Neuroprotective properties of lithium were evaluated by using in vivo NMDA excitotoxicity model. Systemic injection of NMDA to young mice induced neuronal apoptosis mediated by both TNFR-1 and Fas ligand, and long-term lithium treatment showed noticeable neuroprotection against NMDA-induced excitotoxicity: NMDA-damaged neurons expressed several apoptosis-related gene products such as TNFR-1, Fas ligand, and caspase-3, and these gene expressions were not found in the brain of mice chronically treated with lithium. Therefore, it is highly likely that the protection offered by chronic lithium treatment occurred at far upstream of caspase activation, since the chronic lithium treatment increased the expression of Bcl-2, an important antiapoptotic gene known to act upstream of caspase cascade. Timm's histochemistry indicated the complete blockade of the NMDA insults by the treatment. There was no indication of axonal regeneration, which follows synaptic degeneration induced by neuronal damage. Furthermore, this study reports for the first time that TNFR-1 and Fas ligand are involved in neuroprotective effects of lithium in NMDA-induced neuronal apoptosis.
Animals ; Apoptosis ; Axons ; Brain ; Caspase 3 ; Cerebrum* ; Fas Ligand Protein ; Gene Expression ; Lithium* ; Mice* ; N-Methylaspartate ; Neurons ; Neuroprotective Agents* ; Regeneration

BACKGROUND: Numerous studies have suggested that polyunsaturated fatty acids (PUFAs)-supplemented diets may decrease cardiovascular morbidity and mortality. Especially, omega-3 PUFAs may exert beneficial effects to the treatment and prevention of dyslipidemias, arrhythmias, atherosclerosis, and hypertension. METHODS: This study investigated plasma lipid profiles including total cholesterol, triglycerides (TG), LDL, HDL, and antioxidant status indicative of vitamin A, vitamin E, malondialdehyde (MDA) and distribution of plasma long-chain fatty acids (C12-C24) in 28 normal subjects and 24 hypertensive patients. Also, the correlation among PUFAs, levels of antioxidant status, and lipid profiles of the subjects were estimated. RESULTS: The distribution of omega-3 PUFAs, saturated fatty acids, and monounsaturated fatty acids showed significant differences (P<0.05), but that of omega-6 PUFAs did not exhibit significant differences. The omega-6/omega-3 ratio exhibited 36.96 in normal group and 14.29 in the hypertensive patient group. The levels of vitamin A, vitamin E, and MDA were increased significantly in the hypertensive patient group. CONCLUSION: PUFA levels were estimated in the hypertensive patients and normal group. The results suggest that dietary intake of proper omega-6/omega-3 ratio is needed for prevention and treatment of hypertension.
Arrhythmias, Cardiac ; Atherosclerosis ; Cholesterol ; Diet ; Dyslipidemias ; Fatty Acids ; Fatty Acids, Monounsaturated ; Fatty Acids, Unsaturated ; Humans ; Hypertension ; Malondialdehyde ; Plasma ; Triglycerides ; Vitamin A ; Vitamin E ; Vitamins

We examined the expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) mRNAs upon isoproterenol (Iso)-induced cardiac hypertrophy in rats. Then, we tried to investigate the effects of sympatholytics to see if they can modulate the expression of ANP and BNP. In this study, RT-PCR technique was used to characterize the expression of ANP and BNP in right atrium (RA) and left ventricle (LV) of the hypertrophied rat heart. Histologic findings indicated that stimulation of beta-adrenoceptors with Iso for 5 days was sufficient to induce cardiac hypertrophy in rats. A continuous stimulation with Iso for 7 days resulted in an increase of the ANP and BNP expression in the LV and BNP expression in the RA. The increased expressions of ANP and BNP in the LV were slightly inhibited, and the increased expressions of BNP in the RA were markedly inhibited by a continuous treatment with propranolol, metoprolol, and clonidine for 7 days. Overall, our data present a differential expression of the natriuretic peptides in Iso-induced cardiac hypertrophy, and that the mechanisms involved in this differential ANP and BNP gene expression could be mediated via sympathetic nervous system.
Animals ; Atrial Natriuretic Factor ; Cardiomegaly* ; Clonidine ; Gene Expression ; Heart ; Heart Atria ; Heart Ventricles ; Isoproterenol ; Metoprolol ; Natriuretic Peptide, Brain ; Natriuretic Peptides ; Propranolol ; Rats* ; RNA, Messenger* ; Sympathetic Nervous System ; Sympatholytics

