Alleviation of Memory Deficit by Bergenin via the Regulation of Reelin and Nrf-2/NF-κB Pathway in Transgenic Mouse Model
Abstract
:1. Introduction
2. Results
2.1. Bergenin Exerts Neuro-Protective Effect in HT-22 and PC-12 Cells
2.2. Bergenin Reduces Nitrite Production in HT-22 and PC-12 Cells
2.3. Bergenin Enhances Anti-Oxidants and Decreases Oxidative Stress in Cells
2.4. Bergenin Enhances Spatial Memory in 5xFAD Tg Mice
2.5. Effect of Bergenin on Locomotor and Anxiety-Like Behavior in 5xFAD Tg Mice
2.6. Bergenin Protects against Decrease in Proteins, Lipids and Their Secondary Derivatives
2.7. Bergenin Improves Histopathology in H&E Stained 5xFAD Tg Mice Brain Tissues
2.8. Bergenin Attenuates Amyloid Plaque Deposits in 5xFAD Tg Mice Brain Tissues
2.9. Bergenin Decreases Clusters of PAS-Positive Granules in 5xFAD Tg Mice Brain Tissues
2.10. Bergenin Increases Reelin Signaling Pathway and Attenuates Aβ (1-42)
2.11. Effect of Bergenin on DSC Analysis
2.12. Effect of Bergenin on Nrf-2, NF-κB and Bax Signaling Proteins
2.13. Bergenin Decreases Inflammatory and Oxidative Stress Pathway
2.14. Bergenin Reduces Apoptotic Pathway
2.15. Bergenin Enhances Antioxidant Levels in 5xFAD Tg Mice Brain
2.16. Bergenin Reduces Oxidative Stress and Nitrite Production in 5xFAD Tg Mice Brain
2.17. Bergenin Reduces Pro-Inflammatory Cytokine Production in Mice Brain
2.18. Molecular Docking Analysis with Bergenin
3. Discussion
4. Materials and Methods
4.1. Chemicals and Reagents
4.2. Plant Material
4.3. Cells and Culture Media
4.4. Cell Viability Assay
4.5. In-Vitro Determination of Nitric Oxide (NO) Production
4.6. In-Vitro Determination of Antioxidants and Oxidative Stress Level
4.7. Animals
4.8. Experimental Groups
4.9. Dose Preparation and Administration
4.10. Experimental Design and Sample Collection
4.11. Preparation of Brain Tissues for Histological Analysis
4.12. Behavioral Analysis
4.12.1. Y-Maze Test
4.12.2. Morris Water Maze (MWM) Test
4.12.3. Open Field Test (OFT)
4.13. Biochemical Analysis
4.13.1. Fourier Transform-Infrared (FT-IR) Analysis
4.13.2. Differential Scanning Calorimeter (DSC)
4.13.3. Evaluation of Histopathological Changes in Hematoxylin & Eosin (H&E) Stained Tissues
4.13.4. Assessment of Amyloid Beta Deposits in Brain Tissue
4.13.5. Assessment of Periodic Acid-Schiff (PAS) Staining in Brain Tissue
4.13.6. Western Blot Analysis
4.13.7. Immunohistochemical Analysis
4.13.8. Detection of Apoptotic Cells by Annexin V Staining
4.13.9. Determination of Anti-Oxidant Level
4.13.10. Evaluation of Oxidative Stress Level
4.13.11. Determination of Nitrite Content
4.13.12. Evaluation of Pro-Inflammatory Cytokines Level in Mice Brain Tissue
4.13.13. Molecular Docking Analysis
4.13.14. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Wild Type (a.u) | 5xFAD Tg (a.u) | Bergenin (a.u) | ||
---|---|---|---|---|
Proteins | Amide-A | 0.142 ± 0.005 | 0.047 ± 0.005 ### | 0.107 ± 0.01 *** |
Amide-I | 0.273 ± 0.01 | 0.083 ± 0.002 ### | 0.213 ± 0.005 *** | |
Amide-II | 0.24 ± 0.002 | 0.073 ± 0.002 ### | 0.174 ± 0.002 *** | |
CH3 symmetric stretching | 0.103 ± 0.02 | 0.03 ± 0.01 ### | 0.081 ± 0.001 *** | |
Lipids | Olefinic=C-H stretching | 0.075 ± 0.001 | 0.035 ± 0.003 ### | 0.065 ± 0.05 *** |
