Search

Background Post-traumatic stress disorder (PTSD) is a psychiatric disease that develops following exposure to a traumatic event and is a stress-associated mental disorder characterized by an imbalance of neuroinflammation. Korean red ginseng (KRG) is the herbal supplement that is known to be involved in a variety of pharmacological activities. We aimed to investigate the effects of KRG on neuroinflammation as a potential mechanism involved in single prolonged stress (SPS) that negatively influences memory formation and consolidation and leads to cognitive and spatial impairment by regulating BDNF signaling, synaptic proteins, and the activation of NF-kB. Methods We analyzed the cognitive and spatial memory, and inflammatory cytokine levels during the SPS procedure. SPS model rats were injected intraperitoneally with 20, 50, or 100 mg/kg/day KRG for 14 days. Results KRG administration significantly attenuated the cognitive and spatial memory deficits, as well as the inflammatory reaction in the hippocampus associated with activation of NF-κB in the hippocampus induced by SPS. Moreover, the effects of KRG were equivalent to those exerted by paroxetine. In addition, KRG improved the expression of BDNF mRNA and the synaptic protein PSD-95 in the hippocampus. Taken together, these findings demonstrate that KRG exerts memory-improving actions by regulating anti-inflammatory activities and the NF-κB and neurotrophic pathway. Conclusion Our findings suggest that KRG is a potential functional ingredient for protecting against memory deficits in mental diseases, such as PTSD.

Background: Ginsenosides are the main ingredients of Korean Red Ginseng. They have extensively been studied for their beneficial value in neurodegenerative diseases such as Parkinson's disease (PD). However, the multitarget effects of Korean Red Ginseng extract (KRGE) with various components are unclear. Methods: We investigated the multitarget activities of KRGE on neurological dysfunction and neurotoxicity in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–induced mouse model of PD. KRGE (37.5 mg/kg/day, 75 mg/kg/day, or 150 mg/kg/day, per os (p.o.)) was given daily before or after MPTP intoxication. Results: Pretreatment with 150 mg/kg/day KRGE produced the greatest positive effect on motor dysfunction as assessed using rotarod, pole, and nesting tests, and on the survival rate. KRGE displayed a wide therapeutic time window. These effects were related to reductions in the loss of tyrosine hydroxylase–immunoreactive dopaminergic neurons, apoptosis, microglial activation, and activation of inflammatory factors in the substantia nigra pars compacta and/or striatum after MPTP intoxication. In addition, pretreatment with KRGE activated the nuclear factor erythroid 2–related factor 2 pathways and inhibited phosphorylation of the mitogen-activated protein kinases and nuclear factor-kappa B signaling pathways, as well as blocked the alteration of blood–brain barrier integrity. Conclusion: These results suggest that KRGE may effectively reduce MPTP-induced neurotoxicity with a wide therapeutic time window through multitarget effects including antiapoptosis, antiinflammation, antioxidant, and maintenance of blood–brain barrier integrity. KRGE has potential as a multitarget drug or functional food for safe preventive and therapeutic strategies for PD. Keywords: Korean Red Ginseng extract, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Multitarget effect

Approximately, 7-10 million people in the world suffer from Parkinson's disease (PD). Recently, increasing evidence has suggested the protective effect of estrogens against nigrostriatal dopaminergic damage in PD. In this study, we investigated whether estrogen affects 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral impairment in estrogen receptor alpha (ERα)-deficient mice. MPTP (15mg/kg, four times with 1.5-h interval)-induced dopaminergic neurodegeneration was evaluated in ERα wild-type (WT) and knockout (KO) mice. Larger dopamine depletion, behavioral impairments (Rotarod test, Pole test, and Gait test), activation of microglia and astrocytes, and neuroinflammation after MPTP injection were observed in ERα KO mice compared to those in WT mice. Immunostaining for tyrosine hydroxylase (TH) after MPTP injection showed fewer TH-positive neurons in ERα KO mice than WT mice. Levels of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC, metabolite of dopamine) were also lowered in ERα KO mice after MPTP injection. Interestingly, a higher immunoreactivity for monoamine oxidase (MAO) B was found in the substantia nigra and striatum of ERα KO mice after MPTP injection. We also found an increased activation of p38 kinase (which positively regulates MAO B expression) in ERα KO mice. In vitro estrogen treatment inhibited neuroinflammation in 1-methyl-4-phenyl pyridium (MPP+)-treated cultured astrocyte cells; however, these inhibitory effects were removed by p38 inhibitor. These results indicate that ERα might be important for dopaminergic neuronal survival through inhibition of p38 pathway.

