CZ2HF mitigates β-amyloid 25-35 fragment-induced learning and memory impairment through inhibition of neuroinflammation and apoptosis in rats

Zeng,Lingrong; Gao,Jianmei; Deng,Yuanyuan; Shi,Jingshan; Gong,Qihai

doi:10.3892/ijmm.2018.3952

CZ2HF mitigates β-amyloid 25-35 fragment-induced learning and memory impairment through inhibition of neuroinflammation and apoptosis in rats

Authors:
- Lingrong Zeng
- Jianmei Gao
- Yuanyuan Deng
- Jingshan Shi
- Qihai Gong
View Affiliations

Affiliations: Key Laboratory of Basic Pharmacology of Ministry of Education, Department of Pharmacology, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China, Department of Clinical Pharmacotherapeutics, School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
Published online on: October 24, 2018 https://doi.org/10.3892/ijmm.2018.3952
Pages: 557-566

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Cu‑zhi‑2‑hao‑fang (CZ2HF), a traditional Chinese medicine, has been used clinically for the treatment of amnesia. However, whether CZ2HF is capable of alleviating learning and memory impairment in Alzheimer's disease (AD) remains to be elucidated. The present study was designed to explore the effect and mechanism of CZ2HF on β‑amyloid 25‑35 (Aβ25‑35)‑induced impairment in the learning and memory of rats. Morris water maze test was used to determine spatial learning and memory ability in Aβ25‑35‑induced AD rats and hippocampal neuronal damage and apoptosis were observed using hematoxylin and eosin staining, Nissl staining and terminal deoxynucleotidyltransferase‑mediated dUTP nick‑end labeling (TUNEL) assays, respectively. The levels of β‑amyloid 1‑42 (Aβ1‑42), pro‑inflammatory factors, such as cyclooxygenase‑2 (COX‑2), tumor necrosis factor‑α (TNF‑α) and interleukin‑1β (IL‑1β) and apoptosis‑associated genes including B cell leukemia/lymphoma 2 (Bcl‑2), Bcl-2‑associated X, apoptosis regulator (Bax), pro‑caspase‑3, inhibitor of κB (IκB‑α) degradation and phosphorylated‑nuclear factor‑κB p65 (p‑NF‑κB p65) activation were analyzed using western blotting. The findings of the present study revealed that CZ2HF treatment significantly attenuated Aβ25‑35‑induced cognitive impairments in rats. Subsequently, CZ2HF treatment markedly inhibited neuronal damage and deletions. Furthermore, CZ2HF reduced TNF‑α, IL‑1β, COX‑2 protein expression levels, Bax/Bcl‑2 ratio, and reduced Aβ1‑42 and active‑caspase‑3 levels. In addition, IκB‑α degradation and p‑NF‑κB p65 activation were reduced by CZ2HF. These findings suggested that CZ2HF treatment improved Aβ25‑35‑induced learning and memory impairment and hippocampal neuronal injury, and its underlying mechanism may be due to the inhibition of neuroinflammation and neuronal apoptosis. CZ2HF may be a potential agent for the treatment of AD.

