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

Mol Neurobiol. 2018 Feb;55(2):1725-1739. doi: 10.1007/s12035-017-0450-5. Epub 2017 Feb 18.

Abstract

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.

Keywords: AT1 receptor; AT2 receptor; Hypertension; Lipopolysaccharide; Memory impairment; Neuroinflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin Receptor Antagonists / pharmacology*
  • Animals
  • Apoptosis / drug effects*
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Lipopolysaccharides / pharmacology*
  • Male
  • Memory / drug effects*
  • Memory Disorders / chemically induced
  • Memory Disorders / metabolism*
  • NF-kappa B / metabolism*
  • Rats
  • Rats, Inbred SHR
  • Receptor, Angiotensin, Type 2 / metabolism

Substances

  • Angiotensin Receptor Antagonists
  • Brain-Derived Neurotrophic Factor
  • Cyclic AMP Response Element-Binding Protein
  • Lipopolysaccharides
  • NF-kappa B
  • Receptor, Angiotensin, Type 2