The present study investigated whether 3,4,5-trimethoxycinnamic acid (TMCA) treatment ameliorated restraint stress-provoked anxiety- and depression-like behaviors in mice. Fourteen consecutive days of restraint stress produced anxiety- and depression-like behaviors, including reduced time and frequency in the open arms of the elevated plus maze (EPM), as well as enhanced immobility times in the forced swim test (FST). However, TMCA (50 mg/kg) treatment ameliorated this effect; mice showed increased time and frequency of visits in the open arms of the EPM and showed reduced immobility in the FST. In parallel with the behavioral data, long-lasting stimulation of ΔFosB in the nucleus accumbens shell subregion was exhibited in response to TMCA. Furthermore, a reduction in expression of SC1, a target of ΔFosB, in the nucleus accumbens of mice subjected to restraint stress was significantly reversed by TMCA (50 mg/kg) treatment. Collectively, these results suggest that TMCA treatment might provide a therapeutic strategy for treatment of anxiety and depression.

Actoprotectors are preparations that increase the mental performance and enhance body stability against physical loads without increasing oxygen consumption. Actoprotectors are regarded as a subclass of adaptogens that hold a significant capacity to increase physical performance. The focus of this article is studying adaptogen herbs of genus Panax (P. ginseng in particular) and their capabilities as actoprotectors. Some animal experiments and human studies about actoprotective properties of genus Panax attest that P. ginseng (administered as an extract) significantly increased the physical and intellectual work capacities, and the data provided suggests that ginseng is a natural source of actoprotectors. Preparations of ginseng can be regarded as potential actoprotectors which give way to further research of its influence on physical and mental work capacity, endurance and restoration after exhaustive physical loads while compared with reference actoprotectors.

Dimenhydrinate (DIM) is an over-the-counter antihistamine consisting of diphenhydramine (DIP) and 8-chlorotheophylline (CTP). Medical use of DIM is for prevention of nausea and motion sickness. Recently, it has been reported that DIM may be used alone or in combination with other drugs for recreational purposes due to its euphoric and hallucinogenic effects. To investigate the putatively rewarding properties of DIM and its constituents DIP and CTP, we used a conditioned place preference (CPP) test in mice. DIM significantly induced CPP at a dose of 30 mg/kg. Neither DIP (3, 10, and 30 mg/kg) nor CTP (3, 10, and 30 mg/kg) alone induced CPP. Because neither DIP nor CTP resulted in CPP, the rewarding property of DIM appears to be caused by the sum of the effects of its constituents. In addition, low doses of DIM (3 mg/kg), co-administered with low doses of cocaine (7.5 mg/kg), significantly induced CPP, while neither low-dose DIM (3 mg/kg) nor low-dose cocaine (7.5 mg/kg) administered separately induced CPP. This result suggests the liability of DIM use in combination with other abused drugs to create a stronger effect.

Ginseng saponin has been shown to inhibit the development of dependence on morphine, cocaine, methamphetamine, but the antinarcotics effects of ginseng on nalbuphine remains still largely unknown. Ginseng administration attenuated the naloxone-induced jumping behavior on nalbuphine dependent mice. The development of morphine dependence was mediated through receptor, however, development of nalbuphine dependence was mediated through receptor. However, it was found that the efficacy of analgesic antagonism of GTS was mediated through the serotonergic mechanism, not mediated through the opioid receptor. In addition, ginseng administration modulated cellular signal transduction in the brain. The increased NMDA receptor subunit (NR1, pNR1), phosphate extracellular signal regulated protein kinase (pERK), phosphate cAMP response element binding protein (pCREB) expression by nalbuphine was decreased by the administration of ginseng powder in cortex, hippocampus, striatum of rat brain. These results suggest that ginseng could be one of the targets of antinarcotic therapies to reduce the development of tolerance and dependence on nalbuphine as well as morphine.

A simple synthesis and biological properties of 1,3-diphenyl-2-propen-1-ones 18-22 and 25-26 are described. The key synthetic strategies involve Grignard reaction of aldehyde 2 and oxidation reaction of 8-12 in high yields. The prepared compounds 18-22 and 25-26 were evaluated for free-radical scavenging, suppression of LPS-induced NO generation, and anti-excitotoxicity in vitro. It was found that a couple of compounds, especially 21 and 26, were potent suppressors of NO generation and demonstrated anti-excitotoxicity with the concentration range 10-20 microM in vitro.

