Gintonin Attenuates D-Galactose-Induced Hippocampal Senescence by Improving Long-Term Hippocampal Potentiation, Neurogenesis, and Cognitive Functions

Abstract

Background: Ginseng has been used to improve brain function and increase longevity. However, little is known about the ingredients of ginseng and molecular mechanisms of its anti-brain aging effects. Gintonin is a novel exogenous ginseng-derived lysophosphatidic acid (LPA) receptor ligand; LPA and LPA1 receptors are involved in adult hippocampal neurogenesis. D-galactose (D-gal) is used to induce brain ­aging in animal models because long-term treatment with D-gal facilitates hippocampal aging in experimental adult animals by decreasing hippocampal neurogenesis and inducing learning and memory dysfunction. Objective: To investigate the protective effects of gintonin on D-gal-induced hippocampal senescence, impairment of long-term potentiation (LTP), and memory dysfunction. Methods: Brain hippocampal aging was induced by D-gal administration (150 mg/kg/day, s.c.; 10 weeks). From the 7th week, gintonin (50 or 100 mg/kg/day, per os) was co-administered with D-gal for 4 weeks. We performed histological analyses, LTP measurements, and object location test. Results: Co-administration of gintonin ameliorated D-gal-induced reductions in hippocampal Ki67-immunoreactive proliferating cells, doublecortin-immunoreactive neuroblasts, 5-bromo-2’-deoxyuridine-incorporating NeuN-immunoreactive mature neurons, and LPA1 receptor expression. Co-administration of gintonin in D-gal-treated mice increased the expression of phosphorylated cyclic adenosine monophosphate response element binding protein in the hippocampal dentate gyrus. In addition, co-administration of gintonin in D-gal-treated mice enhanced LTP and restored the cognitive functions compared with those in mice treated with D-gal only. Conclusion: These results show that gintonin administration restores D-gal-induced memory deficits by enhancing hippocampal LPA1 receptor expression, LTP, and neurogenesis. Finally, the present study shows that gintonin exerts anti-brain aging effects that are responsible for alleviating brain aging-related dysfunction.

Ongoing Research on the Role of Gintonin in the Management of Neurodegenerative Disorders

“…To show its possible effects against neurodegenerative diseases, gintonin has been used against established models of neurodegeneration. Nam et al analyzed the effects of gintonin against d -galactose-induced neurodegeneration; they showed that gintonin significantly improved the hippocampal LTP, and improved neurogenesis and cognitive performance in mice [ 75 ]. Similarly, in another study, it was suggested that gintonin reduced scopolamine-induced memory dysfunction in mice.…”

Ginseng gintonin, aging societies, and geriatric brain diseases

“…In addition, in an electrophysiological study, d -galactose decreased the long-term potentiation (LTP) amplitude, which is a basic cellular mechanism that underlies learning and memory. 65 Co-administration of gintonin in d -galactose mice enhanced LTP and restored cognitive functions compared with those in mice treated with d -galactose alone. The LPA and LPA1 receptors play a crucial role in early brain development.…”

“…Interestingly, hippocampal LPA1 receptor expression is also diminished under d -galactose insult. 65 Co-administration of gintonin with d -galactose reverses d -galactose-induced reduction of cell proliferation, increases differentiation of immature neurons into mature neurons, and increases LPA1 receptor expression in the mouse hippocampus. Gintonin also increases the expression of phosphorylated cyclic adenosine monophosphate response element binding protein (pCREB), which plays an important role in cognitive functions.…”

“… 54 Gintonin co-administration with d -galactose reversed d -galactose alone-induced hippocampal senescence. 65 Thus, long-term treatment of d -galactose induces hippocampal aging by reducing the hippocampal cell proliferation, differentiation, and maturation observed in human brain aging. Interestingly, hippocampal LPA1 receptor expression is also diminished under d -galactose insult.…”

Preventive Electroacupuncture Ameliorates D‐Galactose‐Induced Alzheimer’s Disease‐Like Pathology and Memory Deficits Probably via Inhibition of GSK3β/mTOR Signaling Pathway

“…Tau phosphorylation is one of the two hallmarks of AD. D-gal was reported to induce tau hyperphosphorylation in rats [43,44] and impact synaptic plasticity [45], so the expression levels of PHF-1 recognizing tau Ser396/404 were evaluated by Western blot. As shown in Figure 5(d), preventive EA prevented and rescued the tau hyperphosphorylation (P < 0.01).…”