Pharmacological effects of ginsenoside Rg1 in neuropsychopharmacology

Panax Ginseng has been used for thousands of years in traditional Chinese medicine(TCM)as a tonic to improver stamina and vitality.Ginsenoside Rg1(Rg1),a saponin extracted from Panax ginseng,is considered one of the most potent pharmacological candidates among TCM.In various diseases related to nervous system,Rg1 has shown excellent pharmacological activities.①Stroke:Rg1 has been well documented to be effective against ischemic/reperfusion(I/R)neuronal injury.A systematic review and meta-analysis revealed a marked efficacy of Rg1 in experi⁃mental acute ischemic stroke,as manifested by its ability to reduce infract volume and improve neurological score.The protective effects of Rg1 were abolished by injecting of AAV-HIF-miR-144-shRNA into the predicted ischemic penumbra.②Depression:In addition,Rg1 showed antidepressive effects in chronic unpredictable mild stress(CUMS)model of depression and in gonadectomized(GDX)model of neuroendocrine disturbance.Rg1 displayed antidepressant activity through the modulation of HPA and HPG axis,markedly alleviated depression-like behavior in rats.Long-term Rg1 treat⁃ment of CUS-exposed rats also significantly prevented the decrease in dye diffusion and improved the ultrastructure of astrocyte gap junctions in the PFC.Rg1 upregulated Cx43 expression in PFC reduced by CUS exposure,indicating beneficial effects on the functional activity of gap junction channels in the brain.③Parkinson disease(PD):Oral treatment with Rg1 significantly attenuated high MPTP-induced mortality,behavior defects,loss of dopamine neurons and abnormal unltrastructure changes in SNpc.It regulated MPTP-induced reactive astrocytes and microglia and decreased the release of cytokines such as TNF-alpha and IL-1βin SNpc.Rg1 also alleviated the unusual MPTP-induced increase in oligomeric,phosphorylated and disease-relatedα-synuclein in SNpc.④Alzheimer disease(AD):Okadaic acid(OKA)intracerebroventricular injection induced memory impairment,including changes in the ability of orientation navigate,spatial probe and relearning memory in behavioral test of Morris water maze(MWM).OKA treated rats showed memory impair⁃ment including increasing of phospho-tau,decreasing of phospho-GSK3βand the formation ofβ-amyloid in special brain regions,which were reversed by Rg1.The possible neuroprotective mechanism might be that Rg1 decreases OKAinduced memory impairment through GSK3β/tau signaling pathway and/or attenuating Aβformation.Meanwhile,Rg1 activated ERK/MAPK pathway by CaMKIIα,and the activation of CREB was not only dependent on ERK induced by Rg1.Additionally,Rg1 inhibited microglial activation by suppressing Iba1 expression.Rg1 inhibited the inflammation mediated by LPS through suppressing NF-κB and MAPK pathway,which provided the explanation for its therapeutic ef⁃fect on neurodegenerative diseases.

Panax Ginseng has been used for thousands of years in traditional Chinese medicine（TCM） as a tonic to improver stamina and vitality. Ginsenoside Rg1（Rg1）, a saponin extracted from Panax ginseng, is considered one of the most potent pharmacological candidates among TCM. In various diseases related to nervous system, Rg1 has shown excellent pharmacological activities.（1） Stroke: Rg1 has been well documented to be effective against ischemic/reperfusion（I/R） neuronal injury. A systematic review and meta-analysis revealed a marked efficacy of Rg1 in experimental acute ischemic stroke, as manifested by its ability to reduce infract volume and improve neurological score. The protective effects of Rg1 were abolished by injecting of AAV-HIF-mi R-144-sh RNA into the predicted ischemic penumbra.（2） Depression: In addition, Rg1 showed antidepressive effects in chronic unpredictable mild stress（CUMS） model of depression and in gonadectomized（GDX） model of neuroendocrine disturbance. Rg1 displayed antidepressant activity through the modulation of HPA and HPG axis, markedly alleviated depression-like behavior in rats. Long-term Rg1 treatment of CUS-exposed rats also significantly prevented the decrease in dye diffusion and improved the ultrastructure of astrocyte gap junctions in the PFC. Rg1 upregulated Cx43 expression in PFC reduced by CUS exposure, indicating beneficial effects on the functional activity of gap junction channels in the brain.（3） Parkinson disease（PD）: Oral treatment with Rg1 significantly attenuated high MPTP-induced mortality, behavior defects, loss of dopamine neurons and abnormal unltrastructure changes in SNpc. It regulated MPTP-induced reactive astrocytes and microglia and decreased the release of cytokines such as TNF-alpha and IL-1β in SNpc. Rg1 also alleviated the unusual MPTP-induced increase in oligomeric, phosphorylated and disease-related α-synuclein in SNpc.（4） Alzheimer disease（AD）: Okadaic acid（OKA）intracerebroventricular injection induced memory impairment, including changes in the ability of orientation navigate, spatial probe and relearning memory in behavioral test of Morris water maze（MWM）. OKA treated rats showed memory impairment including increasing of phospho-tau, decreasing of phospho-GSK3β and the formation of β-amyloid in special brain regions, which were reversed by Rg1. The possible neuroprotective mechanism might be that Rg1 decreases OKAinduced memory impairment through GSK3β/tau signaling pathway and/or attenuating Aβ formation. Meanwhile, Rg1 activated ERK/MAPK pathway by Ca MKIIα, and the activation of CREB was not only dependent on ERK induced by Rg1. Additionally, Rg1 inhibited microglial activation by suppressing Iba1 expression. Rg1 inhibited the inflammation mediated by LPS through suppressing NF-κB and MAPK pathway, which provided the explanation for its therapeutic effect on neurodegenerative diseases.