Ceramide has been involved in cell death and acted as a lipid mediator of stress responses. Elevation of ceramide level was reported to occur in oxidative stress and lead to cell death in many cell types. This study was undertaken to elucidate a protective role of ginsenoside Rg1 in cell death induced by oxidative stress. When LLC-PK1 cells were treated with H₂O₂ at a concentration of 400 μM for 5 hr, cell death was observed and a released LDH activity indicative of cytotoxicity was increased. H₂O₂ exposure to LLC-PK1 cells was shown to elevate the content of total ceramide by approximately 200% compared to control cells. Ceramide level was hypothesized to be a key to a reversal of cell death to survival. Ginsenoside Rg1 at the concentrations ranging from 12.5 to 250 μM protected LLC-PK1 cells from cell death induced by H₂O₂ at 400 μM for 5 hr, and decreased the ceramide level relative to H₂O₂. Ginsenoside Rg1 inhibited neutral human ceramidase by 71% of controls, while sphingomyelinase was not inhibited. These results suggest that ginsenoside Rg1 show the protection against cell death via the modulation of ceramide metabolism, and ceramide may be a promising therapeutic target for human diseases related to cell death.

This study was undertaken to determine the antagonism of the ginseng total saponin (GTS) on the development of nalbuphine-induced tolerance and physical dependence. GTS is known to have antinarcotic action with a dose of 100㎎/kg (i.p.) in rats. GTS significantly inhibits the development of nalbuphine-induced physical dependence as well as the tolerance. The level of pCRES was elevated in the striatum by the chronic treatment with nalbuphine or GTS, however, the elevation of pCRES was inhibited by the GTS co-treatment. It has been suggested that NMDA receptor and/or NO is involved in the penomena of opioid dependence and withdrawal. However, the level of nNOS and NRI was not modulated by the treatment with nalbuphine or GIS on the cortex, hippocampus and striatum in the rat brain. These results suggest that the GTS could be used to ameliorate the nalbuphine tolerance and withdrawal symptoms.

A series of 4-hydroxycoumarin derivatives was prepared and evaluated for antitumor activity. The key fragments were 2a-c, 5c, 12b, 13b, 17, and 18 which were prepared via dianion ring cyclization, Friedel-Crafts acylation, and Reformatsky reaction. Compound 20b showed the most potent antitumor activity among the total 12 derivatives and compounds 19a and 19b exhibited efficacy comparable to etoposide in vitro antitumor activity.

To examine a role of N-methyl-D-aspartate (NMDA) receptors in the locus coeruleus (LC) in the expression of the withdrawal signs from opioids, rats were continuously infused with morphine (a mu-opioid agonist, 26 nmol/microl per h) or butorphanol (a mu/delta/kappa-mixed opioid agonist, 26 nmol/microl per h) intracerebroventricularly (i.c.v.) through osmotic minipumps for 3 days. An LC injection of NMDA (0.1 and 1 nmol/5 microl) induced withdrawal signs in opioid-dependent animals. However, it did not precipitate any abnormal behaviors in saline-treated control rats. The expression of the withdrawal signs precipitated by NMDA (1 nmol/5 microl), glutamate (10 nmol/5 microl), or naloxone (an opioid antagonist, 24 nmol/5 microl) was completely blocked by pretreatment with a NMDA antagonist, MK-801 (5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptan-5,10-imine), 0.1 mg/kg, i.p. In animals that had been infused with opioids in the same manner, naloxone (48 nmol/5 microl, i.c.v.) precipitated withdrawal signs and increased extracellular glutamate levels in the LC of opioid-dependent rats measured by in vivo microdialysis method. Pretreatment with MK-801, however, did not affect the increases of glutamate levels in the LC. These results further demonstrate that the expression of opioid withdrawal induced by an expeditious release of glutamate in the LC region of opioid-dependent animals might be mainly mediated by the postsynaptic NMDA receptors.

