Osthole Stimulated Neural Stem Cells Differentiation into Neurons in an Alzheimer's Disease Cell Model via Upregulation of MicroRNA-9 and Rescued the Functional Impairment of Hippocampal Neurons in APP/PS1 Transgenic Mice

Abstract

Alzheimer's disease (AD) is the most serious neurodegenerative disease worldwide and is characterized by progressive cognitive impairment and multiple neurological changes, including neuronal loss in the brain. However, there are no available drugs to delay or cure this disease. Consequently, neuronal replacement therapy may be a strategy to treat AD. Osthole (Ost), a natural coumarin derivative, crosses the blood-brain barrier and exerts strong neuroprotective effects against AD in vitro and in vivo. Recently, microRNAs (miRNAs) have demonstrated a crucial role in pathological processes of AD, implying that targeting miRNAs could be a therapeutic approach to AD. In the present study, we investigated whether Ost could enhance cell viability and prevent cell death in amyloid precursor protein (APP)-expressing neural stem cells (NSCs) as well as promote APP-expressing NSCs differentiation into more neurons by upregulating microRNA (miR)-9 and inhibiting the Notch signaling pathway in vitro. In addition, Ost treatment in APP/PS1 double transgenic (Tg) mice markedly restored cognitive functions, reduced Aβ plague production and rescued functional impairment of hippocampal neurons. The results of the present study provides evidence of the neurogenesis effects and neurobiological mechanisms of Ost against AD, suggesting that Ost is a promising drug for treatment of AD or other neurodegenerative diseases.

<p>Transferrin-Modified Osthole PEGylated Liposomes Travel the Blood-Brain Barrier and Mitigate Alzheimer’s Disease-Related Pathology in APP/PS-1 Mice</p>

“…Additionally, we also encapsulated Ost, an effective Chinese medicine monomer for Alzheimer's disease in our previous study. [19][20][21][22][23] It was hypothesized that Tf mediates the transport of Ost-Lip through the BBB via TfRs located on the surfaces of brain capillary endothelial cells, thereby increasing the accumulation of Ost in the brain. Several reports have indicated that Tf-modified liposomes could be used to transport drugs across the BBB.…”

“…19,20 Current research indicates that Ost has an improved effect on degenerative diseases of the central nervous system, such as Alzheimer's disease. [21][22][23] Ost can partially pass through the BBB as a small fatsoluble molecule, but its neuroprotective efficacy is limited by its poor solubility, poor stability, poor brain targeting, and low bioavailability. 24 Liposomes, nanoparticles, microspheres, and other nano-drug carriers are considered to be effective methods for the improvement of the bioavailability of Ost.…”

Osthole inhibits proliferation of kainic acid‑activated BV‑2 cells by modulating the Notch signaling pathway

“…Therefore, microglial activation and proliferation is an important mechanism for the progressive development of epilepsy and its inhibition could be an opportune target for alleviating post-epileptic injury. osthole can cross the blood-brain barrier and exert neuroprotective effects against alzheimer's disease, traumatic brain injury and transient cerebral ischemia (12,25). luszczki et al (26), observed that osthole suppresses seizure activity in a mouse maximal electroshock-induced seizure model.…”

“…Osthole can cross the blood-brain barrier and exert neuroprotective effects against Alzheimer's disease, traumatic brain injury and transient cerebral ischemia ( 12 , 25 ). Luszczki et al ( 26 ), observed that osthole suppresses seizure activity in a mouse maximal electroshock-induced seizure model.…”

Precision Medicine in Neurodegenerative Diseases: Some Promising Tips Coming from the microRNAs’ World

“…Li et al [45] demonstrated a protective role of Osthole in the neuronal synapse, since it significantly increased the expression of miR-9 in APP-overexpressed cells [45]. Later on, they hypothesized a cross-talk between miR-9 and the Notch signaling pathway in AD models and observed that Osthole may promote the NSCs differentiation via the upregulation of miR-9 and the subsequent inhibition of the Notch signaling pathway in APP-expressing cells [54]. Jiao et al [48] reported a neuroprotective activity of Osthole that involves the upregulation of miR-107 in AD.…”