View Figures

View References

1	Ding C, Li F, Long Y and Zheng J: Chloroquine attenuates lipopolysaccharide-induced inflammatory responses through upregulation of USP25. Can J Physiol Pharmacol. 95:481–491. 2017. View Article : Google Scholar : PubMed/NCBI
2	Huang L, Luo Y, Pu Z, Kong X, Fu X, Xing H, Wei S, Chen W and Tang H: Oxoisoaporphine alkaloid derivative 8-1 reduces Aβ_1-42 secretion and toxicity in human cell and Caenorhabditis elegans models of Alzheimer’s disease. Neurochem Int. 108:157–168. 2017. View Article : Google Scholar : PubMed/NCBI
3	Kreutzer AG, Yoo S, Spencer RK and Nowick JS: Stabilization, assembly, and toxicity of trimers derived from Aβ. J Am Chem Soc. 139:966–975. 2017. View Article : Google Scholar
4	Liu C, Cao L, Yang S, Xu L, Liu P, Wang F and Xu D: Subretinal injection of amyloid-β peptide accelerates RPE cell senescence and retinal degeneration. Int J Mol Med. 35:169–176. 2015. View Article : Google Scholar
5	Yin K, Jin J, Zhu X, Yu L, Wang S, Qian L, Han L and Xu Y: CART modulates beta-amyloid metabolism-associated enzymes and attenuates memory deficits in APP/PS1 mice. Neurol Res. 39:885–894. 2017. View Article : Google Scholar : PubMed/NCBI
6	Puzzo D, Gulisano W, Arancio O and Palmeri A: The keystone of Alzheimer pathogenesis might be sought in Aβ physiology. Neuroscience. 307:26–36. 2015. View Article : Google Scholar : PubMed/NCBI
7	Park SY, Kim MJ, Kim YJ, Lee YH, Bae D, Kim S, Na Y and Yoon HG: Selective PCAF inhibitor ameliorates cognitive and behavioral deficits by suppressing NF-κB-mediated neuroin-flammation induced by Aβ in a model of Alzheimer’s disease. Int J Mol Med. 35:1109–1118. 2015. View Article : Google Scholar : PubMed/NCBI
8	Ling IF, Golde TE, Galasko DR and Koo EH: Modulation of Aβ42 in vivo by γ-secretase modulator in primates and humans. Alzheimers Res Ther. 7:552015. View Article : Google Scholar
9	Kang EB, Kwon IS, Koo JH, Kim EJ, Kim CH, Lee J, Yang CH, Lee YI, Cho IH and Cho JY: Treadmill exercise represses neuronal cell death and inflammation during Aβ-induced ER stress by regulating unfolded protein response in aged presenilin 2 mutant mice. Apoptosis. 18:1332–1347. 2013. View Article : Google Scholar : PubMed/NCBI
10	Um YH, Kim TW, Jeong JH, Seo HJ, Han JH, Hong SC, Lee CU and Lim HK: Prediction of treatment response to donepezil using automated hippocampal subfields volumes segmentation in patients with mild Alzheimer’s disease. Psychiatry Investig. 14:698–702. 2017. View Article : Google Scholar : PubMed/NCBI
11	Darreh-Shori T, Hosseini SM and Nordberg A: Pharmacodynamics of cholinesterase inhibitors suggests add-on therapy with a low-dose carbamylating inhibitor in patients on long-term treatment with rapidly reversible inhibitors. J Alzheimers Dis. 39:423–440. 2014. View Article : Google Scholar
12	Deardorff WJ and Grossberg GT: Pharmacotherapeutic strategies in the treatment of severe Alzheimer’s disease. Expert Opin Pharmacother. 17:1789–1800. 2016. View Article : Google Scholar : PubMed/NCBI
13	Pérez DI, Martínez A, Gil C and Campillo NE: From bitopic inhibitors to multitarget drugs for the future treatment of Alzheimer’s disease. Curr Med Chem. 22:3789–3806. 2015. View Article : Google Scholar
14	Deng Y, Long L, Wang K, Zhou J, Zeng L, He L and Gong Q: Icariside II, a broad-spectrum anti-cancer agent, reverses beta-amyloid-induced cognitive impairment through reducing inflammation and apoptosis in rats. Front Pharmacol. 8:392017. View Article : Google Scholar : PubMed/NCBI
15	Gao J, Deng Y, Yin C, Liu Y, Zhang W, Shi J and Gong Q: Icariside II, a novel phosphodiesterase 5 inhibitor, protects against H₂O₂-induced PC12 cells death by inhibiting mitochondria-mediated autophagy. J Cell Mol Med. 21:375–386. 2017. View Article : Google Scholar
16	Li F, Dong HX, Gong QH, Wu Q, Jin F and Shi JS: Icariin decreases both APP and Aβ levels and increases neurogenesis in the brain of Tg2576 mice. Neuroscience. 304:29–35. 2015. View Article : Google Scholar : PubMed/NCBI
17	Jia KK, Zheng YJ, Zhang YX, Liu JH, Jiao RQ, Pan Y and Kong LD: Banxiahoupu decoction restores glucose intolerance in CUMS rats through improvement of insulin signaling and suppression of NLRP3 inflammasome activation in liver and brain. J Ethnopharmacol. 209:219–229. 2017. View Article : Google Scholar : PubMed/NCBI
18	Gong QH, Pan LL, Liu XH, Wang Q, Huang H and Zhu YZ: S-propargyl-cysteine (ZYZ-802), a sulphur-containing amino acid, attenuates beta-amyloid-induced cognitive deficits and pro-inflammatory response: Involvement of ERK1/2 and NF-κB pathway in rats. Amino Acids. 40:601–610. 2011. View Article : Google Scholar
