• Natural Product Sciences
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• v.13 no.1
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• pp.68-77
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• 2007

The aim of the present study was to examine the effects of green tea extract (CUMS6335) on the release of CA evoked by cholinergic stimulation and direct membrane-depolarization in the perfused model of the adrenal gland isolated from the spontaneously hypertensive rats (SHRs), and to establish the mechanism of action. Furthermore, it was also to test whether there is species difference between animals, and between CUMS6335 and EGCG, one of biologically the most powerful catechin compounds found in green tea. CUMS6335 $(100\;{\mu}g/ml)$, when perfused into an adrenal vein for 60 min, time-dependently inhibited the CA secretory responses evoked by ACh (5.32mM), high $K^+$(56 mM), DMPP $(100\;{\mu}M)$, and McN-A-343 $(100\;{\mu}M)$ from the isolated perfused adrenal glands of SHRs. However, CUMS6335 itself did fail to affect basal catecholamine output. Also, in adrenal glands loaded with CUMS6335 $(100\;{\mu}g/ml)$, the CA secretory responses evoked by Bay-K-8644 $(10\;{\mu}M)$ and cyclopiazonic acid $(10\;{\mu}M)$ were also inhibited in a relatively time-dependent fashion. However, in the Presence of EGCG $(8.0\;{\mu}g/ml)$ for 60 min, the CA secretory response evoked by ACh, high $K^+$, DMPP, McN-A-343, Bay-K-8644 and cyclopiazonic acid were not affected except for last period. Collectively, these results indicate that CUMS6335 inhibits the CA secretion evoked by stimulation of cholinergic (both nicotinic and muscarinic) receptors as well as by direct membrane-depolarization from the perfused adrenal gland of the SHR. It seems that this inhibitory effect of CUMS6335 is exerted by blocking both the calcium influx into the rat adrenal medullary chromaffin cells and the uptake of $Ca^{2+}$ into the cytoplasmic calcium store, which are at least partly relevant to the direct interaction with the nicotinic receptor itself. It seems likely that there is much difference in mode of the CA-releasing action between CUMS6335 and EGCG.

• Biomolecules & Therapeutics
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• v.12 no.3
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• pp.165-174
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• 2004

The aim of the present study was to investigate the effect of FCCP (carbonyl cyanide p-trifluoromethoxyphenyIhydrazone), which is a potent mitochondrial uncoupler, on secretion of catecholamines (CA) from the perfused model of the rat adrenal gland and to establish the mechanism of its action. The perfusion of FCCP (3 ${\times}$ $10^{-5}$ M) into an adrenal vein of for 90 min resulted in great increases in CA secretions. Tachyphylaxis to CA-releasing effect of FCCP was not observed by repeated perfusion of it. The CA-releasing effects of FCCP were depressed by pre-treatment with pirenzepine, chlorisondamine, nicardipine, TMB-8, and the perfusion of EGTA plus $Ca^{2+}$-free medium. In the presence of FCCP (3 ${\times}$ $10^{-5}$ M), the CA secretory responses induced by Ach (5.32 ${\times}$ $10^{-3}$ M), and DMPP ($10^{-4}$ M) were significantly enhanced. Furthermore, the perfusion of CCCP (3 ${\times}$ $10^{-5}$ M), a similar mitochondrial uncoupler, into an adrenal vein for 90 min also caused an increased response in CA secretion. Taken together these experimental results indicate that FCCP causes the CA secretion the perfused rat adrenal medulla in a calcium-dependent fashion. It is suggested that this facilitatory effects of FCCP may be mediated by cholinergic receptor stimulation, which is relevant to both stimulation of the $Ca^{2+}$ influx and $Ca^{2+}$ release from cytoplasmic $Ca^{2+}$ stores.

