Ginseng Extracts, GS-KG9 and GS-E3D, Prevent Blood–Brain Barrier Disruption and Thereby Inhibit Apoptotic Cell Death of Hippocampal Neurons in Streptozotocin-Induced Diabetic Rats

Abstract

Type 1 diabetes mellitus is known to be linked to the impairment of blood–brain barrier (BBB) integrity following neuronal cell death. Here, we investigated whether GS-KG9 and GS-E3D, bioactive ginseng extracts from Korean ginseng (Panax ginseng Meyer), inhibit BBB disruption following neuronal death in the hippocampus in streptozotocin-induced diabetic rats showing type 1-like diabetes mellitus. GS-KG9 and GS-E3D (50, 150, or 300 mg/kg, twice a day for 4 weeks) administered orally showed antihyperglycemic activity in a dose-dependent manner and significantly attenuated the increase in BBB permeability and loss of tight junction proteins. GS-KG9 and GS-E3D also inhibited the expression and activation of matrix metalloproteinase-9 and the infiltration of macrophages into the brain parenchyma, especially into the hippocampal region. In addition, microglia and astrocyte activation in the hippocampus and the expression of proinflammatory mediators such as tnf-α, Il-1β, IL-6, cox-2, and inos were markedly alleviated in GS-KG9 and GS-E3D-treated group. Furthermore, apoptotic cell death of hippocampal neurons, especially in CA1 region, was significantly reduced in GS-KG9 and GS-E3D-treated groups as compared to vehicle control. These results suggest that GS-KG9 and GS-E3D effectively prevent apoptotic cell death of hippocampal neurons by inhibiting BBB disruption and may be a potential therapy for the treatment of diabetic patients.

Pectin-Lyase-Modified Ginseng Extract and Ginsenoside Rd Inhibits High Glucose-Induced ROS Production in Mesangial Cells and Prevents Renal Dysfunction in db/db Mice

“…The level of ginsenoside Rd in GS-E3D was enriched 3-fold compared to an unmodified red ginseng extract [ 25 ]. Indeed, GS-E3D has shown more potent pharmacological activities in several animal experiments [ 7 , 25 , 27 , 28 , 29 ].…”

Effects of diabetes on microglial physiology: a systematic review of in vitro, preclinical and clinical studies

“…Diabetes-associated inflammation has also been detected by other inflammatory markers. CD68 labeling shows that macrophages are increased in the hippocampus from STZ-treated rats [85] and mice, but not in the midbrain or the cerebellum, suggesting a region-specific vulnerability [79]. Likewise, CD11b labeling with OX42 increased in the hippocampus [85][86][87] and specifically in the hippocampal CA1 pyramidal area [88], as well as in the cortex and striatum [86,89,90], the pars nervosa of the pituitary [91], the hypothalamus, the basolateral amygdala [90] and the supraoptic nucleus [92] as diabetes progresses.…”

“…CD68 labeling shows that macrophages are increased in the hippocampus from STZ-treated rats [85] and mice, but not in the midbrain or the cerebellum, suggesting a region-specific vulnerability [79]. Likewise, CD11b labeling with OX42 increased in the hippocampus [85][86][87] and specifically in the hippocampal CA1 pyramidal area [88], as well as in the cortex and striatum [86,89,90], the pars nervosa of the pituitary [91], the hypothalamus, the basolateral amygdala [90] and the supraoptic nucleus [92] as diabetes progresses. The paraventricular nucleus [91] and the tractus solitarius also show increased presence of microglia by CD11b immunostaining, while the morphology of the cells is altered and they have fewer processes [93].…”

“…Inflammation and vascular injury in the hypothalamus from diabetic mice might be mediated by matrix metalloproteinase-2 activation and indoleamine 2,3-dioxygenase production [84]. BBB compromise in STZ-treated animals results in reduction of zona occludens-1 (ZO-1), occludin and claudin-5 in the hippocampus from diabetic rats [85].…”

Advanced Bioinformatics Tools in the Pharmacokinetic Profiles of Natural and Synthetic Compounds with Anti-Diabetic Activity

“…In rats with type 1-like diabetes mellitus, Lee et al found that ginseng extracts, gs-kg9 and gs-e3d, reduce BBB damage and thereby decrease apoptotic cell death of hippocampus neurons. The findings revealed that GS-KG9 and GS-E3D inhibited MMP-9 expression and activation, had dose-dependent antihyperglycemic action, and dramatically reduced BBB permeability and tight junction protein loss [ 214 ].…”