Nak-Won Sohn

Lithospermi radix Extract Inhibits Histamine Release and Production of Inflammatory Cytokine in Mast Cells

Lithospermi radix (LR, Borraginaceae, the root of Lithospermum erythrorhizon Siebold. et Zuccarinii) is used in herbal medicine to treat such conditions as eczema, skin burns and frostbite. This study investigates the effects of LR on the anti-allergy mechanism. LR inhibited the release of histamine from rat peritoneal mast cells by compound 48/80 in a dose-dependent manner. LR orally administered at 6.59 mg/100 g also inhibited the anti-DNP IgE-induced passive cutaneous anaphylaxis reaction. LR inhibited the PMA plus A23187-induced increase in IL-6, IL-8, and TNF-α expression in HMC-1 cells. In addition, LR also inhibited nuclear factor-kappa B (NF-κB) activation and IκB-α degradation. These results show that LR had an inhibitory effect on the atopic allergic reaction. Furthermore, the in vivo and in vitro anti-allergic effect of LR suggests possible therapeutic applications of this agent for inflammatory allergic diseases.

α-Asarone Ameliorates Memory Deficit in Lipopolysaccharide-Treated Mice via Suppression of Pro-Inflammatory Cytokines and Microglial Activation

α-Asarone exhibits a number of pharmacological actions including neuroprotective, anti-oxidative, anticonvulsive, and cognitive enhancing action. The present study investigated the effects of α-asarone on pro-inflammatory cytokines mRNA, microglial activation, and neuronal damage in the hippocampus and on learning and memory deficits in systemic lipopolysaccharide (LPS)-treated C57BL/6 mice. Varying doses of α-asarone was orally administered (7.5, 15, or 30 mg/kg) once a day for 3 days before the LPS (3 mg/kg) injection. α-Asarone significantly reduced TNF-α and IL-1β mRNA at 4 and 24 hours after the LPS injection at dose of 30 mg/kg. At 24 hours after the LPS injection, the loss of CA1 neurons, the increase of TUNEL-labeled cells, and the up-regulation of BACE1 expression in the hippocampus were attenuated by 30 mg/kg of α-asarone treatment. α-Asarone significantly reduced Iba1 protein expression in the hippocampal tissue at a dose of 30 mg/kg. α-Asarone did not reduce the number of Iba1-expressing microglia on immunohistochemistry but the average cell size and percentage areas of Iba1-expressing microglia in the hippocampus were significantly decreased by 30 mg/kg of α-asarone treatment. In the Morris water maze test, α-asarone significantly prolonged the swimming time spent in the target and peri-target zones. α-Asarone also significantly increased the number of target heading and memory score in the Morris water maze. The results suggest that inhibition of pro-inflammatory cytokines and microglial activation in the hippocampus by α-asarone may be one of the mechanisms for the α-asarone-mediated ameliorating effect on memory deficits.

Inhibitory effects of ginsenoside Rb1 on neuroinflammation following systemic lipopolysaccharide treatment in mice.

Ginsenoside Rb1 (GRb1) is a major ingredient of ginseng and has a wide range of neuroprotection effects. Neuroinflammation is a feature of neurodegenerative conditions and is characterized by microglia activation and the expression of major inflammatory mediators. The present study investigated the modulatory effect of GRb1 on microglia activation, the expression of pro‐inflammatory cytokines and cyclooxygenase (COX)‐2 in the brain induced by systemic lipopolysaccharide (LPS) treatment in C57BL/6 mice. Systemic LPS treatment induces immediate microglia activation in the brain. Based on this information, GRb1 was administered orally, at doses of 10 and 20 mg/kg, 1 h prior to the LPS (3 mg/kg, intraperitoneally) injection. At a dose of 20 mg/kg GRb1 attenuated Iba1 protein expression and morphological activation of microglia by LPS. GRb1 significantly reduced the upregulation of tumor necrosis factor‐α, interleukin (IL)‐1β and IL‐6 mRNA in the brain tissue at 4 h after LPS injection. In addition, the expression of COX‐2 mRNA and protein in the brain tissue were also attenuated at the 20 mg/kg dose of GRb1. These results indicate that GRb1 plays a modulatory role in microglia activation and neuroinflammation. This study shows that GRb1 attenuates microglia activation in the brain using an in vivo animal model. Copyright

Glycyrrhizin Alleviates Neuroinflammation and Memory Deficit Induced by Systemic Lipopolysaccharide Treatment in Mice

