Choon-Gon Jang

Neuroprotective effects of chlorogenic acid on scopolamine-induced amnesia via anti-acetylcholinesterase and anti-oxidative activities in mice.

Chlorogenic acid is a major polyphenolic component of many plants and beverages, and is particularly abundant in coffee. We evaluated the neuroprotective effects of chlorogenic acid on learning and memory impairment induced by scopolamine (0.5 mg/kg, i.p.), a muscarinic antagonist, using the Y-maze, passive avoidance, and Morris water maze tests. The chlorogenic acid significantly improved the impairment of short-term or working memory induced by scopolamine in the Y-maze test, and significantly reversed cognitive impairments in mice as measured by the passive avoidance test. In addition, chlorogenic acid decreased escape latencies in the Morris water maze test. In a probe trial session, chlorogenic acid increased the latency time in the target quadrant in a dose-dependent manner. Ex vivo, chlorogenic acid inhibited acetylcholinesterase activity in the hippocampus and frontal cortex. Chlorogenic acid also decreased malondialdehyde levels in the hippocampus and frontal cortex. In vitro, chlorogenic acid was found to inhibit acetylcholinesterase activity (IC₅₀=98.17 μg/ml) and free radical scavenging activity (IC₅₀=3.09 μg/ml) in a dose-dependent manner. These results indicate that chlorogenic acid may exert anti-amnesic activity via inhibition of acetylcholinesterase and malondialdehyde in the hippocampus and frontal cortex.

Prenatal and postnatal exposure to bisphenol a induces anxiolytic behaviors and cognitive deficits in mice

Bisphenol A (BPA), an environmental endocrine‐disrupting chemical, has been extensively evaluated for reproductive toxicity and carcinogenicity. However, little is known about the behavioral and neurochemical effects of BPA exposure. This study examined whether chronic daily exposure to an environmental endocrine‐disrupting chemical, bisphenol A [(BPA); 100 μg/kg/day or 500 μg/kg/day, p.o.], from prenatal Day 7 to postnatal Day 36 would lead to changes in anxiety and memory in mice. First, we observed the behavioral alterations of BPA‐treated mice using two anxiety‐related models, the open field test and elevated plus maze (EPM) test. In the open field test, BPA treatment (100 μg/kg/day) increased movement in the central zone. BPA treatment (500 μg/kg/day) also increased the time spent in the open arms in the EPM test. Second, we measured cognitive ability in the Y‐maze test and novel object test. BPA‐treated mice showed decreased alternation behavior in the Y‐maze at both of doses, indicating working memory impairment. BPA‐treated mice (100 μg/kg/day) also showed decreased novel object recognition as expressed by central locomotion and frequency in the central zone, showing recognition memory impairment. Finally, to measure changes in the dopaminergic and NMDAergic systems in the brain, we performed autoradiographic receptor binding assays for dopamine D1 and D2 receptors, the NMDA receptor, and the dopamine transporter. BPA treatment increased D2 receptor binding in the caudate putamen (CPu) but decreased DAT binding. BPA treatment also decreased NMDA receptor binding in the frontal cortex and CA1, CA3, and DG of the hippocampus. Taken together, our results suggest that long‐term BPA exposure in mice can induce anxiolytic behaviors, cognitive deficits and changes in the dopaminergic and NMDAergic systems. Synapse 64:432–439, 2010.

Loganin improves learning and memory impairments induced by scopolamine in mice

Loganin is an iridoid glycoside found in the Flos lonicerae, Fruit cornus, and Strychonos nux vomica. We investigated the effect of loganin on learning and memory impairments induced by scopolamine (0.5mg/kg, i.p.), a muscarinic antagonist, using the Y-maze, passive avoidance, and the Morris water maze tests in mice. In the Y-maze test, loganin (40 mg/kg, p.o.) significantly improved the scopolamine-induced memory impairment. In addition, loganin (20 and 40 mg/kg, p.o.) significantly reversed scopolamine-induced impairments measured by the passive avoidance and the Morris water maze tests. A day after the last trial session of the Morris water maze test (probe trial session), loganin (20 and 40 mg/kg) dose-dependently increased the latency time in the target quadrant. Furthermore, loganin significantly inhibited acetylcholinesterase activity in the hippocampus and frontal cortex. Loganin may have anti-amnesic activity that may hold significant therapeutic value in alleviating certain memory impairments observed in Alzheimers disease.

