Association of subjective anxiety, depression, and sleep disturbance with quality-of-life ratings in adults with epilepsy

Purpose :  To determine the relative contributions of subjective anxiety, depression, sleep disturbance, and seizure-related variables to quality-of-life scores in adults with epilepsy, and the interrelationships among these factors.
Methods :  Consecutive adult patients with epilepsy attending neurology outpatient clinics were recruited. Patients completed the following scales: Hospital Anxiety and Depression Scale (HADS), Hamilton Anxiety Rating Scale, Medical Outcomes Study (MOS) Sleep Scale, Epworth Sleepiness Scale, and Quality of Life in Epilepsy Inventory-31 (QOLIE-31). Univariate and multivariate linear regression models were used to identify variables associated with QOLIE-31 overall score. Path analysis model was constructed to test for interrelations between the variables.
Results :  Two hundred forty-seven patients completed the questionnaires. By multivariate analysis, in order of degree of contribution, HADS anxiety subscale score, MOS Sleep Scale Sleep Problems Index score, HADS depression subscale score, number of current antiepileptic drugs used, and seizure freedom in the past 4 weeks, significantly correlated with QOLIE-31 overall score, accounting for 65.2% of the variance. Complex interrelationships were present between these factors. A general linear model to predict QOLIE-31 overall score in the presence of these factors was constructed.
Conclusion :  Subjective anxiety, depression, and sleep disturbance exerted greater effect than short-term seizure control on quality of life scores of patients with epilepsy. These factors should be considered simultaneously when evaluating effects of treatment on quality of life.     

Behavioral depression induced by an amygdala seizure and the opioid fentanyl was mediated through the nucleus accumbens

Purpose:  To study the behavioral depression induced by a generalized limbic seizure and by an opioid. The hypothesis that an opioid fentanyl and an amygdala-evoked seizure induced behavioral depression through the nucleus accumbens was tested.
Methods:  The behavioral depression induced by an amygdala-kindled seizure was studied in fully kindled rats, with or without prior injection of fentanyl (0.05 mg/kg, s.c.). Local infusion of a nonspecific opioid antagonist, naloxone, or saline, was made bilaterally in the nucleus accumbens. The durations of loss of righting reflex (LORR), loss of tail-pinch response, and catalepsy were assessed.
Results:  Fentanyl induced an LORR following a generalized kindled seizure. The combination of fentanyl and a generalized seizure, as compared to fentanyl alone or a generalized seizure alone, resulted in a prolonged duration of LORR, catalepsy, and loss of tail pinch response. Infusion of naloxone as compared to saline in the nucleus accumbens reduced the duration of catalepsy and LORR induced by fentanyl, with or without a generalized seizure.
Conclusions:  Postictal depression that follows a generalized kindled seizure enhanced the behavioral effects of the opioid fentanyl. Network synaptic depression induced by the seizure acted synergistically with fentanyl to produce analgesia, catalepsy, and LORR, in part through the nucleus accumbens.     

The anti-hypertensive effect of Danshen (Salvia miltiorrhiza) and Gegen (Pueraria lobata) formula in rats and its underlying mechanisms of vasorelaxation

Ethnopharmacological relevance

Radix Salviae miltiorrhizae (Danshen) and Radix Puerariae lobatae (Gegen) have long been used in traditional Chinese Medicine and serve as the principal herbs in treating cardiovascular disease.

Aims of the study

In the present study, an aqueous extract comprising Danshen and Gegen in the ratio of 7:3 (DG) was investigated for its anti-hypertension in vivo and vasodilative activities ex vivo.

Materials and methods

The anti-hypertensive effect of DG extract was investigated in spontaneously hypertensive rat (SHR) by measuring systolic blood pressure (SBP). Oral administration of DG extract was started at age of 6 weeks and 14 weeks for the preventive and therapeutic studies, respectively. Blood pressure was measured by tail-cuff method biweekly for 12 weeks. The ex vivo vasodilative activities of DG extract, its dependency on endothelium and the involvement of nitric oxide, prostacyclin and potassium channels were investigated using isolated rat aorta ring in organ bath.