19	Yan L, Deng Y, Gao J, Liu Y, Li F, Shi J and Gong Q: Icariside II effectively reduces spatial learning and memory impairments in Alzheimer’s disease model mice targeting beta-amyloid production. Front Pharmacol. 8:1062017. View Article : Google Scholar
20	Liu Y, Deng Y, Liu H, Yin C, Li X and Gong Q: Hydrogen sulfide ameliorates learning memory impairment in APP/PS1 transgenic mice: A novel mechanism mediated by the activation of Nrf2. Pharmacol Biochem Behav. 150-151:207–216. 2016. View Article : Google Scholar : PubMed/NCBI
21	Li XH, Deng YY, Li F, Shi JS and Gong QH: Neuroprotective effects of sodium hydrosulfide against β-amyloid-induced neurotoxicity. Int J Mol Med. 38:1152–1160. 2016. View Article : Google Scholar : PubMed/NCBI
22	Tikhonova LA, Kaminsky YG, Reddy VP, Li Y, Solomadin IN, Kosenko EA and Aliev G: Impact of amyloid β_25-35 on membrane stability, energy metabolism, and antioxidant enzymes in erythrocytes. Am J Alzheimers Dis Other Demen. 29:685–695. 2014. View Article : Google Scholar : PubMed/NCBI
23	Wu J, Yang H, Zhao Q, Zhang X and Lou Y: Ginsenoside Rg1 exerts a protective effect against Aβ_25-35-induced toxicity in primary cultured rat cortical neurons through the NF-κB/NO pathway. Int J Mol Med. 37:781–788. 2016. View Article : Google Scholar : PubMed/NCBI
24	Schimidt HL, Garcia A, Martins A, Mello-Carpes PB and Carpes FP: Green tea supplementation produces better neuroprotective effects than red and black tea in Alzheimer-like rat model. Food Res Int. 100:442–448. 2017. View Article : Google Scholar : PubMed/NCBI
25	Colvin MT, Silvers R, Ni QZ, Can TV, Sergeyev I, Rosay M, Donovan KJ, Michael B, Wall J, Linse S and Griffin RG: Atomic resolution structure of monomorphic Aβ42 amyloid fibrils. J Am Chem Soc. 138:9663–9674. 2016. View Article : Google Scholar : PubMed/NCBI
26	Patricio-Martínez A, Mendieta L, Martínez I, Aguilera J and Limón ID: The recombinant C-terminal fragment of tetanus toxin protects against cholinotoxicity by intraseptal injection of beta-amyloid peptide (25-35) in rats. Neuroscience. 315:18–30. 2016. View Article : Google Scholar
27	Yu X, Wang LN, Du QM, Ma L, Chen L, You R, Liu L, Ling JJ, Yang ZL and Ji H: Akebia Saponin D attenuates amyloid β-induced cognitive deficits and inflammatory response in rats: Involvement of Akt/NF-κB pathway. Behav Brain Res. 235:200–209. 2012. View Article : Google Scholar : PubMed/NCBI
28	Carrero I, Gonzalo MR, Martin B, Sanz-Anquela JM, Arévalo-Serrano J and Gonzalo-Ruiz A: Oligomers of β-amyloid protein (Aβ1-42) induce the activation of cyclooxygenase-2 in astrocytes via an interaction with interleukin-1β, tumour necrosis factor-α, and a nuclear factor κ-B mechanism in the rat brain. Exp Neurol. 236:215–227. 2012. View Article : Google Scholar : PubMed/NCBI
29	Wu W, Yang JJ, Yang HM, Huang MM, Fang QJ, Shi G, Mao ZM, Han WB, Shen SM and Wan YG: Multi-glycoside of Tripterygium wilfordii Hook. f. attenuates glomerulosclerosis in a rat model of diabetic nephropathy by exerting anti-microinflammatory effects without affecting hyperglycemia. Int J Mol Med. 40:721–730. 2017. View Article : Google Scholar : PubMed/NCBI
30	Choi JH, Chung KS, Jin BR, Cheon SY, Nugroho A, Roh SS and An HJ: Anti-inflammatory effects of an ethanol extract of Aster glehni via inhibition of NF-κB activation in mice with DSS-induced colitis. Food Funct. 8:2611–2620. 2017. View Article : Google Scholar : PubMed/NCBI
31	Cha HY, Ahn SH, Cheon JH, Park SY and Kim K: Hataedock treatment has preventive therapeutic effects for atopic dermatitis through skin barrier protection in Dermatophagoides farinae-in duced NC/Nga mice. J Ethnopharmacol. 206:327–336. 2017. View Article : Google Scholar : PubMed/NCBI
32	Orban Z, Mitsiades N, Burke TR Jr, Tsokos M and Chrousos GP: Caffeic acid phenethyl ester induces leukocyte apoptosis, modulates nuclear factor-kappa B and suppresses acute inflammation. Neuroimmunomodulation. 7:99–105. 2000. View Article : Google Scholar : PubMed/NCBI
33	Wang H, Xu YS, Wang ML, Cheng C, Bian R, Yuan H, Wang Y, Guo T, Zhu LL and Zhou H: Protective effect of naringin against the LPS-induced apoptosis of PC12 cells: Implications for the treatment of neurodegenerative disorders. Int J Mol Med. 39:819–830. 2017. View Article : Google Scholar : PubMed/NCBI
34	Zhang Q, Li J, Liu C, Song C, Li P, Yin F, Xiao Y, Li J, Jiang W, Zong A, et al: Protective effects of low molecular weight chon-droitin sulfate on amyloid beta (Aβ)-induced damage in vitro and in vivo. Neuroscience. 305:169–182. 2015. View Article : Google Scholar : PubMed/NCBI