CH3 asymmetric stretching | 0.123 ± 0.005 | 0.046 ± 0.003 ### | 0.084 ± 0.001 *** | |
CH2 asymmetric stretching | 0.16 ± 0.017 | 0.052 ± 0.01 ### | 0.127 ± 0.02 *** | |
CH2 symmetric stretching | 0.156 ± 0.01 | 0.056 ± 0.01 ### | 0.125 ± 0.021 *** | |
Phospholipids | PO2− asymmetric stretch | 0.21 ± 0.01 | 0.042 ± 0.002 ### | 0.073 ± 0.02 *** |
Nucleic acids | PO2− symmetric stretch | 0.226 ± 0.02 | 0.076 ± 0.002 ### | 0.172 ± 0.002 *** |
Lipid/Protein Ratio | Wild Type (a.u) | 5XFAD Tg (a.u) | Bergenin (a.u) |
---|---|---|---|
Antiparallel β-sheet (I1744/I1695) | 0.53 ± 0.02 | 0.77 ± 0.005 ### | 0.67 ± 0.005 *** |
Parallel β-sheet (I1744/I1629) | 0.23 ± 0.05 | 0.44 ± 0.002 ### | 0.36 ± 0.008 *** |
Proteins | PDB ID | Binding Energy (Kcal/mol) | Hydrogen Bonds | Hydrogen Bond Amino Acids | Hydrophobic Interactions |
---|---|---|---|---|---|
Keap-1 | 1U6D | −7.8 | 6 | Val606, Gly367, Ala607, Val418, Val465, Val467 | Val420 |
Nrf-2 | 2FLU | −8.3 | 3 | Val465, Val608, Ala466 | Val369, Ala607 |
HO-1 | 1irm | −6.6 | 3 | Arg85, Ala87, His84 | Arg86, Pro80 |
TLR-4 | 3vq2 | −7.2 | 3 | Gln505, Ser480, Asn456 | --- |
IκB-α | 6y1j | −7.2 | 4 | Glu182, Ser64,Glu133, Gln67 | Arg60 |
NF-κB | 1vkx | −8.8 | 4 | Gln247, Arg246, DA18, DA17 | Lys541, Lys572 |
Bcl-2 | 2W3L | −7.7 | 2 | Arg26, Arg68 | --- |
Bax | 5W62 | −5.8 | 4 | Ile175, Asn73, Ser72, Glu69 | --- |
Casp-3 | 2XYG | −6.1 | 6 | Met44, Lys82, Gly45, Glu84, Tyr41, Tyr83, Glu43 | --- |
Aβ | 4mvl | −7.3 | 2 | Lys30, GLN26 | His28 |
Wavenumbers (cm−1) | Definition of the Assignment |
---|---|
3304 | Amide A: mainly N–H stretching of proteins |
3012 | Olefinic=C-H stretching: lipids |
2958 | CH3 asymmetric stretching: mainly lipids |
2922 | CH2 asymmetric stretching: mainly lipids |
2872 | CH3 symmetric stretching: mainly proteins |
2851 | CH2 symmetric stretching: mainly lipids |
1739 | Ester C=O stretch: lipids |
1653 | Amide 1: C=O stretching of proteins |
1548 | Amide II: N-H bending and C-N stretching of proteins |
1249 | PO2− asymmetric stretch: mainly phospholipids |
1057 | PO2− symmetric stretch: mainly nucleic acids |
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Shal, B.; Khan, A.; Khan, A.U.; Ullah, R.; Ali, G.; Islam, S.U.; Haq, I.u.; Ali, H.; Seo, E.-K.; Khan, S. Alleviation of Memory Deficit by Bergenin via the Regulation of Reelin and Nrf-2/NF-κB Pathway in Transgenic Mouse Model. Int. J. Mol. Sci. 2021, 22, 6603. https://doi.org/10.3390/ijms22126603
Shal B, Khan A, Khan AU, Ullah R, Ali G, Islam SU, Haq Iu, Ali H, Seo E-K, Khan S. Alleviation of Memory Deficit by Bergenin via the Regulation of Reelin and Nrf-2/NF-κB Pathway in Transgenic Mouse Model. International Journal of Molecular Sciences. 2021; 22(12):6603. https://doi.org/10.3390/ijms22126603
Chicago/Turabian StyleShal, Bushra, Adnan Khan, Ashraf Ullah Khan, Rahim Ullah, Gowhar Ali, Salman Ul Islam, Ihsan ul Haq, Hussain Ali, Eun-Kyoung Seo, and Salman Khan. 2021. "Alleviation of Memory Deficit by Bergenin via the Regulation of Reelin and Nrf-2/NF-κB Pathway in Transgenic Mouse Model" International Journal of Molecular Sciences 22, no. 12: 6603. https://doi.org/10.3390/ijms22126603