The hepatoprotective effects of acetylbergenin were examined against D -galactosamine (GalN)-induced liver damage in rats, compared with that of bergenin reported previously. Acetylbergenin was synthesized from acetylation of bergenin, isolated from Mallotus japonicus, to increase lipophilic and physiological activities. Acetylbergenin was administered orally once daily for 7 days and then GalN (400 mg kg−1, i.p.) was injected at 24 h and 96 h after the final administration of acetylbergenin. Acetylbergenin reduced the elevated serum enzyme activities of alanine/aspartate aminotransferase, sorbitol dehydrogenase and γ -glutamyltransferase and the formation of hepatic malondialdehyde induced by GalN. Acetylbergenin also significantly restored towards normalization the decreased levels of glutathione and the decreased activities of glutathione S-transferase and glutathione reductase induced by GalN. Therefore, these results suggest that acetylbergenin has hepatoprotective effects against GalN-induced hepatotoxicity by inhibiting lipid peroxidation and maintaining an adequate level of GSH for the detoxification of xenobiotics as underlying hepatoprotective mechanisms. In addition, lipophilic acetylbergenin showed more activity in the hepatoprotection than that of the much less lipophilic bergenin reported previously.

In the present study, we have investigated the effects of prolonged inhibition of NMDA receptor by infusion of subtoxic dose of MK-801 to examine the modulation of GABA A receptor binding and GABA A receptor subunit mRNA level in rat brain. It has been reported that NMDA-selective glutamate receptor stimulation alters GABA A receptor pharmacology in cerebellar granule neurons in vitro by altering the levels of selective subunit. However, we have investigated the effect of NMDA antagonist, MK-801, on GABA A receptor binding characteristics in discrete brain regions by using autoradiographic and in situ hybridization techniques. The GABA A receptor bindings were analyzed by quantitative autoradiography using [ 3 H]muscimol, [ 3 H]flunitrazepam, and [ 35 S]TBPS in rat brain slices. Rats were infused with MK-801 (1 pmol/10 μl per h, i.c.v.) for 7 days, through pre-implanted cannula by osmotic minipumps (Alzet, model 2ML). The levels of [ 3 H]muscimol binding were highly elevated in almost all of brain regions including cortex, caudate putamen, thalamus, hippocampus, and cerebellum. However, the [ 3 H]flunitrazepam binding and [ 35 S]TBPS binding were increased only in specific regions; the former level was increased in parts of the cortex, thalamus, and hippocampus, while the latter binding sites were only slightly elevated in parts of thalamus. The levels of β2-subunit were elevated in the frontal cortex, thalamus, hippocampus, brainstem, and cerebellar granule layers while the levels of β3-subunit were significantly decreased in the cortex, hippocampus, and cerebellar granule layers in MK-801-infused rats. The levels of α6- and δ-subunits, which are highly localized in the cerebellum, were increased in the cerebellar granule layer after MK-801 treatment. These results show that the prolonged suppression of NMDA receptor function by MK-801-infusion strongly elevates [ 3 H]muscimol binding throughout the brain, increases regional [ 3 H]flunitrazepam and [ 35 S]TBPS binding, and alters GABA A receptor subunit mRNA levels in different directions. The chronic MK-801 treatment has differential effect on various GABA A receptor subunits, which suggests involvement of differential regulatory mechanisms in interaction of NMDA receptor with the GABA receptors.

The hepatoprotective effects of bergenin, a major constituent of Mallotus japonicus , were evaluated against carbon tetrachloride (CCl 4 )-induced liver damage in rats. Bergenin at a dose of 50, 100 or 200 mg/kg was administered orally once daily for successive 7 days and then a mixture of 0.5 ml/kg (ip) of CCl 4 in olive oil (1:1) was injected two times each at 12 and 36 h after the final administration of bergenin. The substantially elevated serum enzymatic activities of alanine/aspartate aminotransferase, sorbitol dehydrogenase and γ-glutamyltransferase due to CCl 4 treatment were dose dependently restored towards normalization. Meanwhile, the decreased activities of glutathione S-transferase and glutathione reductase were restored towards normalization. In addition, bergenin also significantly prevented the elevation of hepatic malondialdehyde formation and depletion of reduced glutathione content in the liver of CCl 4 -intoxicated rats in a dose dependent fashion. The results of this study clearly indicate that bergenin has a potent hepatoprotective action against CCl 4 -induced hepatic damage in rats.

