Sung-Cherl Jung

Modulatory effects of aromatherapy massage intervention on electroencephalogram, psychological assessments, salivary cortisol and plasma brain-derived neurotrophic factor

OBJECTIVES Aromatherapy massage is commonly used for the stress management of healthy individuals, and also has been often employed as a therapeutic use for pain control and alleviating psychological distress, such as anxiety and depression, in oncological palliative care patients. However, the exact biological basis of aromatherapy massage is poorly understood. Therefore, we evaluated here the effects of aromatherapy massage interventions on multiple neurobiological indices such as quantitative psychological assessments, electroencephalogram (EEG) power spectrum pattern, salivary cortisol and plasma brain-derived neurotrophic factor (BDNF) levels. DESIGN A control group without treatment (n = 12) and aromatherapy massage group (n = 13) were randomly recruited. They were all females whose children were diagnosed as attention deficit hyperactivity disorder and followed up in the Department of Psychiatry, Jeju National University Hospital. Participants were treated with aromatherapy massage for 40 min twice per week for 4 weeks (8 interventions). RESULTS A 4-week-aromatherapy massage program significantly improved all psychological assessment scores in the Stat-Trait Anxiety Index, Beck Depression Inventory and Short Form of Psychosocial Well-being Index. Interestingly, plasma BDNF levels were significantly increased after a 4 week-aromatherapy massage program. Alpha-brain wave activities were significantly enhanced and delta wave activities were markedly reduced following the one-time aromatherapy massage treatment, as shown in the meditation and neurofeedback training. In addition, salivary cortisol levels were significantly reduced following the one-time aromatherapy massage treatment. CONCLUSIONS These results suggest that aromatherapy massage could exert significant influences on multiple neurobiological indices such as EEG pattern, salivary cortisol and plasma BDNF levels as well as psychological assessments.

Neuroprotective effect of methyl lucidone against microglia-mediated neurotoxicity.

Excessive microglial activation-mediated neurotoxicity has been implicated in playing a crucial role in the pathogenesis of stroke and neurodegenerative diseases. Therefore, much attention has been paid to therapeutic strategies aimed at suppressing neurotoxic microglial activation. The microglial regulatory mechanism of methyl lucidone, a cyclopentenedione isolated from the stem bark of Lindera erythrocarpa Makino, was investigated in the present study. Methyl lucidone treatment (0.1-10 μM) significantly inhibited lipopolysaccharide (LPS, 100 ng/ml, 24 h)-stimulated nitric oxide (NO) production in a dose-dependent manner in both primary cortical microglia and BV-2 cell line. Moreover, it strongly inhibited LPS-stimulated secretion of pro-inflammatory cytokines, such as interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α). Methyl lucidone treatment markedly induced down-regulation of LPS-induced nuclear translocation of nuclear factor κB (NF-κB) through preventing the degradation of the inhibitory protein IκBα. In addition, phosphorylation of Akt and mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinase (ERK) and p38 kinases were also suppressed by methyl lucidone. The cell viabilities of HT-22 neurons were significantly attenuated by treatment of the conditioned media containing neurotoxic secretary molecules from LPS-stimulated microglia. However, methyl lucidone significantly blocked neuronal cell death induced by microglial conditioned media. These neuroprotective effects of methyl lucidone were also confirmed in a neuron-microglia co-culture system using EGFP-transfected B35 neuroblastoma cell line. Taken together, these results suggest that methyl lucidone may have a neuroprotective potential via inhibition of neurotoxic microglial activation implicated in neurodegeneration.

Mild mitochondrial depolarization is involved in a neuroprotective mechanism of Citrus sunki peel extract.

Mitochondrial membrane potential (∆Ψm) contributes to determining a driving force for calcium to enter the mitochondria. It has been demonstrated that even a small mitochondrial depolarization is sufficient to prevent mitochondrial calcium overload and the subsequent apoptosis. Therefore, mild mitochondrial depolarization has been recently evaluated as a novel mechanism of neuroprotection via inhibiting neurotoxic mitochondrial calcium overload during neuronal insults. In the present study, using both real‐time recording and flow cytometric analyses of ∆Ψm, we demonstrated that ethanolic peel extract of Citrus sunki Hort. ex Tanaka (CPE) and its active compounds are capable of inducing a mild mitochondrial depolarization. Polymethoxylated flavones such as nobiletin and tangeretin were found as the active compounds responsible for CPE effects on ∆Ψm. Neuronal viability was significantly increased in a dose‐dependent manner by CPE treatment in H2O2‐stimulated HT‐22 cells as an in vitro neuronal insult model. CPE treatment significantly inhibited H2O2‐induced apoptotic processes such as chromatin condensation, caspase 3 activation and anti‐poly (ADP‐ribose) polymerase (PARP) cleavage. CPE treatment significantly blocked mitochondrial calcium overload in H2O2‐stimulated HT‐22 neurons as indicated by rhod‐2 acetoxymethyl ester. Taken together, our findings suggest that CPE and its active compounds may be considered as promising neuroprotective agents via inducing a mild mitochondrial depolarization. Copyright

