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Neurotoxicity Research

, Volume 35, Issue 3, pp 654–667 | Cite as

Carbenoxolone Reverses the Amyloid Beta 1–42 Oligomer–Induced Oxidative Damage and Anxiety-Related Behavior in Rats

  • Sheetal Sharma
  • Neha Sharma
  • Avneet Saini
  • Bimla NehruEmail author
ORIGINAL ARTICLE
  • 86 Downloads

Abstract

The characteristic feature of Alzheimer’s disease (AD) is the deposition of amyloid beta inside the brain mainly consisting of Aβ 40 and 42 aggregates. Soluble aggregates of Aβ 42 are reported to be more toxic and exert their neurotoxicity by the induction of oxidative damage and cognitive deficits such as anxiety-like behavior. These alterations emerge due to the induction of gap junction communication through increased activity and expression of connexins such as connexin43 (Cx43) leading to the release of small neurotoxic molecules. In the present study, single intracerebroventricular (icv) injection of Aβ 42 oligomers (10 μl/rat) was used to induce oxidative damage and anxiety-related behavior in rats. Carbenoxolone (Cbx), a gap junction blocker, was tested (20 mg/kg body weight, i.p., for 6 weeks) against these alterations. Cbx supplementation reversed the Aβ 42 oligomer–induced alterations in the antioxidant defense system. The levels ROS, lipid peroxidation, and protein carbonyls were normalized with Cbx co-treatment leading to the decreased DNA fragmentation and pyknosis in different regions of the rat brain. Cbx induced the anxiolytic behavior and ameliorated the cognitive decline in rats post Aβ 42 oligomer injection. The increased expression of Cx43 post Aβ 42 oligomer injection was also reduced with Cbx supplementation, which might have inhibited the release of small neurotoxic molecules. Our results showed that Cbx prevents the Aβ 42 oligomer–induced oxidative damage and anxiety-like behavior partly by blocking the gap junction communication, which suggests that the therapeutic potential of Cbx may be explored in the progression of AD.

Keywords

Amyloid beta 1–42 Alzheimer’s disease Anxiety-like behavior Oxidative damage Gap junctions Carbenoxolone 

Abbreviations

AD

Alzheimer’s disease

Amyloid beta

APP

Amyloid precursor protein

icv

Intracerebroventricular

HC

Hemichannel

Cx43

Connexin43

Cbx

Carbenoxolone

ROS

Reactive oxygen species

DCFH-DA

2, 7-Dichlorofluorescein diacetate

LPO

Lipid peroxidation

MDA

Malondialdehyde

TBA

Thiobarbituric acid

SOD

Superoxide dismutase

CA

Cornus ammonis

Notes

Funding Information

This work is financially supported by the University Grants Commission (UGC), New Delhi, India.

Compliance with Ethical Standards

The guidelines laid by the Ethics Committee of the Animal Care of Panjab University in accordance with the Indian national law on animal care and use were strictly followed throughout the study.

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12640_2018_9975_Fig11_ESM.png (23 mb)
Suppl Fig. 1a

Effect of Cbx supplementation on oligomeric Aβ 1–42 induced astrocytic activation in the rat brain as depicted by immunohistochemistry (100X). The estimations were performed after 6 weeks of Cbx supplementation post Aβ 1–42 injection. (PNG 23534 kb)

12640_2018_9975_MOESM1_ESM.tif (75.5 mb)
High resolution image (TIF 77273 kb)
12640_2018_9975_Fig12_ESM.png (11 kb)
Suppl Fig. 1b

Quantitative analysis of the astrocytic activation in different regions of the rat brain. Cbx supplementation normalized the astrocytic activation in hippocampal, cortical and striatal regions. Values are expressed as mean ± SD; n = 3. *, p ≤ 0.05, compared to sham control group; #, p ≤ 0.05, compared to Aβ 1–42 treated group. (PNG 11 kb)

12640_2018_9975_MOESM2_ESM.tif (508 kb)
High resolution image (TIF 508 kb)
12640_2018_9975_Fig13_ESM.png (158.5 mb)
Suppl Fig. 2

Effect of Cbx on oligomeric Aβ 1–42 induced pyknosis in the rat brain as depicted by thionin staining (× 200). The estimations were performed after 6 weeks of Cbx supplementation post Aβ 1–42 injection. Presence of pyknotic cells in hippocampal, cortical and striatal regions (a) confirmed neurodegeneration post oligomeric Aβ 1–42 injection. Cbx supplementation prevented neuronal damage as represented in the histogram (b) showing the number of pyknotic cells in different regions. Black arrows represent the normal neurons and red arrows represent the pyknotic neurons. Values are expressed as mean ± SD; n = 3. *, p ≤ 0.05, compared to sham control group; #, p ≤ 0.05, compared to Aβ 1–42 treated group. (PNG 162264 kb)

12640_2018_9975_MOESM3_ESM.tif (70.5 mb)
High resolution image (TIF 72239 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Sheetal Sharma
    • 1
  • Neha Sharma
    • 1
  • Avneet Saini
    • 1
  • Bimla Nehru
    • 1
    Email author
  1. 1.Department of Biophysics, Basic Medical Sciences Block IIPanjab UniversityChandigarhIndia

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