protective effects of ginseng on neurological disorders
DESCRIPTION
PPTTRANSCRIPT
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