In the present study, we first examined whether the changes in the DNA binding activities of the transcription factors, cAMP response element binding protein (CREB) and activator protein-1 (AP-1) mediate the long-term effects of morphine in differentiated SH-SY5Y human neuroblastoma cells. The increases in CREB and AP-1 DNA binding activities were time-dependent up to 6 days of morphine treatment (1, 4, and 6 days). However, the significant reduction in the DNA binding activities of CREB and AP-1 was observed after 10 days of chronic morphine (10 muM) administration. Secondly, we examined whether the changes of CREB and AP-1 DNA binding activities could be modulated by dopamine and haloperidol. Dopamine cotreatment moderately increased the levels of the CREB and AP-1 DNA binding activities induced by 10 days of chronic morphine treatment, and haloperidol cotreatment also resulted in a moderate increase of the CREB and AP-1 DNA binding activities. However, dopamine or haloperidol only treatment showed a significant increase or decrease of the CREB and AP-1 DNA binding activities, respectively. In the case of acute morphine treatment, the CREB and AP-1 DNA binding activities were shown to decrease in a time-dependent manner (30, 60, 90, and 120 min). Taken these together, in differentiated SH-SY5Y cells, morphine tolerance seems to involve simultaneous changes of the CREB and AP-1 DNA binding activities. Our data also suggest the possible involvement of haloperidol in prevention or reversal of morphine tolerance at the transcriptional level.
Cyclic AMP Response Element-Binding Protein ; DNA* ; Dopamine* ; Haloperidol* ; Humans* ; Morphine ; Neuroblastoma* ; Transcription Factor AP-1* ; Transcription Factors

BACKGROUND: Although cardiac hypertrophy contributes to cardiac failure, the underlying mechanism has not yet been precisely determined. This study was planned in order to determine the pathogenesis of heart failure following cardiac hypertrophy induced by -adrenergic stimulation. METHODS: The extent of cardiac hypertrophy was assessed after administrating isoproterenol (ISO, 5 mg/kg) intraperitoneally for 6 hours, 1, 3, 5, 7 and 10 days. The hematoxylin-eosin, Masson's trichrome and phosphotungstic acid hematoxylin stains along with immunohistochemical stainings for proliferating cell nuclear antigen and Ki-67 were performed in the paraffin-embedded left ventricle sections. Apoptosis was assessed by DNA laddering and terminal deoxynucleotidyl transferase TdT-mediated dUTP-biotin nick end labeling (TUNEL) assay. TUNEL positive myocytes and some nonmyocytes appeared in the subepicardium at 6 hours after ISO administration. The localization of these cells was shifted to the subendocardium within 24 hours, and the TUNEL positive cells were seen throughout the myocardium on the 5th day after ISO treatment. Necrotic myocyte death occurred on the 3rd day of ISO administration in the subendocardium, and initial pericellular fibrosis was followed and increased thereafter, with replacement fibrosis accompanied by further necrotic myocyte cell death. CONCLUSIONS: Our data showed that ISO treatment induced apoptotic myocyte death and superimposed necrotic myocyte death with subsequent fibrosis. The observed cardiac myocyte death may reflect myocardial dysfunction.
Animals ; Apoptosis ; Cardiomegaly* ; Cell Death* ; Coloring Agents ; DNA ; DNA Nucleotidylexotransferase ; Fibrosis ; Heart Failure ; Heart Ventricles ; Hematoxylin ; Hypertrophy ; In Situ Nick-End Labeling ; Isoproterenol ; Muscle Cells ; Myocardium ; Myocytes, Cardiac* ; Phosphotungstic Acid ; Proliferating Cell Nuclear Antigen ; Rats*

Coptis chinensis (CC) is one of the traditional herbs used in Oriental medicine for the treatment of gastrointestinal disorders, anxiety, and insomnia. In this study, neurotrophic and neuritogenic effects of CC on rat pheochromocytoma (PC12) cells were evaluated. Pretreatment of PC12 cells with water extracts of CC (120microgram/ml) produced considerable outgrowth of neurites that is comparable to the effect of nerve growth factor (NGF). Therefore, neurite outgrowth was quantified and expression of NGF mRNA was examined. Furthermore, characteristics of neurites were immunocytochemically confirmed using axon and dendrite-specific antibodies. These results suggest that water extracts of CC contain components that have neurotrophic and neuritogenic properties.
Animals ; Antibodies ; Anxiety Disorders ; Axons ; Coptis* ; Medicine, East Asian Traditional ; Nerve Growth Factor ; Neurites ; PC12 Cells* ; Pheochromocytoma ; Rats ; RNA, Messenger ; Sleep Initiation and Maintenance Disorders ; Water*

