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Background Methylphenidate is the most commonly used stimulant drug for the treatment of attentiondeficit/ hyperactivity disorder (ADHD). Research has found that methylphenidate is a "reinforcer" and that individuals with ADHD also abuse this medication. Nevertheless, the molecular consequences of long-term recreational methylphenidate use or abuse in individuals with ADHD are not yet fully known. Methods Spontaneously hypertensive rats (SHR), the most validated and widely used ADHD animal model, were pretreated with methylphenidate (5 mg/kg, i.p.) during their adolescence (postnatal day [PND] 42-48) and tested for subsequent methylphenidate-induced conditioned place preference (CPP) and self-administration. Thereafter, the differentially expressed genes in the prefrontal cortex (PFC) and striatum of representative methylphenidate-treated SHRs, which showed CPP to and self-administration of methylphenidate, were analyzed. Results Genome-wide transcriptome profiling analyses revealed 30 differentially expressed genes in the PFC, which includes transcripts involved in apoptosis (e.g. S100a9, Angptl4, Nfkbia), transcription (Cebpb, Per3), and neuronal plasticity (Homer1, Jam2, Asap1). In contrast, 306 genes were differentially expressed in the striatum and among them, 252 were downregulated. The main functional categories overrepresented among the downregulated genes include those involved in cell adhesion (e.g. Pcdh10, Ctbbd1, Itgb6), positive regulation of apoptosis (Perp, Taf1, Api5), (Notch3, Nsbp1, Sik1), mitochondrion organization (Prps18c, Letm1, Uqcrc2), and ubiquitin-mediated proteolysis (Nedd4, Usp27x, Ube2d2). Conclusion Together, these changes indicate methylphenidate-induced neurotoxicity, altered synaptic and neuronal plasticity, energy metabolism and ubiquitin-dependent protein degradation in the brains of methylphenidate-treated SHRs, which showed methylphenidate CPP and selfadministration. In addition, these findings may also reflect cognitive impairment associated with chronic methylphenidate use as demonstrated in preclinical studies. Future studies are warranted to determine the clinical significance of the present findings with regard to longterm recreational methylphenidate use or abuse in individuals with ADHD. [ABSTRACT FROM AUTHOR]

Background: Danggui-Jakyak-San (DJS), a traditional herbal prescription, has been used to treat insufficient blood supplies. Recently, regenerative medication for the treatment of cerebral ischemia has drawn the attention of many researchers. Methods: In this study, we examined whether DJS exerts a neuronal regenerative effect in the hippocampus of a transient forebrain ischemia mice model. Transient forebrain ischemia was induced by bilateral common carotid artery occlusion (BCCAO). Animals were divided into three groups (sham, BCCAO + vehicle, and BCCAO + DJS). To test the effect of DJS on learning and memory, Morris water maze or passive avoidance test was conducted. To test neuroprotective and neurogenic effect, immunohistochemistry and Western blot analysis were used. Statistical significance was analyzed with Student t-test, one-way or two-way analysis of variance. Results: We found that the administration of DJS ameliorated ischemia-induced spatial memory impairment in the Morris water maze task. Moreover, Akt/glycogen synthase kinase-3β (GSK3β)/β-catenin signaling was increased by DJS, which would be one possible mechanism of DJS for neurogenesis in the hippocampal dentate gyrus region. Conclusions: These results suggest that DJS is a possible candidate for the treatment of ischemia-induced neuronal degeneration. [ABSTRACT FROM AUTHOR]

