Protective effects of ginseng on neurological

disorders Wei-Yi Ong1,2*, Tahira Farooqui3, Hwee-Ling Koh4, Akhlaq

A. Farooqui3 and Eng-Ang Ling1

Ginseng (Order: Apiales, Family: Araliaceae, Genus: Panax)

Roots, stems, and leavesUsed as traditional medicine

>2000yrs

Panax ginseng Korea, ChinaPanax quiquefolium L USA, Canada

Panax notoginseng China

Adaptogenic, RestorativeImmunimodulatory

Anti anxiety, AntidepressantAnti-inflamatory

Anti-aging, AnticancerCognition enhancementAnti-stress, Antioxidant

Introduction

Bioactive ingredients = ginsenosides

>60 ginsenosides:Rb1, Rb2, Rb3, Rc, Rd, Re, Rg1, Rg2 Rg3

Polysaccharides, fatty acids, oligopeptides, polyacetylenic alcohols

Purpose discuss the effects of ginseng on the normal brainits protective effects in neurological disorders

(Alzheimer’sdisease ,major depression, stroke, Parkinson’s disease multiplesclerosis)

Introduction

The most commonly studied ginsenosides are Rb1, Rg1, Rg3, Re, and Rd.

Intact ginsenosides absorbed only from intestines

Metabolized:◦ In stomach acid hydrolisis◦ In intestine bacterial hydrolisis

Metabolism and transformation of intact ginsenosides is an important process.◦ Bioavailability◦ Potential health benefits

Intestinal Metabolism and Actions of Ginseng

Ginsenosides structural classes

Protopanaxadiol (PD)

Ra1, Ra2,Ra3,Rb1,Rb2, Rb3,Rc,Rd,Rg3, Rh2

Protopanaxatriol (PT)

Re,Rf,Rg1,Rg2,Rh1

Oral bioavailability very low

Bacterial metabolized ginsenosides More permeable and

bioactives

Ginsenosides enter brain rapidly concentrations decline

rapidly

Ginsenosides with higher concentrations in the brain :

◦ Rg1, Re, Rb1 and Rc

Rg1 & Re better brain distribution directly affecting CNS

Ginsenosides PD longer time in circulation protect brain

trough peripheral effect

Biovailability of Ginseng

Glutamatergic Neurotransmission

Monoamine Neurotransmission Estrogen Signaling Nitric Oxide

Production

Keap1/Nrf2 Adaptive Cellular Stress Pathway

Neuronal Cell Survival Apoptosis

Neural Stem Cells and

Neuroregeneration

Microglia Astrocytes Oligodendrocytes and myelination

Cerebral Micovessels

Molecular Mechanisms of Effects of Ginseng on the Brain

Neurodegenerative disease Loss of cognitive function & motor disabilities.◦ Alzheimer’s disease◦ Parkinson’s disease◦ Huntington’s disease◦ Amyotropic lateral sclerosis

Accompanied by:◦ Oxidative stress◦ Neuroinflammation◦ Increased generation of lipid mediators◦ Abnormal protein aggregation◦ Slow excitotoxicity◦ Loss of synapses and disintegration of neural network

Protective Effects of Ginseng on Neurological Disorders

Neurotraumatic disease Metabolic or mechanical insult to brain or spinal cord◦ Cerebral ischemia or stroke◦ Spinal cord injury◦ Traumatic brain injury

Neurochemical event:◦ Release of glutamate◦ Overstimulation of glutamate receptors◦ Rapid Ca influx◦ Activation of cytosolic phospolipase◦ Induction of oxidative stress and neuroinflammation

Protective Effects of Ginseng on Neurological Disorders

Neuropsychiatric disorders neurodevelopmental behavioral or psychological difficulties◦ Depression◦ Schizophrenia◦ Bipolar dissorder◦ Impairment of cognitive processes

Abnormalities:◦ Cerebral cortex◦ Ventral striatum◦ Limbic system

Protective Effects of Ginseng on Neurological Disorders

Characterized by extracellular plaques:◦ Aggregated Aβ peptides◦ Neurofibrillary tangles ◦ Hyperphosporilated tau protein

Cerebral amyloid angiopathy:◦ Aβ deposition on arterioles & capillaries wall in brain

Panax notoginseng flavonol glycosides: ◦ inhibited aggregation of Aβ◦ Modulated cell death◦ Reduced memory impairment

Alzheimer’s Disease

Effect on Aβ Formation◦ Neuroprotective effects by reducing Aβ levels◦ Gintonin:

Supress neuroblastoma by decrease Aβ1–42 release, and attenuated Aβ1–40 induced toxicity.

