SCM-198 Ameliorates Cognitive Deficits, Promotes Neuronal Survival and Enhances CREB/BDNF/TrkB Signaling without Affecting Aβ Burden in AβPP/PS1 Mice

Abstract

SCM-198 is an alkaloid found only in Herba leonuri and it has been reported to possess considerable neuroprotective effects in animal models of ischemic stroke, Parkinson’s disease and Alzheimer’s disease (AD). In this study, we demonstrated for the first time that 3-month oral SCM-198 treatment could significantly improve both recognition and spatial memory, inhibit microgliosis and promote neuronal survival in amyloid-β protein precursor and presenilin-1(AβPP/PS1) double-transgenic mice without affecting amyloid-β (Aβ) burden. In addition, decreases in cAMP-response element-binding protein (CREB) phosphorylation, brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) phosphorylation were attenuated by SCM-198 both in vivo and in primary cortical neurons, which could be blocked by protein kinase A (PKA) inhibitors, suggesting the involvement of upstream PKA in enhancing the BDNF/TrkB/CREB signaling by SCM-198. Our results indicate that SCM-198, a drug that could promote neuronal survival and enhance BDNF/TrkB/CREB signaling, has beneficial effects on behavioral and biochemical alterations without affecting Aβ burden in AβPP/PS1 mice and might become a potential drug candidate for AD treatment in the future.

Leonurine Exerts Antidepressant-Like Effects in the Chronic Mild Stress-Induced Depression Model in Mice by Inhibiting Neuroinflammation

“…Previous studies showed that leonurine, an alkaloid isolated from Herba leonuri , exerts the potential neuroprotective effects in animal models of ischemic stroke, PD, and AD ( Qi et al, 2010 ; Shi et al, 2011 ; Hong et al, 2015 ). However, the effect of leonurine on depression remains unclear.…”

“… Shikov et al (2011) reported that Herba leonuri was used to calm pregnant women suffering from anxiety. In recent years, it is found that leonurine possess neuroprotective effects in animal models of ischemic stroke, PD, and AD ( Liu et al, 2010 ; Shi et al, 2011 ; Hong et al, 2015 ). Leonurine treatment significantly rescued behavioral deficit of animals, promoted neuronal survival, and inhibited inflammation.…”

Actions of Brain-Derived Neurotrophin Factor in the Neurogenesis and Neuronal Function, and Its Involvement in the Pathophysiology of Brain Diseases

“…Oral administration of SCM-198, an alkaloid extracted from Herba leonuri , for 3 months improved both recognition and spatial memory in the APP/PS1 transgenic mice without affecting the amount of Aβ. Importantly, SCM-198 ameliorated the decline in BDNF expression and TrkB activation both in in vivo and in cortical cultures [ 109 ].…”

Chinese Medicine: A Hope for Neurodegenerative Diseases?

“…In addition, SCM198 (4-guanidino-n-butyl syringate), a new compound from HL, was proved to attenuate the neurotoxin (6-OHDA)-induced apoptotic cell death in dopaminergic cells and improve rotational behavior in 6-OHDA-induced motor deficit rat model via an increase in superoxide dismutase antioxidant activity with a decrease in levels of ROS [65]. Furthermore, SCM-198 was confirmed to ameliorate the recognition ability, spatial memory, cognitive deficits, and promote survival of neurons in A␤PP and PS1 transgenic mice [66], suggesting the potential therapeutic value of TCMs on neuroprotection (Fig. 1).…”