Jie-Zhong Yu 1 , Yan-Hua Li 1 , Chun-Yun Liu 1 , Qing Wang 2 , Qing-Fang Gu 3 , Hui-Qing Wang 4 , Guang-Xian Zhang 5 , Bao-Guo Xiao 3 , Cun-Gen Ma 3 Show Affiliations »
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. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
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. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
Entities: Chemical
Disease
Gene
Species
Keywords:
APP/PS1 Tg mice; Alzheimer's disease; Fasudil; Rho kinase
Mesh： See more »
Substances： See more »
Year: 2017
PMID： 27401064 DOI： 10.2174/1871527315666160711104719
Source DB: PubMed Journal: CNS Neurol Disord Drug Targets ISSN： 1871-5273 Impact factor: 4.388