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Multitarget Therapeutic Effect of Fasudil in APP/PS1transgenic Mice.
CNS Neurol Disord Drug Targets 2017; 16(2):199-209CN

Abstract

INTRODUCTION

Therapeutic strategies targeting Alzheimer's disease-related molecule β- amyloid (Aβ), Tau protein and β-site amyloid precursor protein cleaving enzyme (BACE) have been recently explored. However, the treatment effect for single target is not ideal. Based on multiaspect roles of Rho kinase inhibitor Fasudil on neuroprotection, neurorepair and immunomodulation, we observed therapeutic potential of Fasudil and explored possible mechanisms in amyloid precursor protein/ presenilin-1 transgenic (APP/PS1 Tg) mice, an animal model of Alzheimer's disease.

METHODS

APP/PS1 Tg mice were treated with Fasudil (25 mg/kg/day) for 2 months by intraperitoneal injection. Mouse behavior tests were recorded every day. The expression of Aβ deposition, Tau protein phosphorylation, BACE and postsynaptic density 95 (PSD-95) in hippocampus was assayed. The levels in the brain of Toll-like receptors (TLRs)-nuclear factor kappa B/p65(NF-κB/p65)- myeloid differentiation primary response gene 88 (MyD88) inflammatory cytokine axis were measured.

RESULTS

Fasudil treatment ameliorated learning and memory deficits, accompanied by reduced Aβ deposition, Tau protein phosphorylation, and BACE expression, as well as increased PSD-95 expression in hippocampus. Fasudil intervention also inhibited TLR-2/4, p-NF-κB/p65, MyD88, interleukin-1beta, interleukin-6 and tumor necrosis factor-α for TLRs-NF-κB-MyD88 inflammatory cytokine axis and the induction of interleukin-10.

CONCLUSION

Fasudil exhibited multitarget therapeutic effect in APP/PS1 Tg mice. The study provides preclinical evidence that Fasudil treatment ameliorated memory deficits in APP/PS1 Tg mice, accompanied by the reduction of Aβ deposition and Tau protein phosphorylation, the decrease of BACE and the increase of PSD-95, as well as inhibition of TLRs-NF-κB-MyD88 inflammatory cytokine axis. However, these results still need to be repeated and confirmed before clinical application.

Authors+Show Affiliations

Institute of Brain Science, Shanxi Datong University, Datong, China.Institute of Brain Science, Shanxi Datong University, Datong, China.Institute of Brain Science, Shanxi Datong University, Datong, China.. China.Institute of Brain Science, Shanxi Datong University, Datong. China.The Fifth People`s Hospital of Datong, Datong. China.Department of Neurology, Thomas Jefferson University, Philadelphia, PA. United States.Institute of Brain Science, Shanxi Datong University, Datong. China.Institute of Brain Science, Shanxi Datong University, Datong. China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27401064

Citation

Yu, Jie-Zhong, et al. "Multitarget Therapeutic Effect of Fasudil in APP/PS1transgenic Mice." CNS & Neurological Disorders Drug Targets, vol. 16, no. 2, 2017, pp. 199-209.
Yu JZ, Li YH, Liu CY, et al. Multitarget Therapeutic Effect of Fasudil in APP/PS1transgenic Mice. CNS Neurol Disord Drug Targets. 2017;16(2):199-209.
Yu, J. Z., Li, Y. H., Liu, C. Y., Wang, Q., Gu, Q. F., Wang, H. Q., ... Ma, C. G. (2017). Multitarget Therapeutic Effect of Fasudil in APP/PS1transgenic Mice. CNS & Neurological Disorders Drug Targets, 16(2), pp. 199-209. doi:10.2174/1871527315666160711104719.
Yu JZ, et al. Multitarget Therapeutic Effect of Fasudil in APP/PS1transgenic Mice. CNS Neurol Disord Drug Targets. 2017;16(2):199-209. PubMed PMID: 27401064.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Multitarget Therapeutic Effect of Fasudil in APP/PS1transgenic Mice. AU - Yu,Jie-Zhong, AU - Li,Yan-Hua, AU - Liu,Chun-Yun, AU - Wang,Qing, AU - Gu,Qing-Fang, AU - Wang,Hui-Qing, AU - Zhang,Guang-Xian, AU - Xiao,Bao-Guo, AU - Ma,Cun-Gen, PY - 2016/01/28/received PY - 2016/06/10/revised PY - 2016/07/11/accepted PY - 2016/7/13/pubmed PY - 2018/5/16/medline PY - 2016/7/13/entrez KW - APP/PS1 Tg mice KW - Alzheimer's disease KW - Fasudil KW - Rho kinase SP - 199 EP - 209 JF - CNS & neurological disorders drug targets JO - CNS Neurol Disord Drug Targets VL - 16 IS - 2 N2 - INTRODUCTION: Therapeutic strategies targeting Alzheimer's disease-related molecule β- amyloid (Aβ), Tau protein and β-site amyloid precursor protein cleaving enzyme (BACE) have been recently explored. However, the treatment effect for single target is not ideal. Based on multiaspect roles of Rho kinase inhibitor Fasudil on neuroprotection, neurorepair and immunomodulation, we observed therapeutic potential of Fasudil and explored possible mechanisms in amyloid precursor protein/ presenilin-1 transgenic (APP/PS1 Tg) mice, an animal model of Alzheimer's disease. METHODS: APP/PS1 Tg mice were treated with Fasudil (25 mg/kg/day) for 2 months by intraperitoneal injection. Mouse behavior tests were recorded every day. The expression of Aβ deposition, Tau protein phosphorylation, BACE and postsynaptic density 95 (PSD-95) in hippocampus was assayed. The levels in the brain of Toll-like receptors (TLRs)-nuclear factor kappa B/p65(NF-κB/p65)- myeloid differentiation primary response gene 88 (MyD88) inflammatory cytokine axis were measured. RESULTS: Fasudil treatment ameliorated learning and memory deficits, accompanied by reduced Aβ deposition, Tau protein phosphorylation, and BACE expression, as well as increased PSD-95 expression in hippocampus. Fasudil intervention also inhibited TLR-2/4, p-NF-κB/p65, MyD88, interleukin-1beta, interleukin-6 and tumor necrosis factor-α for TLRs-NF-κB-MyD88 inflammatory cytokine axis and the induction of interleukin-10. CONCLUSION: Fasudil exhibited multitarget therapeutic effect in APP/PS1 Tg mice. The study provides preclinical evidence that Fasudil treatment ameliorated memory deficits in APP/PS1 Tg mice, accompanied by the reduction of Aβ deposition and Tau protein phosphorylation, the decrease of BACE and the increase of PSD-95, as well as inhibition of TLRs-NF-κB-MyD88 inflammatory cytokine axis. However, these results still need to be repeated and confirmed before clinical application. SN - 1996-3181 UR - https://www.unboundmedicine.com/medline/citation/27401064/Multitarget_Therapeutic_Effect_of_Fasudil_in_APP/PS1transgenic_Mice_ L2 - http://www.eurekaselect.com/143854/article DB - PRIME DP - Unbound Medicine ER -