Inhibition by MK-801 of cocaine-induced sensitization, conditioned place preference, and dopamine-receptor supersensitivity in mice

Repeated administration of cocaine led to increases in ambulation-accelerating activity (sensitization) and conditioned place preference (CPP). Dopamine (DA)-receptor supersensitivity was also developed in cocaine-induced sensitized and CPP mice. An N-methyl-D-aspartate (NMDA)-receptor antagonist, MK-801, blocked simultaneously developments of cocaine-induced behavioral sensitization, CPP, and DA-receptor supersensitivity. Furthermore, MK-801 inhibited a apomorphine-induced striatal dopaminergic action: climbing behavior. These results suggest that the cocaine-induced dopaminergic behaviors such as sensitization to ambulatory activity and CPP may be produced via activation of the NMDA receptor. The development of postsynaptic DA-receptor supersensitivity may be an underlying common mechanism that mediates cocaine-induced behavioral sensitization and CPP.

Involvement of 5-HT1A and GABAA receptors in the anxiolytic-like effects of Cinnamomum cassia in mice.

An elevated plus maze (EPM) test was used to determine if the 5-HT1A, GABAA, and benzodiazepine receptors play a role in the anxiolytic-like effects of a 50% EtOH extract of Cinnamomum cassia (C. cassia) in mice. A single treatment with C. cassia (750 mg/kg, p.o.) significantly increased the number of entries into and the time spent in the open arms of the EPM compared with the controls. A repeated treatment with C. cassia (100 mg/kg, 5 days, p.o.) significantly increased the time spent in the open arms of the EPM. Moreover, WAY 100635, (+)-bicuculline, and flumazenil blocked the effect of C. cassia. However, there were no changes in the locomotor activity and horizontal wire test observed in any group compared with the controls. Taken together, these results show that C. cassia has no adverse effects, such as myorelaxant effects, and might be an effective anxiolytic agent by regulating the serotonergic and GABAergic system.

Loganin protects against hydrogen peroxide-induced apoptosis by inhibiting phosphorylation of JNK, p38, and ERK 1/2 MAPKs in SH-SY5Y cells

We investigated the mechanisms underlying the protective effects of loganin against hydrogen peroxide (H(2)O(2))-induced neuronal toxicity in SH-SY5Y cells. The neuroprotective effect of loganin was investigated by treating SH-SY5Y cells with H(2)O(2) and then measuring the reduction in H(2)O(2)-induced apoptosis using 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) release assays. Following H(2)O(2) exposure, Hoechst 33258 staining indicated nuclear condensation in a large proportion of SH-SY5Y cells, along with an increase in reactive oxygen species (ROS) production and an intracellular decrease in mitochondria membrane potential (MMP). Loganin was effective in attenuating all the above-stated phenotypes induced by H(2)O(2). Pretreatment with loganin significantly increased cell viability, reduced H(2)O(2)-induced LDH release and ROS production, and effectively increased intracellular MMP. Pretreatment with loganin also significantly decreased the nuclear condensation induced by H(2)O(2). Western blot data revealed that loganin inhibited the H(2)O(2)-induced up-regulation of cleaved poly (ADP-ribose) polymerase (PARP) and cleaved caspase-3, increased the H(2)O(2)-induced decrease in the Bcl-2/Bax ratio, and attenuated the H(2)O(2)-induced release of cytochrome c from mitochondria to the cytosol. Furthermore, pretreatment with loganin significantly attenuated the H(2)O(2)-induced phosphorylation of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and extracellular signal-regulated kinase 1/2 (ERK 1/2). These results suggest that the protective effects of loganin against H(2)O(2)-induced apoptosis may be due to a decrease in the Bcl-2/Bax ratio expression due to the inhibition of the phosphorylation of JNK, p38, and ERK 1/2 MAPKs. Loganins neuroprotective properties indicate that this compound may be a potential therapeutic agent for the treatment of neurodegenerative diseases.

Ginsenoside Re Rescues Methamphetamine-Induced Oxidative Damage, Mitochondrial Dysfunction, Microglial Activation, and Dopaminergic Degeneration by Inhibiting the Protein Kinase Cδ Gene

Ginsenoside Re, one of the main constituents of Panax ginseng, possesses novel antioxidant and anti-inflammatory properties. However, the pharmacological mechanism of ginsenoside Re in dopaminergic degeneration remains elusive. We suggested that protein kinase C (PKC) δ mediates methamphetamine (MA)-induced dopaminergic toxicity. Treatment with ginsenoside Re significantly attenuated methamphetamine-induced dopaminergic degeneration in vivo by inhibiting impaired enzymatic antioxidant systems, mitochondrial oxidative stress, mitochondrial translocation of protein kinase Cδ, mitochondrial dysfunction, pro-inflammatory microglial activation, and apoptosis. These protective effects were comparable to those observed with genetic inhibition of PKCδ in PKCδ knockout (−/−) mice and with PKCδ antisense oligonucleotides, and ginsenoside Re did not provide any additional protective effects in the presence of PKCδ inhibition. Our results suggest that PKCδ is a critical target for ginsenoside Re-mediated protective activity in response to dopaminergic degeneration induced by MA.

