Abstract
Indirubins are natural occurring alkaloids extracted from indigo dye-containing plants. Indirubins could inhibit various kinases, and might be used to treat chronic myelocytic leukemia, cancer and neurodegenerative disorders. 7-bromoindirubin-3-oxime (7Bio), an indirubin derivative derived from indirubin-3-oxime, possesses inhibitory effects against cyclin-dependent kinase-5 (CDK5) and glycogen synthase kinase-3β (GSK3β), two pharmacological targets of Alzheimer's disease (AD). In this study, we have discovered that 2.3–23.3 μg/kg 7Bio effectively prevented β-amyloid (Aβ) oligomer-induced impairments of spatial cognition and recognition without affecting bodyweight and motor functions in mice. Moreover, 7Bio potently inhibited Aβ oligomer-induced expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Furthermore, 7Bio significantly prevented the decreased expression of synapsin-1 and PSD-95, biomarkers of pre-synaptic and post-synaptic proteins in Aβ oligomer-treated mice. The mean optical density (OD) with hyper-phosphorylated tau (pTau), glial fibrillary acidic protein (GFAP) and CD45 positive staining in the hippocampus of 7Bio-treated mice were significantly decreased compared to those of Aβ oligomer-treated mice. In addition, Western blotting analysis showed that 7Bio attenuated Aβ oligomer-decreased expression of pSer9-GSK3β. Those results suggested that 7Bio could potently inhibit Aβ oligomer-induced neuroinflammation, synaptic impairments, tau hyper-phosphorylation, and activation of astrocytes and microglia, which may contribute to the neuroprotective effects of 7Bio. Based on these findings, we expected that 7Bio might be developed as a novel anti-AD lead compound.
Highlights
Indirubins are indoline alkaloids which were extracted from indigo dye-containing natural plants (Gaboriaud-Kolar et al, 2015; Fang et al, 2017)
7-bromoindirubin-3-oxime (7Bio), a novel indirubin derivative with a bromine molecule in the aromatic ring of indirubin-3-oxime, was one of the most potent indirubin derivatives to induce the death of cancer cells (Ribas et al, 2006). 7Bio at 25 μM could lead to apoptosis in many tumor cell lines, such as SH-SY5Y cells, Jurkat cells, and MDA-MB-231 cells (Nicolaou et al, 2012). 7Bio possesses inhibitory effects against many kinases
We have evaluated the neuroprotective effects of many indirubin derivatives, and found that 7Bio is one of the most potent chemical to inhibit Aβ oligomer-induced neuronal death in SH-SY5Y cells (Figure 1A)
Summary
Indirubins are indoline alkaloids which were extracted from indigo dye-containing natural plants (Gaboriaud-Kolar et al, 2015; Fang et al, 2017). Previous studies have shown that indirubins could inhibit various kinases, including cyclin-dependent kinases (CDKs) and glycogen synthase kinase-3β (GSK3β) in particular, via competitively occupying their ATP binding sites (Ribas et al, 2006; Begum et al, 2015). Indirubins could be used to treat various diseases related to the abnormity of kinases, such as cancer and chronic myelocytic leukemia. 7-bromoindirubin-3-oxime (7Bio), a novel indirubin derivative with a bromine molecule in the aromatic ring of indirubin-3-oxime, was one of the most potent indirubin derivatives to induce the death of cancer cells (Ribas et al, 2006). It was revealed that 7Bio inhibits the activities of CDK1, CDK5, and GSK3β with IC50s at 22, 33 and 32 μM, respectively (Ribas et al, 2006)
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