNF and p-CREB expression. Oral administration of candesartan (an AT1R blocker) at a non-anti-hypertensive dose (0.1 mg/kg) for 15 days attenuated LPS-induced (ICV) apoptosis, amyloidogenesis, and memory impairment. Candesartan shows neuroprotection by inhibiting TLR4/Ang II-induced NF-κB inflammatory signaling and by enhancing associated BDNF/CREB expression in SHRs. Our study also demonstrated that when both AT1R and angiotensin type 2 receptor (AT2R) were blocked by candesartan and PD123319 concomitantly, the protective effects of candesartan were blunted suggesting that functionally active AT2R is required for beneficial effects of AT1R blockade.


Lipopolysaccharide Hypertension Neuroinflammation Memory impairment AT1 receptor AT2 receptor 



This study was funded by the Indian Council of Medical Research (ICMR, project no. 58/13/2010BMS), New Delhi. Further, Senior Research Fellowships (SRFs) to RG from University Grants Commission (UGC) and SAB from ICMR, New Delhi, are greatly acknowledged. The CSIR-CDRI communication number of this manuscript is 9436.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no competing interests.

Supplementary material

12035_2017_450_MOESM1_ESM.docx (1.3 mb)
ESM 1 (DOCX 1376 kb)


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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Ruby Goel
    • 1
  • Shahnawaz Ali Bhat
    • 1
  • Kashif Hanif
    • 1
  • Chandishwar Nath
    • 2
  • Rakesh Shukla
    • 1
    Email author
  1. 1.Division of PharmacologyCSIR-Central Drug Research InstituteLucknowIndia
  2. 2.Division of ToxicologyCSIR-Central Drug Research InstituteLucknowIndia

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