• The Korean Journal of Physiology and Pharmacology
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• v.11 no.5
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• pp.197-206
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• 2007

The aim of the present study was to investigate the effects of 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine(SKF81297), a selective agonist of dopaminergic $D_1$ receptor, on the secretion of catecholamines(CA) evoked by cholinergic stimulation and membrane-depolarization in the isolated perfused rat adrenal gland, and also to elucidate the mechanism involved. SKF81297($10{\sim}100{\mu}M$) perfused into an adrenal vein for 60 min produced dose- and time-dependent inhibition of CA secretory responses evoked by ACh(5.32 mM), high $K^+$(56 mM), DMPP($100{\mu}M$) and McN-A-343($100{\mu}M$). Also, in adrenal glands loaded with SKF81297($30{\mu}M$), the CA secretory responses evoked by Bay-K-8644($10{\mu}M$), an activator of L-type $Ca^{2+}$ channels and cyclopiazonic acid($10{\mu}M$), an inhibitor of cytoplasmic $Ca^{2+}$-ATPase were also inhibited. However, in the presence of the dopamine $D_1$ receptor antagonist, (R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-benzazepine-7-ol(SCH23390, $3{\mu}M$), which is a selective antagonist of dopaminergic $D_1$ receptor, the inhibitory responses of SKF81297($30{\mu}M$) on the CA secretion evoked by ACh, high $K^+$, DMPP, McN-A-343, Bay-K-8644, and cyclopiazonic acid were significantly reduced. Collectively, these experimental results suggest that SKF81297 inhibits the CA secretion from the rat adrenal medulla evoked by cholinergic stimulation(both nicotininc and muscarinic receptors) and membrane depolarization. This inhibitory of SKF81297 seems to be mediated by stimulation of dopaminergic $D_1$ receptors located on the rat adrenomedullary chromaffin cells, which are relevant to extra- and intracellular calcium mobilization. Therefore, it is thought that the presence of the dopaminergic $D_1$ receptors may be involved in regulation of CA release in the rat adrenal medulla.

• The Korean Journal of Physiology and Pharmacology
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• v.24 no.6
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• pp.517-527
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• 2020

Layer 2/3 pyramidal neurons (L2/3 PyNs) of the cortex extend their basal dendrites near the soma and as apical dendritic tufts in layer 1, which mainly receive feedforward and feedback inputs, respectively. It is suggested that neuromodulators such as serotonin and acetylcholine may regulate the information flow between brain structures depending on the brain state. However, little is known about the dendritic compartment-specific induction of synaptic transmission in single PyNs. Here, we studied layer-specific serotonergic and cholinergic induction of long-term synaptic plasticity in L2/3 PyNs of the agranular insular cortex, a lateral component of the orbitofrontal cortex. Using FM1-43 dye unloading, we verified that local electrical stimulation to layers 1 (L1) and 3 (L3) activated axon terminals mostly located in L1 and perisomatic area (L2/3). Independent and AMPA receptor-mediated excitatory postsynaptic potential was evoked by local electrical stimulation of either L1 or L3. Application of serotonin (5-HT, 10 μM) induced activity-dependent longterm depression (LTD) in L2/3 but not in L1 inputs. LTD induced by 5-HT was blocked by the 5-HT₂ receptor antagonist ketanserin, an NMDA receptor antagonist and by intracellular Ca²⁺ chelation. The 5-HT₂ receptor agonist α-me-5-HT mimicked the LTD induced by 5-HT. However, the application of carbachol induced muscarinic receptor-dependent LTD in both inputs. The differential layer-specific induction of LTD by neuromodulators might play an important role in information processing mechanism of the prefrontal cortex.

• Biomolecules & Therapeutics
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• v.25 no.3
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• pp.249-258
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• 2017

To examine the effect of biflorin, a component of Syzygium aromaticum, on memory deficit, we introduced a scopolamine-induced cognitive deficit mouse model. A single administration of biflorin increased latency time in the passive avoidance task, ameliorated alternation behavior in the Y-maze, and increased exploration time in the Morris water maze task, indicating the improvement of cognitive behaviors against cholinergic dysfunction. The biflorin-induced reverse of latency in the scopolamine-treated group was attenuated by MK-801, an NMDA receptor antagonist. Biflorin also enhanced cognitive function in a naïve mouse model. To understand the mechanism of biflorin for memory amelioration, we performed Western blot. Biflorin increased the activation of protein kinase C-${\zeta}$ and its downstream signaling molecules in the hippocampus. These results suggest that biflorin ameliorates drug-induced memory impairment by modulation of protein kinase C-${\zeta}$ signaling in mice, implying that biflorin could function as a possible therapeutic agent for the treatment of cognitive problems.