Results

For in vivo study, systolic blood pressure was significantly reduced in DG extract-treated groups (90.2 and 300 mg/kg) as compared with the SHR control in both preventive and therapeutic studies. However, DG extract was unable to suppress or delay the onset of hypertension in the preventive study. For ex vivo study, the results showed that DG extract induced a concentration-dependent relaxation in aorta and persisted response was observed with the removal of endothelium. Besides, pretreatment with a non-selective potassium channel inhibitor tetraethylammonium (TEA) also significantly inhibited DG extract-induced vasodilation. Further investigations on specific potassium channel blockers revealed that ATP-sensitive potassium (K_ATP) channel inhibitor glibenclamide, inward rectifier potassium (Kir) inhibitor barium chloride and voltage-dependent potassium (K_v) channel inhibitor 4-aminopyridine, but not BK_Ca channel inhibitor iberiotoxin, exerted significant inhibition on DG extract-induced vasodilation.

Conclusions

The results of in vivo SHR animal model suggested that DG aqueous extract possessed blood pressure lowering effect on both pre- and post-hypertensive rats, which could be explained by its endothelium-independent vasodilation via the opening of K_ATP, Kir and K_v channels.     

Danshen-Gegen decoction exerts proliferative effect on rat cardiac myoblasts H9c2 via MAPK and insulin pathways

Ethnopharmacological relevance

Danshen (root of Salvia miltiorrhiza) and Gegen (roots of Pueraria lobata) are traditional Chinese medicines that have been used in combination for cardiovascular disease treatment.

Aim of the study

The present study was performed to investigate the effect of Danshen-Gegen decoction on rat myocardium cell line H9c2 and the possible molecular mechanisms.

Materials and methods

Rat heart myocardium H9c2 cells were treated with or without Danshen-Gegen decoction (DG) ranging from 10 to 1000 μg/ml for 24 h. Cell viability was measured by Alarma blue assay and cell proliferation assay was performed by BrdU Cell Proliferation ELISA kit. The activation of mitogen-activated protein kinase and insulin pathways was analyzed by Luminex technology and the growth factors and cytokine expression of H9c2 cells induced by DG was evaluated by protein array. Moreover, a rat functional specific cDNA microarray was constructed to study the gene expression profiles of H9c2 cells upon the DG treatment at 50 μg/ml for 24 h.

Results

DG promoted H9c2 cell viability and cell proliferation at dose-dependent manner within the range between 0 and 250 μg/ml. A Bio-Plex assay kit (Bio-Rad Bioscience) was used to detect the expression level of phosphoprotein as well as total proteins involved in the MAPK and insulin pathways. Significant phosphorylation of ERK, c-Jun, JNK, p38, AKT, IGF-IR, IRS-1and I kappa B were observed after DG treatment at 2 h or 4 h. A rat cytokine antibody array was used to detect and quantify 22 growth factors and cytokines in samples collected from the control and DG treated H9c2 cells. In the category of growth factors, GM-CSF, CNIF and b-NGF were stimulated by DG, while the expression of TIMP-1 was suppressed. For cytokine expression, it was found that DG stimulated three interleukin subclasses, IL-1α, 1X and 6, respectively. However, the expression of pro-inflammatory factors such as TNF-α and IFN-γ were down-regulated significantly. Moreover, the microarray analysis revealed that DG significantly up-regulated anti-apoptosis related genes such as Cdkn2c and Ppp3ca, and several cardiovascular disease suppressers and anti-inflammatory mediators; on the other hand, pro-apoptotic related genes including Caspase and Tnf-α were down-regulated by DG. Based on the results, a tentative scheme was proposed to show that the activation of the MAPK and insulin pathways are involved in the bioactive effect of Danshen-Gegen decoction on cardiomyocytes.

Conclusion

Our study suggested that Danshen-Gegen decoction has proliferative effect on myocardium cells via MAPK and insulin signaling pathways. The molecular mechanism of the action may include the up-regulation of IRS/AKT and JNK pathways as well as the inhibition of TNF and p38 pathways.     