The function and the role phytoceramide (PCER) and phytosphingosine (PSO) in the central nervous system has not been well studied. This study was aimed at investigating the possible roles of PCER and PSO in glutamate-induced neurotoxicity in cultured neuronal cells and memory function in mice. Phytoceramide showed neuroprotective activity in the glutamate-induced toxicity in cultured cortical neuronal cells. Neither phytosphingosine nor tetraacetylphytosphingosine (TAPS) showed neuroproective effects in neuronal cells. PCER (50 mg/kg, p.o.) recovered the scopolamine-induced reduction in step-through latency in the passive avoidance test; however, PSO did not modulate memory function on this task. The ameliorating effects of PCER on spatial memory were confirmed by the Morris water maze test. In conclusion, through behavioral and neurochemical experimental results, it was demonstrated that central administration of PCER produces amelioration of memory impairment. These results suggest that PCER plays an important role in neuroprotection and memory enhancement and PCER could be a potential new therapeutic agent for the treatment of neurodegenerative diseases such as Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Substrains of the Spontaneously Hypertensive rat (SHR), a putative animal model of Attention-Deficit/Hyperactivity Disorder (ADHD), have demonstrated increased sensitivity to many drugs of abuse, including psychostimulants. Therefore, it was suggested that studies in SHR may help elucidate ADHD and comorbidity with substance use disorder (SUD). However, the drug intake profile of the SHR in the most relevant animal model of drug addiction, the self-administration (SA) test, and its response on the conditioned place preference (CPP) paradigm are not yet determined. In the present study, we employed SA and CPP tests to investigate the reinforcing effects of the psychostimulant methamphetamine in an SHR substrain obtained from Charles River, Japan (SHR/NCrlCrlj). Concurrent tests were also performed in Wistar rats, the strain representing "normal" heterogeneous population. To address if the presence of ADHD behaviors further increases sensitivity to the rewarding effect of methamphetamine during adolescence, a critical period for the onset of drug abuse, CPP tests were especially conducted in adolescent Wistar and SHR/NCrlCrlj. We found that the SHR/NCrlCrlj also acquired methamphetamine SA and CPP, indicating reinforcing effects of methamphetamine in this ADHD animal model. However, we did not observe increased responsiveness of the SHR/NCrlCrlj to methamphetamine in both SA and CPP assays. This indicates that the reinforcing effects of methamphetamine may be similar in strains and that the SHR/NCrlCrlj may not adequately model ADHD and increased sensitivity to methamphetamine. [ABSTRACT FROM AUTHOR]

Ameliorating effects of ginseng were observed on neuronal cell death associated with ischemia or glutamate toxicity. Ginseng saponins are transformed by intestinal microflora and the transformants would be absorbed from intestine. In the present study, we have investigated the effects of transformed ginsenoside Rg3, Rh2 and compound K on the modulation of NMDA receptor and GABAA receptor binding in rat brain. The NMDA receptor binding was analyzed by quantitative autoradiography using [3H]MK-801 binding, and GABAA receptor bindings were analyzed by using [3H]muscimol and [3H]flunitrazepam binding in rat brain slices. Ginsenoside Rg3, Rh2 and compound K were infused (10 μg/10 μl/h) into rat brain lateral ventricle for 7 days, through pre-implanted cannula by osmotic minipumps (Alzet, model 2ML). The levels of [3H]MK-801 binding were highly decreased in almost all regions of frontal cortex and hippocampus by ginsenoside Rh2 and compound K. The levels of [3H]muscimol binding were elevated in part of frontal cortex and granule layer of cerebellum by the treatment of ginsenoside Rh2 and compound K. However, the [3H]flunitrazepam binding was not modulated by any tested ginsenosides. Ginsenoside Rh2 and compound K induced the downregulation of the [3H]MK-801 binding as well as upregulation of the and [3H]muscimol binding in a region-specific manner after prolonged infusion into lateral ventricle. However, ginsenoside Rg3 did not show the significant changes of ligand bindings. In addition, ginsenoside Rh2 decreased the expression of nNOS in the hippocampus although Rg3 decreased the expression in the cortex. These results suggest that biotransformed ginsenoside Rh2 and compound K could play an important role in the biological activities in the central nervous systems and neurodegenerative disease. [ABSTRACT FROM AUTHOR]

Natural flavone and isoflavone analogs such as 3′,4′,7-trihydroxyflavone (1), 3′,4′,7-trihydroxyisoflavone (2), and calycosin (3) possess significant neuroprotective activity in Alzheimer’s and Parkinson’s disease. This study highlights the in vitro human monoamine oxidase (hMAO) inhibitory potential and functional effect of those natural flavonoids at dopamine and serotonin receptors for their possible role in neuroprotection. In vitro hMAO inhibition and enzyme kinetics studies were performed using a chemiluminescent assay. The functional effect of three natural flavonoids on dopamine and serotonin receptors was tested via cell-based functional assays followed by a molecular docking simulation to predict interactions between a compound and the binding site of the target protein. A forced swimming test was performed in the male C57BL/6 mouse model. Results of in vitro chemiluminescent assays and enzyme kinetics depicted 1 as a competitive inhibitor of hMAO-A with promising potency (IC50 value: 7.57 ± 0.14 μM) and 3 as a competitive inhibitor of hMAO-B with an IC50 value of 7.19 ± 0.32 μM. Likewise, GPCR functional assays in transfected cells showed 1 as a good hD4R antagonist. In docking analysis, these active flavonoids interacted with a determinant-interacting residue via hydrophilic and hydrophobic interactions, with low docking scores comparable to reference ligands. The post-oral administration of 1 to male C57BL/6 mice did not reduce the immobility time in the forced swimming test. The results of this study suggest that 1 and 3 may serve as effective regulators of the aminergic system via hMAO inhibition and the hD4R antagonist effect, respectively, for neuroprotection. The route of administration should be considered.