• Nutrition Research and Practice
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• v.17 no.2
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• pp.192-205
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• 2023

BACKGROUND/OBJECTIVES: It is known that the renin-angiotensin system (RAS) in the brain could regulate cognitive functions as well as blood pressure. Inhibition of RAS for the improvement of cognitive function may be a new strategy, but studies so far have mostly reported on the effects of RAS inhibition by drugs, and there is no research on cognitive improvement through RAS inhibition of food ingredients. Therefore, this study investigated the effect of curcumin on blood pressure and cognitive function and its related mechanism in spontaneously hypertensive rat/Izm (SHR/Izm). MATERIALS/METHODS: Six-week-old SHR/Izm rats were divided into 5 groups: control group (CON), scopolamine group (SCO, drug for inducing cognitive deficits), positive control (SCO and tacrine [TAC]), curcumin 100 group (CUR100, SCO + Cur 100 mg/kg), and curcumin 200 group (CUR200, SCO + Cur 200 mg/kg). Changes in blood pressure, RAS, cholinergic system, and cognitive function were compared before and after cognitive impairment. RESULTS: The SCO group showed increased blood pressure and significantly reduced cognitive function based on the y-maze and passive avoidance test. Curcumin treatments significantly improved blood pressure and cognitive function compared with the SCO group. In both the CUR100 and CUR200 groups, the mRNA expressions of angiotensin-converting enzyme (ACE) and angiotensin II receptor type1 (AT1), as well as the concentrations of angiotensin II (Ang II) in brain tissue were significantly decreased. The mRNA expression of the muscarinic acetylcholine receptors (mAChRs) and acetylcholine (ACh) content was significantly increased, compared with the SCO group. CONCLUSIONS: The administration of curcumin improved blood pressure and cognitive function in SCO-induced hypertensive mice, indicating that the cholinergic system was improved by suppressing RAS and AT1 receptor expression and increasing the mAChR expression.

• Journal of Ginseng Research
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• v.48 no.1
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• pp.59-67
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• 2024

Background: Alzheimer's disease (AD) has memory impairment associated with aggregation of amyloid plaques and neurofibrillary tangles in the brain. Although anti-amyloid β (Aβ) protein antibody and chemical drugs can be prescribed in the clinic, they show adverse effects or low effectiveness. Therefore, the development of a new drug is necessarily needed. We focused on the cognitive function of Panax ginseng and tried to find active ingredient(s). We isolated panaxcerol D, a kind of glycosyl glyceride, from the non-saponin fraction of P. ginseng extract. Methods: We explored effects of acute or sub-chronic administration of panaxcerol D on cognitive function in scopolamine- or Aβ_25-35 peptide-treated mice measured by several behavioral tests. After behavioral tests, we tried to unveil the underlying mechanism of panaxcerol D on its cognitive function by Western blotting. Results: We found that pananxcerol D reversed short-term, long-term and object recognition memory impairments. The decreased extracellular signal-regulated kinases (ERK) or Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) in scopolamine-treated mice was normalized by acute administration of panaxcerol D. Glial fibrillary acidic protein (GFAP), caspase 3, NF-kB p65, synaptophysin and brainderived neurotrophic factor (BDNF) expression levels in Aβ_25-35 peptide-treated mice were modulated by sub-chronic administration of panaxcerol D. Conclusion: Pananxcerol D could improve memory impairments caused by cholinergic blockade or Aβ accumulation through increased phosphorylation level of ERK or its anti-inflammatory effect. Thus, panaxcerol D as one of non-saponin compounds could be used as an active ingredient of P. ginseng for improving cognitive function.