The present study showed that the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists, MK-801 {(+)-5-methyl-10,11-dihydroxy-5H-dibenzo-[a,d]-cyclohepten-5,10-im ine hydrogen maleate}, ketamine, dextrorphan and dextromethorphan attenuated apomorphine-induced climbing behavior in reserpine-treated mice. In addition, the competitive NMDA receptor antagonists, D(-)-2-amino-5-phosphonopentanoic acid (AP-5) and D(-)-3-(2-carboxypipera-zine-4-yl)-propyl-1-phosphonic acid (CPP), also inhibited the apomorphine-induced climbing behavior in reserpine-treated mice as well as in intact mice. Previous work in our laboratory had shown that the noncompetitive NMDA receptor antagonists, MK-801, ketamine, dextrorphan and dextromethorphan cause a pronounced inhibition of apomorphine-induced cage climbing behavior in intact mice, suggesting the involvement of NMDA receptors in the glutamatergic modulation of dopaminergic function at the postsynaptic dopamine (DA) receptors. Therefore, the present results strongly support our previous conclusion that the NMDA receptors play important roles in the glutamatergic modulation of dopaminergic function at the postsynaptic DA receptors.

The influence of centrally administered pentobarbital on [3H]glutamate receptor binding in the rat brain was examined. Animals were rendered tolerant by intracerebroventricular (i.c.v.) infusion through osmotic minipumps with pentobarbital (300 microg/10 microl/h, for 6 days), and dependent, by 24 h after withdrawal from pentobarbital. Pentobarbital tolerant rats have significant increases in [3H]glutamate binding in the cortex and hippocampus area. Pentobarbital withdrawal produced increases in glutamate binding in many regions, e.g., the cortex, hippocampus area, thalamus, and cerebellum. These results show that chronic i.c.v. infusion with pentobarbital increases N-methyl-D-aspartate (NMDA) displaceable [3H]glutamate binding, suggesting that an increase in NMDA binding sites may play an important role in the development of tolerance to and withdrawal from pentobarbital.

The NMDA receptor has been implicated in opioid tolerance and physical dependence. Using in situ hybridization techniques, the effects of chronic morphine treatment on the expression of mRNAs encoding the NMDA receptor subunits NRI, NR2A, and NR2B were investigated. A significant increase in the level of the NR1 subunit mRNA was found in the locus coeruleus and the hypothalamic paraventricular nucleus following 3 days of intracerebroventricular (i.c.v.) morphine infusion (26 nmol microl(-1) h(-1)) through osmotic minipumps. No changes were detected in expression of the NRI mRNA in the frontal cortex, caudate-putamen, nucleus accumbens, amygdala, CA1, CA2, and the dentate gyrus of the hippocampus, and in the central grey after morphine treatment. The expression of NR2A and NR2B subunit mRNAs did not change after morphine treatment in any brain region. These results suggest that changes in gene expression of the NRI subunit of the NMDA receptor are involved in the development of morphine tolerance and dependence.

Effects of activation of protein kinase C (PKC) on N-methyl-D-aspartate) NMDA receptor function were analyzed by quantitative autoradiography using [3H]MK-801 in rat brain slices. The density of [3H]MK-801 binding was highest in hippocampus and high levels were found in cortex, striatum and thalamus. Levels in brainstem and molecular layer of cerebellum were low. The receptor binding was markedly decreased in almost all areas by addition of 2. 5 mM Mg2+. After activation of PKC by 100 nM phorbol-12, 13-dibutyrate (PDBu), [3H]MK-801 binding was increased in most areas, but binding levels were not changed in brainstem and cerebellum. The elevated [3H]MK-801 binding produced by PDBu was significantly inhibited by addition of Mg2+ except in inferior colliculus and cerebellum. These results suggest that activation of PKC potentiates NMDA receptor function in a region-specific manner in the rat brain.

1. 1. Treatment of cultured cerebellar granule cells for 3 min with N-methyl-D-aspartate (NMDA) resulted in a concentration-dependent elevation of cyclic GMP. However, neither kainate (KA) nor NMDA produced a concentration-dependent elevation of this nucleotide after exposing cells to the agonist for 60 min. 2. 2. Unlike the case for cGMP, both KA and NMDA produced concentration-dependent elevations of glutamate for 60 min incubation. 3. 3. The NMDA-induced elevations of cGMP and glutamate were blocked by selective NMDA receptor antagonists. 4. 4. The selective KA/α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist, 6,7-nitroquinoxaline-2,3-dione (DNQX), blocked the KA-induced elevations of cGMP with 3-min exposures, but it augmented the response with 60-min exposures. However, the KA-induced release of glutamate was prevented by DNQX. 5. 5. The KA/AMPA receptor antagonist, GYKI 52466, blocked all KA-induced responses regardless of the incubation times.