The article discusses the study on the neuroprotective effects of selenoflavanones and flavanones. The study reportedly involved synthesis of flavanones and selenoflavanones to determine whether they can pass through blood-brain barrier. The results revealed that selenoflavanones have an in vitro antioxidant effects against hydrogen peroxide and does not cause severe cytotoxicity.

Initial and recurrent stroke produces central nervous system (CNS) damage, involving neuroinflammation. Receptor-mediated S1P signaling can influence neuroinflammation and has been implicated in cerebral ischemia through effects on the immune system. However, S1P-mediated events also occur within the brain itself where its roles during stroke have been less well studied. Here we investigated the involvement of S1P signaling in initial and recurrent stroke by using a transient middle cerebral artery occlusion/reperfusion (M/R) model combined with analyses of S1P signaling. Gene expression for S1P receptors and involved enzymes was altered during M/R, supporting changes in S1P signaling. Direct S1P microinjection into the normal CNS induced neuroglial activation, implicating S1P-initiated neuroinflammatory responses that resembled CNS changes seen during initial M/R challenge. Moreover, S1P microinjection combinedwithM/R potentiated brain damage, approximating amodel for recurrent stroke dependent on S1P and suggesting that reduction in S1P signaling could ameliorate stroke damage. Delivery of FTY720 that removes S1P signaling with chronic exposure reduced damage in both initial and S1P-potentiated M/R-challenged brain, while reducing stroke markers like TNF-α. These results implicate direct S1P CNS signaling in the etiology of initial and recurrent stroke that can be therapeutically accessed by S1P modulators acting within the brain. [ABSTRACT FROM AUTHOR]

In intracerebral hemorrhage, microglia become rapidly activated and remove the deposited blood and cellular debris. To survive in a harmful hemorrhagic or posthemorrhagic condition, activated microglia must be equipped with appropriate self-defensive mechanism(s) to resist the toxicity of hemin, a component released from damaged RBCs. In the current study, we found that activation of microglia by pretreatment with LPS markedly reduced their vulnerability to hemin toxicity in vitro. Similarly, intracorpus callosum microinjection of LPS prior to hemin treatment reduced the brain tissue damage caused by hemin and increased microglial density in the penumbra in rats. LPS induced the expressions of inducible NO synthase (iNOS) and heme oxygenase (HO)-1, the rate-limiting enzyme in heme degradation in microglia. The preventive effect by LPS was significantly diminished by an iNOS inhibitor, L-N6-(1-iminoethyl)lysine, whereas it was mimicked by a NO donor, diethylamine-NONOate, both suggesting the crucial role of NO in the modulation of hemin-induced toxicity in activated microglia. We further found that NO reduced hemin toxicity via inhibition of hemin-induced activation of JNK and p38 MAPK pathways in microglia. Whereas HO-1 expression in LPS-stimulated microglia was markedly blocked by L-N6-(1-iminoethyl)lysine, the HO-1 inhibitor, tin protoporphyrin, increased iNOS expression and decreased the susceptibility of LPS-activated microglia to hemin toxicity. The data indicate that the mutual interaction between NO and HO-1 plays a critical role in modulating the adaptive response of activated microglia to hemin toxicity. Better understanding of the survival mechanism of activated microglia may provide a therapeutic strategy to attenuate the devastating intracerebral hemorrhagic injury. [ABSTRACT FROM AUTHOR]

Aims: The multifunctional potential of neferine derived from the embryo of Nelumbo nucifera seeds for the age-related neurodegenerative disorders, in vivo anti-amnesic activities and in vitro cholinesterases (ChEs)- and β-site APP cleaving enzyme 1 (BACE1)-inhibitory activities, as well as anti-inflammatory and antioxidant activities were investigated. Main methods: In vivo anti-amnesic activities were performed via the passive avoidance, Y-maze, and Morris water maze tasks in a scopolamine-induced amnesia model. The cell-free antioxidant capacities were evaluated by in vitro scavenging activities against 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) radicals, and peroxynitrite (ONOO−), as well as inhibitory activities against nitric oxide (NO·), superoxide anion (·O2−), lipid peroxidation, and ONOO−-mediated tyrosine nitration. The intracellular antioxidant capacities were also determined via inhibitory activities of lipopolysaccharide (LPS)-induced NO· generation and NF-κB activation in RAW 264.7 cells. Key findings: Neferine showed significant improvement in cognitive impairment in scopolamine-induced amnesia animal models and moderate inhibitory activities in ChEs and BACE1 assays. In addition, it exhibited notable scavenging activities against DPPH, ABTS, NO·, and ·O2− radicals, as well as ONOO−. Neferine also demonstrated remarkable inhibitory activity against lipid peroxidation and protein nitration in cell-free antioxidant assays and moderate inhibitory activity of NO· generation with exceptional suppression of NF-κB activation in cell-based assays. Significance: The results demonstrate that the anti-amnesic effect of neferine may be mediated via antioxidant and anti-inflammatory capacities, as well as inhibition of ChEs and BACE1. [ABSTRACT FROM AUTHOR]