Apocynum venetum leaf aqueous extract inhibits voltage-gated sodium channels of mouse neuroblastoma N2A cells

Ethnopharmacological relevance

Apocynum venetum Linn. (Apocynaceae family), also called Luobuma, is a shrub which grows widely in the Xinjiang Autonomous Region of China. Its leaves are used in herbal tea for the treatment of hypertension, anxiety and depression. Animal studies have also shown that Apocynum venetum leaf extract (AVLE) also exerts anti-depressant and anti-anxiety activities. The effects of AVLE on neuronal tissues in vitro are not fully understood.

Materials and methods

Using the whole-cell voltage-clamp method, we studied the effects of AVLE on ion channels in cultured mouse neuroblastoma N2A cells.

Results

AVLE inhibited voltage-gated inward Na⁺ current in a reversible and concentration-dependent manner (half-inhibitory concentration was 18 μg/ml and maximum inhibition at 100 μg/ml). AVLE specifically promoted steady-state inactivation of Na⁺ channels but did not affect voltage-dependence of activation. The inhibitory effect was not use-dependent and was not affected by 300 μM L-NAME, suggesting that NO was not involved in the action of AVLE in neuronal cells. AVLE also had a mild inhibitory effect on voltage-gated K⁺ channels, but did not affect ATP-sensitive K⁺ channels.

Conclusions

Since voltage-gated Na⁺ and K⁺ channels are associated with neuronal excitability and therefore affect neurotransmission, the modulation of neuronal ion channels by AVLE may exert neuropharmacological effects. In particular, the inhibition of voltage-gated Na⁺ currents by AVLE may in part account for the psychopharmacological effects of this herbal remedy.     

Seven quassinoids from Fructus Bruceae with cytotoxic effects on pancreatic adenocarcinoma cell lines

Our previous studies showed that the alcohol extract of the fruit of Brucea javanica (Fructus Bruceae) possessed significant cytotoxicity in pancreatic adenocarcinoma cell lines. A bioassay‐guided fractionation and purification resulted in the isolation and characterization of seven quassinoids including brusatol, bruceine D, bruceine H, yadanzioside A, yadanzioside G, javanicoside C and bruceantinoside A. Among them, brusatol exhibited the most potent in vitro antipancreatic cancer action, with IC₅₀ values of 0.36 µm and 0.10 µm on PANC‐1 and SW1990 cell lines, respectively. This is the first report on the antipancreatic adenocarcinoma activity of brusatol. Copyright © 2011 John Wiley & Sons, Ltd.     

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone promoted gastric cancer growth through prostaglandin E receptor (EP2 and EP4) in vivo and in vitro

Prostaglandin E (EP) receptor is positively related with COX-2, which is involved in cancer biology. A mechanistic study on how 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) promotes gastric carcinogenesis is lacking. Recently, we found that nicotine promoted tumor growth through upregulation of the COX-2/prostaglandin E(2) pathway. This extended our study on the involvement of EP receptors in gastric carcinogenesis. Both in vitro and in vivo studies showed that NNK promoted cancer cell growth with concomitant EP2 and EP4 upregulation. We found that NNK stimulated vascular endothelial growth factor (VEGF) and angiogenesis, but suppressed apoptosis by increasing Bcl2 and decreasing caspase-3 expressions. Both EP2 and EP4 siRNA significantly impaired these tumorigenic actions of NNK in xenograft tumor. Cell cycle analysis showed that NNK increased S phase entry with increased cyclin D1 and the associated cyclin-dependent kinase 4/6, and downregulation of p21 and p27. The p38 phosphorylation was EP2/4-dependent, and SB203580 (p38 inhibitor) suppressed NNK-induced prostaglandin E(2) , VEGF, and cell proliferation. Antagonists of EP2 or EP4 abolished the elevated VEGF and VEGF receptor-2. These data strongly indicate that EP2/4 are important for NNK-promoted gastric carcinogenesis, thus providing a framework for future evaluation of EP antagonist(s) as anticancer drugs for smokers.