The present study investigated the effects of glycyrrhizin (GRZ) on neuroinflammation and memory deficit in systemic lipopolysaccharide (LPS)-treated C57BL/6 mice. Varying doses of GRZ was orally administered (10, 30, or 50 mg/kg) once a day for 3 days before the LPS (3 mg/kg) injection. At 24 h after the LPS injection, GRZ significantly reduced TNF-α and IL-1β mRNA at doses of 30 and 50 mg/kg. COX-2 and iNOS protein expressions were significantly reduced by GRZ at doses of 30 and 50 mg/kg. In the Morris water maze test, GRZ (30 mg/kg) significantly prolonged the swimming time spent in the target and peri-target zones. GRZ also significantly increased the target heading and memory score numbers. In the hippocampal tissue, GRZ significantly reduced the up-regulated Iba1 protein expression and the average cell size of Iba1-expressing microglia induced by LPS. The results indicate that GRZ ameliorated the memory deficit induced by systemic LPS treatment and the effect of GRZ was found to be mediated through the inhibition of pro-inflammatory mediators and microglial activation in the brain tissue. This study supports that GRZ may be a putative therapeutic drug on neurodegenerative diseases associated with cognitive deficits and neuroinflammation such as Alzheimer’s disease.

Immunomodulatory effect of water extract of cinnamon on anti-CD3-induced cytokine responses and p38, JNK, ERK1/2, and STAT4 activation.

Context: Cinnamon bark is a very popular herb used in traditional medicine to treat various disorders such as chronic gastric symptoms, arthritis, and the common cold. Objective: The immunomodulatory effect of water extract of cinnamon bark (CWE) on cytokine secretion and involvement of intracellular signaling molecules in activated T cells have been examined. Materials and methods: Mice were orally administered CWE for 7 days. Serum was obtained 90 min after intravenous injection of anti-CD3 antibody (Ab). Splenocytes were cultured with anti-CD3 Ab and CWE for cytokine expression, cell cycle, apoptotic/necrotic changes, and viability. IκBα, p38, JNK, ERK1/2, STAT4, and STAT6 were analyzed using western blotting. Results: Administration of CWE decreased systemic levels of IFN-γ, but not the levels of IL-4 or IL-2. In vitro, CWE inhibited anti-CD3 Ab-stimulated IFN-γ and IL-4 at the mRNA and secreted protein levels. Despite its inhibition of IL-2 transcript, CWE enhanced IL-2 secretion. CWE treatment caused a reduction in the sub-G1 phase, accompanied by an increased ratio of apoptotic cells to necrotic cells. The increased IL-2 secretion by CWE was not mediated by its direct effect on CD4 T cells. CWE inhibited the activation of p38, JNK, ERK1/2, and STAT4, but not IκBα degradation or STAT6. Discussion and conclusions: These observations provided evidence that CWE was able to down-regulate IFN-γ expression in activated T cells without altering IL-2 production, involving inhibition of p38, JNK, ERK1/2, and STAT4. Our results contribute to a better understanding of the immunomodulatory action of cinnamon bark for the application of inflammatory disorders.

Ameliorating the Effect of Astragaloside IV on Learning and Memory Deficit after Chronic Cerebral Hypoperfusion in Rats

Astragaloside IV (AS-IV) has been reported to have a prominent antioxidant effect and was proposed as a promising agent for the prevention of neurodegenerative disorders accompanied by cognitive impairment. The present study investigated the ameliorating effect of AS-IV on learning and memory deficits induced by chronic cerebral hypoperfusion in rats. Rats were treated with two doses of AS-IV (10 and 20 mg/kg, i.p.) daily for 28 days starting from the 5th week after permanent bilateral common carotid artery occlusion. AS-IV treatment (at dose of 20 mg/kg) significantly improved the spatial learning and memory deficits assessed using the Morris water maze test in rats with chronic cerebral hypoperfusion. AS-IV significantly attenuated neuronal apoptosis as well as the levels of superoxide dismutase and lipid peroxidation markers, including malondialdehyde and 4-hydroxy-2-nonenal, in the hippocampus. AS-IV also significantly reduced 8-hydroxy-2’-deoxyguanosine expression, a maker of oxidative DNA damage, while significantly inhibited the astrocyte and microglia activation in the hippocampus. The results indicate that AS-IV has therapeutic potential for the prevention of dementia caused by cerebral hypoperfusion and suggest that the ameliorating effect of AS-IV on learning and memory deficits might be the result of suppressing neuronal apoptosis and oxidative damage in the hippocampus.

