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.
Highlights
Diabetes mellitus, characterized by chronic hyperglycemia, is a metabolic disorder with semeiotic symptoms such as polyuria, polyphagia, and polydipsia along with low-grade inflammation [1].Recent clinical and experimental studies suggest that prolonged hyperglycemic conditions influence a progressive impairment of neuronal function in the brain [2,3,4]
Since GS-KG9 and GS-E3D caused a significant reduction in blood glucose levels in STZ-induced diabetic rats, we investigated whether STZ-induced hyperglycemia would lead to microvascular changes and whether GS-KG9 and GS-E3D inhibit blood–brain barrier (BBB) disruption in the brain parenchyma, especially in the hippocampal region
The intensity of Evans blue was reduced in GS-KG9 or GS-E3D-treated groups (Figure 3B,C). These results indicate that GS-KG9 and GS-E3D inhibit BBB disruption by STZ-induced hyperglycemia
Summary
Recent clinical and experimental studies suggest that prolonged hyperglycemic conditions influence a progressive impairment of neuronal function in the brain [2,3,4]. Diabetes mellitus has been associated with increased severity of epileptic seizure [5] and risk of mortality following traumatic brain injury [6]. Diabetes mellitus has been strongly linked to mild cognitive impairments [7,8]. Altered glycemic conditions observed in diabetic patients are prodromal to blood–brain barrier (BBB) impairment [13,14,15,16]. Experimental evidence from in vitro and in vivo studies has shown that BBB integrity in diabetes is somewhat compromised, resulting in increased barrier permeability [13,14,17,18]
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