Long-term Synaptic Plasticity: Circuit Perturbation and Stabilization

At central synapses, activity-dependent synaptic plasticity has a crucial role in information processing, storage, learning, and memory under both physiological and pathological conditions. One widely accepted model of learning mechanism and information processing in the brain is Hebbian Plasticity: long-term potentiation (LTP) and long-term depression (LTD). LTP and LTD are respectively activity-dependent enhancement and reduction in the efficacy of the synapses, which are rapid and synapse-specific processes. A number of recent studies have a strong focal point on the critical importance of another distinct form of synaptic plasticity, non-Hebbian plasticity. Non-Hebbian plasticity dynamically adjusts synaptic strength to maintain stability. This process may be very slow and occur cell-widely. By putting them all together, this mini review defines an important conceptual difference between Hebbian and non-Hebbian plasticity.

Dieckol Attenuates Microglia-mediated Neuronal Cell Death via ERK, Akt and NADPH Oxidase-mediated Pathways

Excessive microglial activation and subsequent neuroinflammation lead to synaptic loss and dysfunction as well as neuronal cell death, which are involved in the pathogenesis and progression of several neurodegenerative diseases. Thus, the regulation of microglial activation has been evaluated as effective therapeutic strategies. Although dieckol (DEK), one of the phlorotannins isolated from marine brown alga Ecklonia cava, has been previously reported to inhibit microglial activation, the molecular mechanism is still unclear. Therefore, we investigated here molecular mechanism of DEK via extracellular signal-regulated kinase (ERK), Akt and nicotinamide adenine dinuclelotide phosphate (NADPH) oxidase-mediated pathways. In addition, the neuroprotective mechanism of DEK was investigated in microglia-mediated neurotoxicity models such as neuron-microglia co-culture and microglial conditioned media system. Our results demonstrated that treatment of anti-oxidant DEK potently suppressed phosphorylation of ERK in lipopolysaccharide (LPS, 1 µg/ml)-stimulated BV-2 microglia. In addition, DEK markedly attenuated Akt phosphorylation and increased expression of gp91phox, which is the catalytic component of NADPH oxidase complex responsible for microglial reactive oxygen species (ROS) generation. Finally, DEK significantly attenuated neuronal cell death that is induced by treatment of microglial conditioned media containing neurotoxic secretary molecules. These neuroprotective effects of DEK were also confirmed in a neuron-microglia co-culture system using enhanced green fluorescent protein (EGFP)-transfected B35 neuroblastoma cell line. Taken together, these results suggest that DEK suppresses excessive microglial activation and microglia-mediated neuronal cell death via downregulation of ERK, Akt and NADPH oxidase-mediated pathways.

Roles of somatic A-type K+ channels in the synaptic plasticity of hippocampal neurons

In the mammalian brain, information encoding and storage have been explained by revealing the cellular and molecular mechanisms of synaptic plasticity at various levels in the central nervous system, including the hippocampus and the cerebral cortices. The modulatory mechanisms of synaptic excitability that are correlated with neuronal tasks are fundamental factors for synaptic plasticity, and they are dependent on intracellular Ca2+-mediated signaling. In the present review, the A-type K+ (IA) channel, one of the voltage-dependent cation channels, is considered as a key player in the modulation of Ca2+ influx through synaptic NMDA receptors and their correlated signaling pathways. The cellular functions of IA channels indicate that they possibly play as integral parts of synaptic and somatic complexes, completing the initiation and stabilization of memory.

Activation of ryanodine receptors is required for PKA‐mediated downregulation of A‐type K+ channels in rat hippocampal neurons

A‐type K+ channels (IA channels) contribute to learning and memory mechanisms by regulating neuronal excitabilities in the CNS, and their expression level is targeted by Ca2+ influx via synaptic NMDA receptors (NMDARs) during long‐term potentiation (LTP). However, it is not clear how local synaptic Ca2+ changes induce IA downregulation throughout the neuron, extending from the active synapse to the soma. In this study, we tested if two major receptors of endoplasmic reticulum (ER), ryanodine (RyRs), and IP3 (IP3R) receptors, are involved in Ca2+‐mediated IA downregulation in cultured hippocampal neurons of rats. The downregulation of IA channels was induced by doubling the Ca2+ concentration in culture media (3.6 mM for 24 hrs) or treating with glycine (200 μM for 3 min) to induce chemical LTP (cLTP), and the changes in IA peaks were measured electrophysiologically by a whole‐cell patch. We confirmed that Ca2+ or glycine treatment significantly reduced IA peaks and that their effects were abolished by blocking NMDARs or voltage‐dependent Ca2+ channels (VDCCs). In this cellular processing, blocking RyRs (by ryanodine, 10 μM) but not IP3Rs (by 2APB, 100 μM) completely abolished IA downregulation, and the LTP observed in hippocampal slices was more diminished by ryanodine rather than 2APB. Furthermore, blocking RyRs also reduced Ca2+‐mediated PKA activation, indicating that sequential signaling cascades, including the ER and PKA, are involved in regulating IA downregulation. These results strongly suggest a possibility that RyR contribution and mediated IA downregulation are required to regulate membrane excitability as well as synaptic plasticity in CA3‐CA1 connections of the hippocampus.

