Multitarget Therapeutic Effect of Fasudil in APP/PS1transgenic Mice.

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: Jie-Zhong Yu, Yan-Hua Li, Chun-Yun Liu, Qing Wang, Qing-Fang Gu, Hui-Qing Wang, Guang-Xian Zhang, Bao-Guo Xiao, Cun-Gen Ma
• Journal: CNS & neurological disorders drug targets (CNS Neurol Disord Drug Targets) Vol. 16 Issue 2 Pg. 199-209 ( 2017) ISSN: 1996-3181 [Electronic] United Arab Emirates
• PMID: 27401064 (Publication Type: Journal Article)
• Copyright: Copyright© Bentham Science Publishers; For any queries, please email at [email protected].

Chemical References

• APP protein, human
• Amyloid beta-Protein Precursor
• Cytokines
• Disks Large Homolog 4 Protein
• Dlg4 protein, mouse
• Mapt protein, mouse
• Neuroprotective Agents
• Nootropic Agents
• PSEN1 protein, human
• Presenilin-1
• tau Proteins
• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
• Amyloid Precursor Protein Secretases
• fasudil

Topics

• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine (analogs & derivatives, pharmacology)
• Alzheimer Disease (drug therapy, metabolism, pathology)
• Amyloid Precursor Protein Secretases (metabolism)
• Amyloid beta-Protein Precursor (genetics, metabolism)
• Animals
• Brain (drug effects, metabolism, pathology)
• Cytokines (metabolism)
• Disks Large Homolog 4 Protein (metabolism)
• Drug Evaluation, Preclinical
• Humans
• Male
• Memory Disorders (drug therapy, metabolism, pathology)
• Mice, Transgenic
• Neuroimmunomodulation (drug effects, physiology)
• Neuroprotective Agents (pharmacology)
• Nootropic Agents (pharmacology)
• Phosphorylation (drug effects)
• Presenilin-1 (genetics, metabolism)
• Spatial Learning (drug effects, physiology)
• tau Proteins (metabolism)