Attenuated amyloid plaque deposition Attenuated short- and long-term memory impairment

◦ Chronic suplementation of ginsenosides: Modulated age-related memory impairment Preserve cognitive function Protection of spatial learning abilities and memory

Alzheimer’s Disease

Effect on tau Phosporilation:◦ Effect by reducing tau hyperphosporilation and

neurofibrillary tangle formation

◦ Rd(10mg/kg 7 days) ↑ activities of protein phosphatase 2A (PP2A) ↓okadaic acid-induced neurotoxicity & tau hyperphosphorylation.

◦ Rb1 mantain PP2A level in cortex and hippocampus.

◦ Rg1(20mg/kg) Supress Aβ formation & phosporilated tau reversed memory impairment

Alzheimer’s Disease

Effect on Reactive Oxygen and Nitrogen Species:◦ Increased Superoxide dismutase (SOD) & glutathione

peroxidase (GSH-Px) activity improve learning & memory

◦ Rg1 modulated reactive nitrogen species in endothelial cells

Effect on Cholinergic and neurotropic Signaling:◦ Loss of ACh is found in AD brain◦ Rg5 ↓ Acetylcholine ssterase(AChE) & ↑ Choline

acetyltransferase (ChAT)◦ modulated cognitive dysfunction and

neuroinflammation

Alzheimer’s Disease

Clinical Studies on Use of Ginseng in AD:◦ High-dose Korean Red Ginseng (9g/day)

Significant improvement on Alzhemer’s Disease Assessment Scale (ADAS) & Clinical Dementia Rating (CDR) after 12 weeks.

In long term (24th, 48th, 96th weeks) MMSE score remained without significant decline

Long- term beneficial effects of Korean Red Ginseng in patients with AD.

Alzheimer’s Disease

Precilinical Studies:◦ Ginseng saponins attenuated depression in rats via:

Effects on Glutamanergic Neurotransmission Effects on Esterogen Signalling Effect on Neural Stem Cells and Neuroregeneration

Clinical Studies:◦ Post menopausal women treated with ginseng

shows significant difference favor of ginseng when compared with placebo.

◦ Korean red ginseng 3g/day decrease depressive symptom by Depression Residual Symptom Scale

Major Depression

Neuroprotective effect via inhibition of ion channels or modulation of vasospasm.

Interaction + anticoagulant Risk of bleeding↑

Ginsenosides Rd (10-50mg/kg):◦ Significantly decreased infarct volume after middle cerebral

artery occusion (MCAO).◦ Neuroprotection transient MCAO/ permanent MCAO

Ginsenosides Rb1 on Hemorrgahic stroke reduce:◦ Neurological deficits◦ Brain edema◦ BBB disruption

Stroke

Ginsenosides Rb1, Rg1, Rd, Re Neuroprotective for Parkinson’s Disesase◦ Inhibition of oxidatives stress & neuroinflammation◦ Decrease toxin-induced apoptosis ◦ Decrease nigral iron levels◦ Regulation of N-methyl-D-aspartate receptor

channel activity

Panax notoginseng provided neuroprotection against loss of dopaminergic neurons and behavioral impairment

Parkinson’s Disease

Ginsenosides Rd:◦ Intraperitoneally administered ginsenoside Rd at

40 mg/kg/day: reduced the permeability of the BBB regulated the secretion of interferon-gamma and IL-

4, and decreased the severity Decreased the severity of multiple sclerosis

Multiple Sclerosis

Many ginsenosides have been isolated and characterized

Molecular mechanism :◦ scavenging free radicals◦ inhibition of inflammation◦ prevention of excitotoxicity

Animal and cell culture studies have indicated that ginsenosides have different activities in both physiological and pathologic conditions.

Conclusions and Future Directions

Ginsenosides produce neuroprotective effects by reducing free radical production and enhancing brain function.

Studies involving each ginsenoside should: ◦ include mechanisms of action◦ Specificity◦ structure and function relationship◦ detailed pharmacokinetics and toxicity studies ◦ therapeutic studies in animal models

Conclusions and Future Directions