Prevention of Ischemic Neuronal Death by Intravenous Infusion of a Ginseng Saponin, Ginsenoside Rb₁, That Upregulates Bcl-x_L Expression

Abstract

Almost all agents that exhibit neuroprotection when administered into the cerebral ventricles are ineffective or much less effective in rescuing damaged neurons when infused into the blood stream. Search for an intravenously infusible drug with a potent neuroprotective action is essential for the treatment of millions of patients suffering from acute brain diseases. Here, we report that postischemic intravenous infusion of a ginseng saponin, ginsenoside Rb(1) (gRb(1)) (C(54)H(92)O(23), molecular weight 1109.46) to stroke-prone spontaneously hypertensive rats with permanent occlusion of the middle cerebral artery distal to the striate branches significantly ameliorated ischemia-induced place navigation disability and caused an approximately 50% decrease in the volume of the cortical infarct lesion in comparison with vehicle-infused ischemic controls. In subsequent studies that focused on gRb(1)-induced expression of gene products responsible for neuronal death or survival, we showed that gRb(1) stimulated the expression of the mitochondrion-associated antiapoptotic factor Bcl-x(L) in vitro and in vivo. Moreover, we revealed that a Stat5 responsive element in the bcl-x promoter became active in response to gRb(1) treatment. Ginsenoside Rb(1) appears to be a promising agent not only for the treatment of cerebral stroke, but also for the treatment of other diseases involving activation of mitochondrial cell death signaling.

Intranasal Ginsenoside Rb1 Targets the Brain and Ameliorates Cerebral Ischemia/Reperfusion Injury in Rats

“…3,4,8) These results suggest that GRb1 might have difficulty entering the CNS. The blood-brain barrier (BBB) or other specialized CNS barriers are the main obstacles to the delivery of many potentially therapeutic and diagnostic compounds to specific areas of the brain.…”

“…6,7) Also, some studies have demonstrated that the effects of 0.1-100 nmol/kg intracerebroventricular GRb1 on ischemic injury are comparable to that of several mg/kg GRb1 systemically administrated. 3,4,8) These results suggest that GRb1 might have difficulty entering the CNS. The blood-brain barrier (BBB) or other specialized CNS barriers are the main obstacles to the delivery of many potentially therapeutic and diagnostic compounds to specific areas of the brain.…”

“…3,8) Whether the state of autophagy after focal cerebral ischemia could be influenced by GRb1 has remained unknown.…”

“…17) GRb1 has been proven to ameliorate cerebral ischemic insults. 3,8) Whether the state of autophagy after focal cerebral ischemia could be influenced by GRb1 has remained unknown.…”

Ginsenoside Rb1 protects PC12 cells against β-amyloid-induced cell injury

“…GRb1 (one protopanaxadiol type saponin) is one of the key active compounds of ginseng. Grb1 was recently found to play a role in neuronal cell protection against ischemic insult (15,16). The mechanisms of Grb1 neuroprotection under ischemic stress may be related to the up-regulation of the anti-apoptotic protein expression of Bcl-2 and Bcl-xl and the down-regulation of the proapoptotic protein expression Bax, which inhibited apoptosis by preventing the release of cytochrome c. it is conceivable that Grb1 operates as a roS scavenger, considering its properties in vitro against toxic reactive species, such as hydrogen peroxide and glutamate (13,14).…”