Suppressive Effects of SuHeXiang Wan on Amyloid-β42-Induced Extracellular Signal-Regulated Kinase Hyperactivation and Glial Cell Proliferation in a Transgenic <i>Drosophila</i> Model of Alzheimer’s Disease

Abstract

SuHeXiang Wan (SHXW), a Chinese traditional medicine, has been used to treat infantile convulsions, seizures and strokes. Previously, we reported that modified SHXW, called KSOP1009, suppressed the hyperactivation of c-Jun N-terminal kinase (JNK) and Alzheimer's disease (AD)-like phenotypes in amyloid-β42 (Aβ42)-expressing Drosophila AD models. In the present study, we, further, investigated the detailed mechanism by which KSOP1009 suppresses the AD-like phenotypes of the model flies. As seen in the brains of AD patients, pan-neuronal expression of Aβ42 in Drosophila increased activation of extracellular signal-regulated kinase (ERK), which was monitored by its phosphorylation level, and the number of glial cells in the brain. Suppression of caspase activity did not affect these phenomena, suggesting that Aβ42 induces ERK activation and glial cell proliferation independently of apoptotic processes. KSOP1009 intake significantly reduced the level of ERK activation and the number of glial cells. Moreover, KSOP1009 intake also effectively decreased the defects in the wing vein formation induced by Epidermal growth factor receptor (Egfr) overexpression in fly wings, suggesting that it may contain an inhibitory substance that inhibits the EGFR/ERK signaling pathway. In addition, the Aβ42-induced locomotive defect was partially rescued by inhibition of the elevated ERK activity through its antagonistic drug treatment. Taken together, these results suggest that KSOP1009 exerts its therapeutic effect by inhibiting the EGFR/ERK pathway and glial cell proliferation and by suppressing the JNK pathway and apoptosis.

<i>In Vivo</i> Screening of Traditional Medicinal Plants for Neuroprotective Activity against Aβ42 Cytotoxicity by Using <i>Drosophila</i> Models of Alzheimer’s Disease

“…SH-SY5Y Cells were grown at 37°C in an incubator with 5% CO 2 . To investigate the effects of P. multiflorum and S. commixta extracts on cell viability, cells were pre-treated with P. multiflorum or S. commixta extract for 30 min, and then treated with 25 µM Aβ [25][26][27][28][29][30][31][32][33][34][35] (Sigma-Aldrich) for a further 24 h. Then, the cells were incubated with 2 mg/mL of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT; Sigma-Aldrich) at 37°C in a CO 2 incubator for 3 h. MTT medium was carefully aspirated, and the formazan dye was eluted using dimethyl sulfoxide (DMSO). The plate was shaken, and the absorbance was read using a spectrophotometer (Versamax) at a wavelength of 580 nm.…”

“…8) Our laboratory study revealed that SuHeXiang Wan, a traditional prescription, is neuroprotective against the cytotoxicity of Aβ42 by using Drosophila AD models. 24,25) In the present study, Drosophila AD models were used to screen 23 medicinal plants from Chinese traditional medicine to identify those that possess protective activity against the Aβ42 neurotoxicity. The study revealed that the extracts of five plants showed neuroprotective activities in Aβ42-expressing flies, as seen by their increased survival rates and recovered eye development.…”

“…24,25,37,38) Therefore, we investigated the effects of P. multiflorum and S. commixta extracts intake on JNK or EGFR activity. As shown in Figs.…”

Terpenes from Forests and Human Health

“…Among those, borneol is a bicyclic monoterpene present in several medicinal plants (91)(92)(93)(94). Previous studies showed that borneol has free radical scavenging activity (95) and is a major component of essential oil of SuHeXiang Wan (92) whose neuroprotective function has been reported in in vivo and in vitro models of Alzheimer's disease (AD) (96)(97)(98)(99). Moreover, a recent study showed that borneol exerts a neuroprotective effect against β-amyloid (Aβ) cytotoxicity via upregulation of nuclear translocation of Nrf2 and expression of Bcl-2 (100).…”

Evaluation of Traditional Medicines for Neurodegenerative Diseases Using Drosophila Models

“…Therefore, inhibitors of these signaling molecules are potentially therapeutic drugs. Indeed, when Drosophila AD models were treated with inhibitors of JNK or ERK, their AD-like phenotypes were alleviated [70, 101]. …”