• The Korean Journal of Pain
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• v.37 no.3
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• pp.218-232
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• 2024

Background: Cynara scolymus has bioactive constituents and has been used for therapeutic actions. The present study was undertaken to investigate the mechanisms underlying pain-relieving effects of the hydroethanolic extract of C. scolymus (HECS). Methods: The antinociceptive activity of HECS was assessed through formalin and acetic acid-induced writhing tests at doses of 50, 100 and 200 mg/kg intraperitoneally. Additionally, naloxone (non-selective opioid receptors antagonist, 2 mg/kg), atropine (non-selective muscarinic receptors antagonist, 1 mg/kg), chlorpheniramine (histamine H₁-receptor antagonist, 20 mg/kg), cimetidine (histamine H₂-receptor antagonist, 12.5 mg/kg), flumazenil (GABA_A/BDZ receptor antagonist, 5 mg/kg) and cyproheptadine (serotonin receptor antagonist, 4 mg/kg) were used to determine the systems implicated in HECS-induced analgesia. Impact of HECS on locomotor activity was executed by open-field test. Determination of total phenolic content (TPC) and total flavonoid content (TFC) was done. Evaluation of antioxidant activity was conducted employing 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assay. Results: HECS (50, 100 and 200 mg/kg) significantly indicated dose dependent antinociceptive activity against pain-related behavior induced by formalin and acetic acid (P < 0.001). Pretreatment with naloxone, atropine and flumazenil significantly reversed HECS-induced analgesia. Antinociceptive effect of HECS remained unaffected by chlorpheniramine, cimetidine and cyproheptadine. Locomotor activity was not affected by HECS. TPC and TFC of HECS were 59.49 ± 5.57 mgGAE/g dry extract and 93.39 ± 17.16 mgRE/g dry extract, respectively. DPPH free radical scavenging activity (IC₅₀) of HECS was 161.32 ± 0.03 ㎍/mL. Conclusions: HECS possesses antinociceptive activity which is mediated via opioidergic, cholinergic and GABAergic pathways.

• Journal of Pharmacopuncture
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• v.23 no.1
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• pp.1-7
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• 2020

Nicotine, primary component of tobaco produces craving and withdrawal effect both in humans and animals. Nicotine shows a close resemblance to other addictive drugs in molecular, neuroanatomical and pharmacological, particularly the drugs which enhances the cognitive functions. Nicotine mainly shows its action through specific nicotinic acetylcholine receptors located in brain. It stimulates presynaptic acetylcholine receptors thereby enhancing Ach release and metabolism. Dopaminergic system is also stimulated by it, thus increasing the concentration of dopamine in nuclear accumbens. This property of nicotine according to various researchers is responsible for reinforcing behavioral change and dependence of nicotine. Various researchers have also depicted that some non dopaminergic systems are also involved for rewarding effect of nicotinic withdrawal. Neurological systems such as GABAergic, serotonergic, noradrenergic, and brain stem cholinergic may also be involved to mediate the actions of nicotine. Further, the neurobiological pathway to nicotine dependence might perhaps be appropriate to the attachment of nicotine to nicotinic acetylcholine receptors, peruse by stimulation of dopaminergic system and activation of general pharmacological changes that might be responsible for nicotine addiction. It is also suggested that MAO A and B both are restrained by nicotine. This enzyme helps in degradation dopamine, which is mainly responsible for nicotinic actions and dependence. Various questions remain uninsurable to nicotine mechanism and require more research. Also, various genetic methods united with modern instrumental analysis might result for more authentic information for nicotine addiction.

• The Korean Journal of Physiology and Pharmacology
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• v.19 no.5
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• pp.473-478
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• 2015

To see the inhibitory mechanism of gentamicin in response to electrical field stimulation (EFS) using the rat bladder smooth muscle, atropine or guanethidine was treated but had no effect. Methylsergide, a non-selective 5-$HT_1$, 5-$HT_2$ receptor antagonist was also treated but had on effect. Kinase inhibitors, such as chelerythrine (PKC inhibitor), ML-9 (MLCK inhibitor), or Y27632 (rho kinase inhibitor) were pretreated before gentamicin treatment, but did not have effect. For U73122, a phospholipase C (PLC) inhibitor however, the inhibitory effect to gentamicin was significantly attenuated in all frequencies given by the EFS. Therefore gentamicin induced inhibitory effect on EFS response in rat bladder smooth muscle was not mediated by the activation of adrenergic, cholinergic, or serotonergic receptor. The inhibition of gentamicin might be mediated through the PLC dependent pathway, but not through the PKC, MLCK or rho kinase dependent pathway.