Induction of Th1 cytokines by Leuconostoc mesenteroides subsp. mesenteroides (KCTC 3100) under Th2-type conditions and the requirement of NF-κB and p38/JNK

Leuconostoc mesenteroides subsp. mesenteroides (LMM) KCTC 3100, is one of the prominent species in the fermentation of kimchi, a traditional Korean food. In the present study, we investigated the capacity of this microorganism in inducing Th1 cytokines in the presence of Th2 signals in vitro and in vivo and the requirement of NF-kappaB and MAPK signaling. Stimulation with heat-killed LMM in mouse splenocytes induced the expression of IFN-gamma, which was dependent on IL-12 production by LMM. Pre-treatment with LMM in vitro augmented the production of IFN-gamma and IL-4 in response to anti-CD3 plus recombinant IL-4 (rIL-4). LMM administration to mice, beginning either before or after the development of OVA sensitization, increased OVA-restimulated IFN-gamma production in the splenocytes and reduced serum total and OVA-specific IgE levels. However, only the pre-sensitization treatment induced a slight reduction in IL-4 from the same cells, but the post-sensitization treatment did not. Induction of IL-12 by LMM in peritoneal macrophages involved NF-kappaB, p38 and JNK, but not ERK1/2. In conclusion, our data presented the upregulation of IFN-gamma by LMM under the pro-Th2 conditions and the requirement of NF-kappaB, p38 and JNK for IL-12 production. These observations suggest that this microorganism can be a useful Th1-inducing agent in modulating the Th1/Th2 imbalance.

Detection of Aβ plaques in mouse brain by using a disaggregation-induced fluorescence-enhancing probe

We herein report a fluorescence probe 1 capable of detecting water-soluble oligomeric Aβ aggregates and Aβ fibrils. Upon injection into Aβ42-challenged mouse brains, probe 1 shows increased fluorescence intensity, indicating its facile binding to extracellular Aβ fibrils in brain tissues.

Effects of Tetramethylpyrazine on Microglia Activation in Spinal Cord Compression Injury of Mice

Secondary mechanisms, including inflammation and microglia activation, serve as targets for the development and application of pharmacological strategies in the management of spinal cord injury (SCI). Tetramethylpyrazine (TMP), an active ingredient of Ligusticum wallichii (chuanxiong), has shown anti-inflammatory and neuroprotective effects against SCI. However, it remains uncertain whether the inflammation-suppressive effects of TMP play a modulatory role over microglia activation in SCI. The present study investigated the effects of TMP on microglia activation and pro-inflammatory cytokines in spinal cord compression injury in mice. For a real-time PCR measurement of pro-inflammatory cytokines, SCI was induced in mice by the clip compression method (30 g force, 1 min) and TMP (15 or 30 mg/kg, i.p.) was administered once, 30 minutes before the SCI induction. For immunohistochemistry, TMP (30 mg/kg, i.p.) treatment was given three times during the first 48 hours after the SCI. 30 mg/kg of TMP treatment reduced the up-regulation of TNF-α, IL-1β and COX-2 mRNA in the spinal tissue at four hours after the SCI induction. TMP also significantly attenuated microglia activation and neutrophil infiltration at 48 hours after the SCI induction. In addition, iNOS expression in the spinal tissue was attenuated with TMP treatment. These results suggest that TMP plays a modulatory role in microglia activation and may protect the spinal cord from or potentially delay secondary spinal cord injury.

Scutellaria baicalensis attenuates blood-brain barrier disruption after intracerebral hemorrhage in rats.

Disruption of the blood-brain barrier (BBB) contributes to the inflammatory response and edema formation in the brain, exacerbating brain damage. The present study evaluated the effects of Scutellaria baicalensis (SR) water extracts on BBB disruption after intracerebral hemorrhage (ICH) in rats. ICH was induced by stereotaxic intrastriatal injection of bacterial type VII collagenase, and SR was administrated orally three times (50 mg/ml/kg) during the 48 h after ICH onset. SR treatment significantly reduced the degree of (1) hemorrhage volume and edema percentage of the ipsilateral hemisphere, (2) brain water content, (3) MPO-positive neutrophil infiltration in the peri-hematoma, and (4) BBB permeability measured by Evans blue leakage. In addition, expression of matrix metalloproteinase (MMP)-9, MMP-12, and tissue inhibitor of MMPs (TIMP)-1 were investigated with immunohistochemistry. SR treatment reduced MMP-9 and MMP-12 expression in the peri-hematoma after ICH. These results indicate that SR attenuates the BBB disruption through anti-inflammatory effects and suppression of MMP expression. These findings provide a pharmacological basis for the use of SR in the treatment of the BBB disruption following stroke and trauma.