In this study, the antistress effects of the water extract of Tenebrio molitor larvae (WTML) were investigated. To determine the effects of WTML on fish stress, changes in whole-body cortisol levels and behaviour were monitored in zebrafish (Danio rerio). To induce physical stress, we used net handling stress (NHS). Fish were treated with WTML for 6 min before exposure to stress. Then, the fish were used for evaluation via behavioural tests, including novel tank tests and open field tests, or sacrificed for collection of the whole body fluid. Increased anxiety-like behaviours in the novel tank test and open field test under stress were significantly and concentration-dependently recovered after treatment with WTML (p < 0.05). Moreover, compared with the normal group, which was not induced by NHS, the whole-body cortisol levels of the control group were significantly increased after induction by NHS. Compared with the control group, pretreatment with WTML at concentrations of 25, 50 and 100 mg/L for 6 min significantly prevented the increase in whole-body cortisol levels induced by NHS (p < 0.05). In addition, challenge studies showed that WTML completely blocked the effects of intraperitoneally-injected adrenocorticotropin hormone (ACTH; 0.2 IU/g) on cortisol secretion. These results suggest that WTML may be a good antistress candidate, and that its mechanism of action may be related to its positive effects on cortisol release. • Stress-induced increase of cortisol level was reduced by mealworm in zebrafish. • Mealworm completely blocked adrenocorticotropic hormone-induced cortisol secretion. • Mealworm can be used as a functional supplement for stress-related disorders. [ABSTRACT FROM AUTHOR]

ABSTRACTWe previously reported that uridine blocked glucose deprivation-induced death of immunostimulated astrocytes by preserving ATP levels. Uridine phosphorylase (UPase), an enzyme catalyzing the reversible phosphorylation of uridine, was involved in this effect. Here, we tried to expand our previous findings by investigating the uridine effect on the brain and neurons using in vivoand in vitroischemic injury models. Orally administrated uridine (50–200 mg/kg) reduced middle cerebral artery occlusion (1.5 h)/reperfusion (22 h)–induced infarct in mouse brain. Additionally, in the rat brain subjected to the same ischemic condition, UPase mRNA and protein levels were up-regulated. Next, we employed glucose deprivation-induced hypoglycemia in mixed cortical cultures of neurons and astrocytes as an in vitromodel. Cells were deprived of glucose and, two hours later, supplemented with 20 mM glucose. Under this condition, a significant ATP loss followed by death was observed in neurons but not in astrocytes, which were blocked by treatment with uridine in a concentration-dependent manner. Inhibition of cellular uptake of uridine by S-(4-nitrobenzyl)-6-thioinosine blocked the uridine effect. Similar to our in vivodata, UPase expression was up-regulated by glucose deprivation in mRNA as well as protein levels. Additionally, 5-(phenylthio)acyclouridine, a specific inhibitor of UPase, prevented the uridine effect. Finally, the uridine effect was shown only in the presence of astrocytes. Taken together, the present study provides the first evidence that uridine protects neurons against ischemic insult–induced neuronal death, possibly through the action of UPase. [ABSTRACT FROM AUTHOR]

A new vortex-flow membrane module with glass balls was developed to enhance the permeate flux through a flat-sheet membrane. As a preliminary study for a practical application of our new module configuration, the effects of operating parameters on the microfiltration of an oil-in-water emulsion were investigated. The glass balls used in this study had an average diameter of 4 mm and an average weight of 0.08 g, giving an average density of 2.39 g/ cm3. The number of glass balls inserted into the module was 500, leading to an effective volume fraction of 0.23. Under the same operating conditions, a significant flux enhancement was observed in the presence of glass balls. The flux enhancement due to the presence of glass balls increased with the feed flow rate. The influence of glass balls on the flux enhancement was found to be most significant when the emulsion was more highly concentrated, indicating that the mechanism of this enhancement is based on the disruption of the concentration boundary layer. [Copyright &y& Elsevier]