The neuroprotective effects of Lonicera japonica THUNB. against hydrogen peroxide-induced apoptosis via phosphorylation of MAPKs and PI3K/Akt in SH-SY5Y cells.

We investigated the neuroprotective effects of Lonicera japonica THUNB. (Caprifoliaceae) (LJ) extract against hydrogen peroxide (H(2)O(2)), a toxin created by oxidative stress and implicated in neurodegenerative diseases, in human SH-SY5Y neuroblastoma cells. We examined the effects of LJ against H(2)O(2)-induced cytotoxicity, apoptosis, the production of reactive oxygen species (ROS), the proteolysis of cleaved poly-ADP-ribose polymerase (PARP), and the expression of Bcl-2, Bcl-xL, and cleaved caspase-3. Moreover, we attempted to determine whether LJ suppressed the phosphorylation of Akt, c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and extracellular signal-regulated kinase 1/2 (ERK 1/2). We found that LJ improved cell viability, inhibited cytotoxicity and apoptosis, and attenuated elevations in ROS and nuclear condensation. In addition, LJ showed radical scavenging ability in 2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2-azinobis-(3-ethyl-benzthiazoline-6-sulfonic acid) (ABTS) assays. Western blot data revealed that LJ inhibited H(2)O(2)-induced up- and down-regulation of cleaved PARP, cleaved caspase-3, Bcl-2, and Bcl-xL. Furthermore, LJ significantly attenuated the H(2)O(2)-induced phosphorylation of Akt, JNK, p38 MAPK, and ERK1/2. These results demonstrate that LJ possesses potent neuroprotective activity. Its potential to treat neurodegenerative diseases warrants further research.

Gintonin, a Ginseng-Derived Lysophosphatidic Acid Receptor Ligand, Attenuates Alzheimer's Disease-Related Neuropathies: Involvement of Non-Amyloidogenic Processing

Ginseng extracts show cognition-enhancing effects in Alzheimers disease (AD) patients. However, little is known about the active components and molecular mechanisms of how ginseng exerts its effects. Recently, we isolated a novel lysophosphatidic acid (LPA) receptor-activating ligand from ginseng, gintonin. AD is caused by amyloid-β protein (Aβ) accumulation. Aβ is derived from amyloid-β protein precursors (AβPPs) through the amyloidogenic pathway. In contrast, non-amyloidogenic pathways produce beneficial, soluble AβPPα (sAβPPα). Here, we describe our investigations of the effect of gintonin on sAβPPα release, Aβ formation, Swedish-AβPP transfection-mediated neurotoxicity in SH-SY5Y neuroblastoma cells, and Aβ-induced neuropathy in mice. Gintonin promoted sAβPPα release in a concentration- and time-dependent manner. Gintonin action was also blocked by the Ca2+ chelator BAPTA, α-secretase inhibitor TAPI-2, and protein-trafficking inhibitor brefeldin. Gintonin decreased Aβ1-42 release and attenuated Aβ1-40-induced cytotoxicity in SH-SY5Y cells. Gintonin also rescued Aβ1-40-induced cognitive dysfunction in mice. Moreover, in a transgenic mouse AD model, long-term oral administration of gintonin attenuated amyloid plaque deposition as well as short- and long-term memory impairment. In the present study, we demonstrated that gintonin mediated the promotion of non-amyloidogenic processing to stimulate sAβPPα release to restore brain function in mice with AD. Gintonin could be a useful agent for AD prevention or therapy.

Antidepressant-like effects of Albizzia julibrissin in mice: involvement of the 5-HT1A receptor system.

The present study was undertaken to investigate the antidepressant-like effects of the methylene chloride fraction of Albizzia julibrissin (MCAJ) using a tail suspension test in mice. MCAJ was orally administered at 50, 100, or 200 mg/kg to mice, 1 h before the tail suspension test. Acute treatment with MCAJ at 200 mg/kg significantly reduced the immobility time compared with the control group, and thus showed an antidepressant-like effect. This effect was comparable to that of imipramine at 10 mg/kg. This antidepressant-like effect was reversed by treatment with WAY-100635 (a 5-HT1A receptor antagonist) or pindolol (a 5-HT1A/1B receptor antagonist). However, the antidepressant effect of MCAJ was not effected by treatment with GR55562 (a 5-HT1B receptor antagonist) or ketanserin (a 5-HT2A receptor antagonist). Therefore, our findings suggest that MCAJ exerts its antidepressant-like effect via the 5-HT1A receptor system.