The Downregulation of Somatic A-Type K+ Channels Requires the Activation of Synaptic NMDA Receptors in Young Hippocampal Neurons of Rats

The downregulation of A-type K+ channels (IA channels) accompanying enhanced somatic excitability can mediate epileptogenic conditions in mammalian central nervous system. As IA channels are dominantly targeted by dendritic and postsynaptic processings during synaptic plasticity, it is presumable that they may act as cellular linkers between synaptic responses and somatic processings under various excitable conditions. In the present study, we electrophysiologically tested if the downregulation of somatic IA channels was sensitive to synaptic activities in young hippocampal neurons. In primarily cultured hippocampal neurons (DIV 6~9), the peak of IA recorded by a whole-cell patch was significantly reduced by high KCl or exogenous glutamate treatment to enhance synaptic activities. However, the pretreatment of MK801 to block synaptic NMDA receptors abolished the glutamate-induced reduction of the IA peak, indicating the necessity of synaptic activation for the reduction of somatic IA. This was again confirmed by glycine treatment, showing a significant reduction of the somatic IA peak. Additionally, the gating property of IA channels was also sensitive to the activation of synaptic NMDA receptors, showing the hyperpolarizing shift in inactivation kinetics. These results suggest that synaptic LTP possibly potentiates somatic excitability via downregulating IA channels in expression and gating kinetics. The consequential changes of somatic excitability following the activity-dependent modulation of synaptic responses may be a series of processings for neuronal functions to determine outputs in memory mechanisms or pathogenic conditions.

Ih channels prevent overexcitability of early developmental CA1 neurons showing high input resistance in rats

Immature hippocampal neurons with high input resistances (R(in)) are vulnerable to hyperexcitable or epileptogenic conditions. This phenomenon has been suggested to explain the neuroprotective roles of hyperpolarization-activated cation channels (I(h) channels) to regulate membrane R(in). In the present study, we tried to electrophysiologically clarify the relationship between membrane R(in) and I(h) channels and determine the neuroprotective roles of these channels in development. The CA1 neurons from rats (within 3 postnatal weeks) were classified into two groups based on the onset time (shorter or longer than 20 ms) to fire the first action potential (AP) in response to a current injection (100 pA, 800 ms). Neurons with a shorter onset time (Short-OsT), exhibited higher R(in), while neurons with longer onset times (Long-OsT) revealed lower R(in). Unexpectedly, Short-OsT neurons with higher R(in) exhibited larger amplitudes of I(h) compared with Long-OsT neurons. Furthermore, the application of temporal depolarization stimulus (TDS, -14 mV holding for 150 s) significantly enhanced suprathreshold excitabilities of repetitive APs in Long-OsT but not Short-OsT neurons, suggesting a protective role of I(h) channels under high R(in) conditions. In the presence of the specific hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker ZD7288, TDS also enhanced the excitability of Short-OsT neurons, suggesting that young CA1 neurons regulate I(h) channel expression for neuroprotective modulation against epileptogenic conditions.

Chronic Ca2+influx through voltage-dependent Ca2+channels enhance delayed rectifier K+currents via activating Src family tyrosine kinase in rat hippocampal neurons

Excessive influx and the subsequent rapid cytosolic elevation of Ca2+ in neurons is the major cause to induce hyperexcitability and irreversible cell damage although it is an essential ion for cellular signalings. Therefore, most neurons exhibit several cellular mechanisms to homeostatically regulate cytosolic Ca2+ level in normal as well as pathological conditions. Delayed rectifier K+ channels (IDR channels) play a role to suppress membrane excitability by inducing K+ outflow in various conditions, indicating their potential role in preventing pathogenic conditions and cell damage under Ca2+-mediated excitotoxic conditions. In the present study, we electrophysiologically evaluated the response of IDR channels to hyperexcitable conditions induced by high Ca2+ pretreatment (3.6 mM, for 24 hours) in cultured hippocampal neurons. In results, high Ca2+-treatment significantly increased the amplitude of IDR without changes of gating kinetics. Nimodipine but not APV blocked Ca2+-induced IDR enhancement, confirming that the change of IDR might be targeted by Ca2+ influx through voltage-dependent Ca2+ channels (VDCCs) rather than NMDA receptors (NMDARs). The VDCC-mediated IDR enhancement was not affected by either Ca2+-induced Ca2+ release (CICR) or small conductance Ca2+-activated K+ channels (SK channels). Furthermore, PP2 but not H89 completely abolished IDR enhancement under high Ca2+ condition, indicating that the activation of Src family tyrosine kinases (SFKs) is required for Ca2+-mediated IDR enhancement. Thus, SFKs may be sensitive to excessive Ca2+ influx through VDCCs and enhance IDR to activate a neuroprotective mechanism against Ca2+-mediated hyperexcitability in neurons.