I15 Nootropic effect and action mechanisms of Ginsenoside Rg1, a smart drug candidate

Abstract

Cognitive drugs can be classified into two major categories: one improving cognitive impairment in patients and the other increasing mental ability or intelligence capacity in healthy people with neither toxicity nor serious side effects even after long term use. Since decades ago, cognitive scientists have been trying their best to search for the second category of cognitive drugs but with no success. Here, we report ginsenoside Rg1 (Rg1), a molecule isolated from Panax ginseng, as such an excellent candidate with the following pharmacological actions: (1) increasing learning ability and memory acquisition; (2) accelerating neural development measured as an increase in brain weight and cerebral cortex thickness in normal weaning mice; (3) enhancing basic synaptic transmission and inducing LTP; (4) activating nootropic signal transduction pathways including PLC-PKC-pCREB and Ca2+/CaMKII-ERK-pCREB cascades in normal adult rats; (5) promoting acetylcholine synthesis and release; (6) augmenting hippocampal neural stem cell proliferation and differentiation to neurons as well as synaptogenesis in normal adult rats and gerbils. To disclose the mechanistic underpinnings of these Rg1 actions, we found that: (1) Rg1 mainly targets NMDA receptors and nitric oxide synthase (NOS) including nNOS and iNOS, both of which play important roles in personal intelligence, emotional intelligence, neurogenesis and synaptogenesis; (2) Rg1 upregulates acetylcholine content and M-cholinergic receptors in the brain, effects consistent with its action to potentiate learning and memory; (3) Rg1 elevates testosterone level in plasma, which could influence two major memory enhancing transmitters dopamine (DA) and NO - increasing DA level in the medial preoptic area of hypothalamus and inducing NO release in the CNS; (4) Rg1 increases the level of pCREB, which transcribed and expressed gene products identified as FOS, BDNF, and NT-3, which are close-related with long memory, neuron’s growth and development, synaptic plasticity formation. In addition, our chronic toxicity study demonstrated that Rg1 exhibited neither toxicity nor serious side effects in rats and dogs or in human beings with long term use. The brainpower of human beings as a whole is immense. However, individuals use less than twenty percent of their brain capacity, indicating a huge potential room for us to enhance brain function by medical or other interventions. Our research findings on Rg1 boost our confidence in a bright future of cognitive drug development.