PHPB ameliorates memory deficits and reduces oxidative injury in Alzheimer's disease mouse model by activating Nrf2 signaling pathway
© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society..
Alzheimer's disease (AD), a progressive neurodegenerative disorder, is the most common cause of dementia in elderly people and substantially affects patient quality of life. Oxidative stress is considered a key factor in the development of AD. Nrf2 plays a vital role in maintaining redox homeostasis and regulating neuroinflammatory responses in AD. Previous studies show that potassium 2-(1-hydroxypentyl)-benzoate (PHPB) exerts neuroprotective effects against cognitive impairment in a variety of dementia animal models such as APP/PS1 transgenic mice. In this study we investigated whether PHPB ameriorated the progression of AD by reducing oxidative stress (OS) damage. Both 5- and 13-month-old APP/PS1 mice were administered PHPB (100 mg·kg-1·d-1, i.g.) for 10 weeks. After the cognition assessment, the mice were euthanized, and the left hemisphere of the brain was harvested for analyses. We showed that 5-month-old APP/PS1 mice already exhibited impaired performance in the step-down test, and knockdown of Nrf2 gene only slightly increased the impairment, while knockdown of Nrf2 gene in 13-month-old APP/PS1 mice resulted in greatly worse performance. PHPB administration significantly ameliorated the cognition impairments and enhanced antioxidative capacity in APP/PS1 mice. In addition, PHPB administration significantly increased the p-AKT/AKT and p-GSK3β/GSK3β ratios and the expression levels of Nrf2, HO-1 and NQO-1 in APP/PS1 mice, but these changes were abolished by knockdown of Nrf2 gene. In SK-N-SH APPwt cells and primary mouse neurons, PHPB (10 μM) significantly increased the p-AKT/AKT and p-GSK3β/GSK3β ratios and the level of Nrf2, which were blocked by knockdown of Nrf2 gene. In summary, this study demonstrates that PHPB exerts a protective effect via the Akt/GSK3β/Nrf2 pathway and it might be a promising neuroprotective agent for the treatment of AD.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
|---|---|
| Enthalten in: |
Acta pharmacologica Sinica - (2024) vom: 26. Feb. |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Shang, Nian-Ying [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Alzheimer disease |
|---|
| Anmerkungen: |
Date Revised 27.02.2024 published: Print-Electronic Citation Status Publisher |
|---|
| doi: |
10.1038/s41401-024-01240-9 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM368991741 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM368991741 | ||
| 003 | DE-627 | ||
| 005 | 20240229171218.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240229s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s41401-024-01240-9 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1310.xml |
| 035 | |a (DE-627)NLM368991741 | ||
| 035 | |a (NLM)38409216 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Shang, Nian-Ying |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a PHPB ameliorates memory deficits and reduces oxidative injury in Alzheimer's disease mouse model by activating Nrf2 signaling pathway |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 27.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status Publisher | ||
| 520 | |a © 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society. | ||
| 520 | |a Alzheimer's disease (AD), a progressive neurodegenerative disorder, is the most common cause of dementia in elderly people and substantially affects patient quality of life. Oxidative stress is considered a key factor in the development of AD. Nrf2 plays a vital role in maintaining redox homeostasis and regulating neuroinflammatory responses in AD. Previous studies show that potassium 2-(1-hydroxypentyl)-benzoate (PHPB) exerts neuroprotective effects against cognitive impairment in a variety of dementia animal models such as APP/PS1 transgenic mice. In this study we investigated whether PHPB ameriorated the progression of AD by reducing oxidative stress (OS) damage. Both 5- and 13-month-old APP/PS1 mice were administered PHPB (100 mg·kg-1·d-1, i.g.) for 10 weeks. After the cognition assessment, the mice were euthanized, and the left hemisphere of the brain was harvested for analyses. We showed that 5-month-old APP/PS1 mice already exhibited impaired performance in the step-down test, and knockdown of Nrf2 gene only slightly increased the impairment, while knockdown of Nrf2 gene in 13-month-old APP/PS1 mice resulted in greatly worse performance. PHPB administration significantly ameliorated the cognition impairments and enhanced antioxidative capacity in APP/PS1 mice. In addition, PHPB administration significantly increased the p-AKT/AKT and p-GSK3β/GSK3β ratios and the expression levels of Nrf2, HO-1 and NQO-1 in APP/PS1 mice, but these changes were abolished by knockdown of Nrf2 gene. In SK-N-SH APPwt cells and primary mouse neurons, PHPB (10 μM) significantly increased the p-AKT/AKT and p-GSK3β/GSK3β ratios and the level of Nrf2, which were blocked by knockdown of Nrf2 gene. In summary, this study demonstrates that PHPB exerts a protective effect via the Akt/GSK3β/Nrf2 pathway and it might be a promising neuroprotective agent for the treatment of AD | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Alzheimer disease | |
| 650 | 4 | |a NF-E2-related factor 2 | |
| 650 | 4 | |a cognition | |
| 650 | 4 | |a oxidative stress | |
| 650 | 4 | |a potassium 2-(1-hydroxypentyl)-benzoate (PHPB) | |
| 700 | 1 | |a Huang, Long-Jian |e verfasserin |4 aut | |
| 700 | 1 | |a Lan, Jia-Qi |e verfasserin |4 aut | |
| 700 | 1 | |a Kang, Yu-Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Tang, Jing-Shu |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Hong-Yue |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Xin-Nan |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Zhuo |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Qiu-Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Meng-Yao |e verfasserin |4 aut | |
| 700 | 1 | |a Wen, Zi-Peng |e verfasserin |4 aut | |
| 700 | 1 | |a Feng, Xin-Hong |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Lei |e verfasserin |4 aut | |
| 700 | 1 | |a Peng, Ying |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Acta pharmacologica Sinica |d 2000 |g (2024) vom: 26. Feb. |w (DE-627)NLM111735181 |x 1745-7254 |7 nnns |
| 773 | 1 | 8 | |g year:2024 |g day:26 |g month:02 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1038/s41401-024-01240-9 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |j 2024 |b 26 |c 02 | ||