Osthole Reverses Beta-Amyloid Peptide Cytotoxicity on Neural Cells by Enhancing Cyclic AMP Response Element-Binding Protein Phosphorylation

Abstract

Accumulation of β-amyloid peptide (Aβ) in the brain plays an important role in the pathogenesis of Alzheimer's disease (AD). Previous studies have demonstrated the neuroprotective role of osthole against oxygen and glucose deprivation in cortical neurons. However, the effects of osthole on Aβ-induced neurotoxicity in neural cells have rarely been reported. The current study was designed to investigate the protective effects of osthole on a cell model of AD insulted by exogenous Aβ 25-35 and the potential mechanism(s). In this study, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, immunofluorescence analysis, apoptosis assay, reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) techniques were used in primary cortical neurons and SH-SY5Y cells. Our data showed that osthole reduced intracellular Aβ levels in neural cells, which was associated with decreased BACE1 protein; osthole reversed exogenous Aβ 25-35 -induced cell viability loss, apoptosis, and synapsin-1 reduction, which was related to the reestablishment of phosphorylation of cyclic AMP response element-binding protein (CREB). The collective evidence indicates that osthole possesses the ability to protect cortical neurons and SH-SY5Y cells against Aβ injury, and the underlying mechanism may be attributed to the enhancement of CREB phosphorylation.Key words osthole; Alzheimer's disease; cyclic AMP response element-binding protein; β-amyloid peptide [25][26][27][28][29][30][31][32][33][34][35] Alzheimer's disease (AD) is an irreversible neurodegenerative disorder of the brain characterized by progressive cognitive loss and memory decline. The abnormal deposition of β-amyloid peptide (Aβ) is one of the most notable neuropathological hallmarks of AD. Aβ-Induced synaptic loss and subsequent neuronal death have been implicated as a major cause of the cognitive decline associated with AD.1-4) Accumulating evidence suggests that multiple cellular targets and signaling pathways mediate Aβ-induced neurotoxicity, including N-methyl-D-aspartate (NMDA) receptors and cyclic AMP response element-binding protein (CREB).5,6) CREB is a prosurvival transcription factor responsible for the expression of a large number of downstream genes, 7) such as brain-derived neurotrophic factor (BDNF), an important neurotrophic factor that possessed ability to promote neural protection, plasticity, and regeneration in a variety of conditions, such as central nervous system (CNS) injury, cerebral ischemia, and electrical stimulation.8-10) It is well established that several protein kinase pathways converge to co-regulate CREB activity. Aβ has been shown to interfere with events downstream of activated CREB, especially gene expression of BDNF.11) Moreover, reduced phosphorylation of CREB (p-CREB) has been observed in postmortem brains of AD patients and in transgenic (Tg)-AD mice overexpressing Aβ.12,13) It has been reported that enhanced CREB function in the CA1 region of the dorsal hippocampus rescues the spatia...

Osthole Upregulates BDNF to Enhance Adult Hippocampal Neurogenesis in APP/PS1 Transgenic Mice

“…13,14) Memory impairments were seen as early as 7 months of age, 43) thus, in the present study, we used APP/PS1 mice at age of 8-9 months. Osthole, an active constituent of Angelica Pubescentis Radix (R. angelicae pubescentis) and Cnidium monnieri (L.) CUS-SON, has been reported to exert neuroprotective effects [21][22][23][24][25][26] and possess the capable of improvement of neural stem cell proliferation. 27) Recently, osthole also has been reported to reverse Aβ neurotoxicity by stimulating BDNF production and enhancing CREB phosphorylation in cultured cortical neurons.…”

“…27) Recently, osthole also has been reported to reverse Aβ neurotoxicity by stimulating BDNF production and enhancing CREB phosphorylation in cultured cortical neurons. 21) However, the therapeutic effects of osthole on AD animals are largely unknown. Our results showed that osthole treatment improved the learning and memory impairment in APP/PS1mice in MWM tests and PAT, decreasing the escape latency and the path length to goal, prolonging the time spent in target quadrant and increasing the times of passing through the goal, indicating that osthole treatment ameliorated the cognitive deficits in APP/PS1 transgenic mice.…”

“…21) It has been previously reported that osthole exerts neuroprotective effects in some experimental models of cerebral ischemia/reperfusion and brain injury via anti-oxidative and anti-inflammatory activities, [22][23][24][25][26] and it attenuates clinical severity and demyelination of experimental autoimmune encephalomyelitis (EAE) in mice. 27) Recently osthole has been reported to be capable of improving the proliferation of neural stem cells (NSCs) in vitro and enhancing the expression of BDNF in the CNS, 28) displaying a promising capacity to augment adult hippocampal neurogenesis in AD.…”

The Coumarin Derivative Osthole Stimulates Adult Neural Stem Cells, Promotes Neurogenesis in the Hippocampus, and Ameliorates Cognitive Impairment in APP/PS1 Transgenic Mice

“…5C, D), and our previous study which indicated that Ost reduced intracellular level of Aβ both in neurons and SH-SY5Y cells. 54) Mechanisms underlying the reduction of Aβ by Ost-treatment still needs to be further investigated. There is increasing evidence that some compounds act directly on a nucleotide-binding site within γ-secretase to selectively block cleavage of APP-but not Notch-based substrates, thus specifically modulate the generation of Aβ while sparing Notch.…”

Osthole Enhances the Therapeutic Efficiency of Stem Cell Transplantation in Neuroendoscopy Caused Traumatic Brain Injury

“…In Kampo Cnidium monnieri (L.) has been shown to be effective on improving intelligence. 14) Osthole is known for its therapeutic effect on central nervous system diseases such as Alzheimer's disease, 15) Autoimmune encephalomyelitis, 16) and Cognitive impairment. 17) Previous studies demonstrated that osthole is an effective compound for the treatment of traumatic brain injury.…”