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Isorhynchophylline treatment improves the amyloid-β-induced cognitive impairment in rats via inhibition of neuronal apoptosis and tau protein hyperphosphorylation.

Abstract

The progressive accumulation of amyloid-β (Aβ) in the form of senile plaques has been recognized as a key causative factor leading to the cognitive deficits seen in Alzheimer's disease (AD). Recent evidence indicates that Aβ induces neurotoxicity in the primary neuronal cultures as well as in the brain. Previously, we have demonstrated that isorhynchophylline (IRN), the major chemical ingredient of Uncaria rhynchophylla, possessed potent neuroprotective effects. In the present study, we aimed to investigate the effect of IRN on cognitive function, neuronal apoptosis, and tau protein hyperphosphorylation in the hippocampus of the Aβ25-35-treated rats and to elucidate its action mechanisms. We showed that Aβ25-35 injection caused spatial memory impairment, neuronal apoptosis, and tau protein hyperphosphorylation. Treatment with IRN (20 or 40 mg/kg) for 21 days could significantly ameliorate the cognitive deficits induced by Aβ25-35 in the rats. In addition, IRN attenuated the Aβ25-35-induced neuronal apoptosis in hippocampus by down-regulating the protein and mRNA levels of the ratio of Bcl-2/Bax, cleaved caspase-3 and caspase-9, as well as suppressing the tau protein hyperphosphorylation at the Ser396, Ser404, and Thr205 sites. Mechanistic study showed that IRN could inhibit the glycogen synthase kinase 3β (GSK-3β) activity, and activate the phosphorylation of phosphatidylinositol 3-kinase (PI3K) substrate Akt. These results indicate that down-regulation of GSK-3β activity and activation of PI3K/Akt signaling pathway are intimately involved in the neuroprotection of IRN. The experimental findings provide further evidence to affirm the potential of IRN as a worthy candidate for further development into a therapeutic agent for AD and other tau pathology-related neurodegenerative diseases.

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  • Authors+Show Affiliations

    ,

    School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China.

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    School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China.

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    Institute of Integrative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China.

    ,

    College of Chinese Medicines, Guangzhou University of Chinese Medicine, Guangzhou, China.

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    College of Chinese Medicines, Guangzhou University of Chinese Medicine, Guangzhou, China.

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    College of Chinese Medicines, Guangzhou University of Chinese Medicine, Guangzhou, China.

    ,

    School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China.

    School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China.

    Source

    MeSH

    Alzheimer Disease
    Amyloid beta-Peptides
    Animals
    Apoptosis
    Caspases
    Cognition Disorders
    Cytochromes c
    Disease Models, Animal
    Glycogen Synthase Kinase 3
    Glycogen Synthase Kinase 3 beta
    Hippocampus
    Indole Alkaloids
    Male
    Maze Learning
    Neurons
    Neuroprotective Agents
    Oxindoles
    Peptide Fragments
    Phosphorylation
    Proto-Oncogene Proteins c-akt
    Proto-Oncogene Proteins c-bcl-2
    Rats
    Rats, Sprague-Dawley
    Space Perception
    bcl-2-Associated X Protein
    tau Proteins

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    24164737

    Citation

    Xian, Yan-Fang, et al. "Isorhynchophylline Treatment Improves the Amyloid-β-induced Cognitive Impairment in Rats Via Inhibition of Neuronal Apoptosis and Tau Protein Hyperphosphorylation." Journal of Alzheimer's Disease : JAD, vol. 39, no. 2, 2014, pp. 331-46.
    Xian YF, Mao QQ, Wu JC, et al. Isorhynchophylline treatment improves the amyloid-β-induced cognitive impairment in rats via inhibition of neuronal apoptosis and tau protein hyperphosphorylation. J Alzheimers Dis. 2014;39(2):331-46.
    Xian, Y. F., Mao, Q. Q., Wu, J. C., Su, Z. R., Chen, J. N., Lai, X. P., ... Lin, Z. X. (2014). Isorhynchophylline treatment improves the amyloid-β-induced cognitive impairment in rats via inhibition of neuronal apoptosis and tau protein hyperphosphorylation. Journal of Alzheimer's Disease : JAD, 39(2), pp. 331-46. doi:10.3233/JAD-131457.
    Xian YF, et al. Isorhynchophylline Treatment Improves the Amyloid-β-induced Cognitive Impairment in Rats Via Inhibition of Neuronal Apoptosis and Tau Protein Hyperphosphorylation. J Alzheimers Dis. 2014;39(2):331-46. PubMed PMID: 24164737.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Isorhynchophylline treatment improves the amyloid-β-induced cognitive impairment in rats via inhibition of neuronal apoptosis and tau protein hyperphosphorylation. AU - Xian,Yan-Fang, AU - Mao,Qing-Qiu, AU - Wu,Justin C Y, AU - Su,Zi-Ren, AU - Chen,Jian-Nan, AU - Lai,Xiao-Ping, AU - Ip,Siu-Po, AU - Lin,Zhi-Xiu, PY - 2013/10/30/entrez PY - 2013/10/30/pubmed PY - 2014/10/22/medline KW - Amyloid-β KW - PI3K/Akt signaling pathway KW - apoptosis KW - isorhynchophylline KW - spatial memory KW - tau protein hyperphosphorylation SP - 331 EP - 46 JF - Journal of Alzheimer's disease : JAD JO - J. Alzheimers Dis. VL - 39 IS - 2 N2 - The progressive accumulation of amyloid-β (Aβ) in the form of senile plaques has been recognized as a key causative factor leading to the cognitive deficits seen in Alzheimer's disease (AD). Recent evidence indicates that Aβ induces neurotoxicity in the primary neuronal cultures as well as in the brain. Previously, we have demonstrated that isorhynchophylline (IRN), the major chemical ingredient of Uncaria rhynchophylla, possessed potent neuroprotective effects. In the present study, we aimed to investigate the effect of IRN on cognitive function, neuronal apoptosis, and tau protein hyperphosphorylation in the hippocampus of the Aβ25-35-treated rats and to elucidate its action mechanisms. We showed that Aβ25-35 injection caused spatial memory impairment, neuronal apoptosis, and tau protein hyperphosphorylation. Treatment with IRN (20 or 40 mg/kg) for 21 days could significantly ameliorate the cognitive deficits induced by Aβ25-35 in the rats. In addition, IRN attenuated the Aβ25-35-induced neuronal apoptosis in hippocampus by down-regulating the protein and mRNA levels of the ratio of Bcl-2/Bax, cleaved caspase-3 and caspase-9, as well as suppressing the tau protein hyperphosphorylation at the Ser396, Ser404, and Thr205 sites. Mechanistic study showed that IRN could inhibit the glycogen synthase kinase 3β (GSK-3β) activity, and activate the phosphorylation of phosphatidylinositol 3-kinase (PI3K) substrate Akt. These results indicate that down-regulation of GSK-3β activity and activation of PI3K/Akt signaling pathway are intimately involved in the neuroprotection of IRN. The experimental findings provide further evidence to affirm the potential of IRN as a worthy candidate for further development into a therapeutic agent for AD and other tau pathology-related neurodegenerative diseases. SN - 1875-8908 UR - https://www.unboundmedicine.com/medline/citation/24164737/Isorhynchophylline_treatment_improves_the_amyloid_β_induced_cognitive_impairment_in_rats_via_inhibition_of_neuronal_apoptosis_and_tau_protein_hyperphosphorylation_ L2 - https://content.iospress.com/openurl?genre=article&id=doi:10.3233/JAD-131457 DB - PRIME DP - Unbound Medicine ER -