The mechanisms underlying opiate tolerance and dependence are not fully understood. We used human neuroblastoma SH-SY5Y cells as a model system for studying effects of morphine tolerance and withdrawal on c-myc induction and cAMP levels. It has been reported that regulation of c-fos by acute and chronic morphine withdrawal is mediated through alterations in CREB transcription factor. In this study, we examined the effects of morphine tolerance on c-myc expression and cAMP concentrations. The activation of opiate receptors by an acute morphine administration resulted in an increase in c-myc mRNA and a decrease in cAMP concentrations in a dose-dependent manner (5, 10, 15, and 20 muM). On the other hand, the chronic treatment of morphine (10 muM for six days) did not induce the elevated expression of c-myc mRNA. The c-myc expression was slightly inhibited in comparison with that of the acute morphine response. However, cAMP concentrations were increased with regard to morphine withdrawal response. These results suggest that the alterations in c-myc expression might imply a significant opiate regulation relating to morphine tolerance. This observation differs from increased expression of c-fos via regulation of cAMP pathway.
Hand ; Humans* ; Morphine ; Neuroblastoma* ; Receptors, Opioid ; RNA, Messenger ; Transcription Factors

The existence of opioid receptors in mammalian cerebellum except human, has not been clearly understood. In the present study, we found that NPY was inducible by morphine in the mouse cerebellar granular and Purkinje cell layers. We performed in situ RT-PCR and immunohistochemistry to characterize the NPY expression. The increase of NPY gene expression by morphine (30 mg/kg, i.p.) was inhibited by pretreatment with not only naloxone (100 mg/kg, i.p.) but also a noncompetitive NMDA antagonist, MK-801 (0.3 mg/kg, i.p.). The competitive NMDA antagonist, AP-5 (0.9 mg/kg, i.p.) slightly attenuated the increased NPY expression by morphine. Also, the finding similar to morphine was shown by NMDA (70 mg/kg, i.p.) treatment. Our results indicate that NPY was inducible by morphine and this might reflect activation of NMDA receptors in granule cells that relay mossy fiber inputs to Purkinje cells via parallel fibers.
Animals ; Cerebellum* ; Dizocilpine Maleate ; Gene Expression ; Humans ; Immunohistochemistry ; Mice* ; Morphine* ; N-Methylaspartate* ; Naloxone ; Negotiating* ; Neuropeptide Y* ; Neuropeptides* ; Purkinje Cells ; Receptors, N-Methyl-D-Aspartate ; Receptors, Opioid

Neuroprotective properties of lithium were investigated by using in vivo NMDA excitotoxicity model. The appearance of TUNEL positive cells was prominent within 24 h of NMDA (70 mg/kg, i.p.) injection in the regions of the cortex, hippocampal formation, and thalamus of mouse cerebrum. NMDA treatment resulted in the extensive enhancement of Bax immunoreactivity in the cortical and hippocampal regions. NMDA also increased the immunoreactivity of caspase 8 in the similar regions of the mouse cerebrum. However, the increased immunoreactivity of Bax and caspase 8 were dramatically attenuated by chronic lithium pretreatment (lithium chloride, 300 mg/kg/d, i.p. for 7-10 days). At the same time, lithium ion blocked the appearance of TUNEL positive cells, and the morphological assessment indicated an effective neuroprotection by lithium against NMDA excitotoxicity. Although the exact action mechanism of lithium is not straightforward at this time, we propose that the inhibition of Bax and caspase cascade is involved in the neuroprotective action of lithium.
Animals ; Caspase 8* ; Cerebrum ; Hippocampus ; In Situ Nick-End Labeling ; Lithium* ; Mice ; N-Methylaspartate ; Thalamus

OBJECTIVE: The purpose of the present study was to investigate the efficacy, safety, and tolerability of aripiprazole in patients with schizophrenia, schizophreniform disorder, and schizoaffective disorder during acute treatment phase. METHODS: Prospective, multicenter, single group, and 8-week study was conducted in patients with schizophrenia, schizophreniform disorder, and schizoaffective disorder. A total of 300 patients were enrolled in the present study. The primary efficacy measure was the Positive and Negative Syndrome Scale (PANSS) total score, and secondary efficacy measures were the PANSS positive and negative subscales scores, and Clinical Global Impression-Severity of Illness (CGI-S) score. Treatment-emergent adverse events, extrapyramidal symptoms (EPS), weight, vital signs, and laboratory tests were assessed as measures of tolerability and safety. RESULTS: Significant improvements in all efficacy measures were achieved by aripiprazole as early as 1-week and sustained through 8-week period. First-episode patients showed greater improvements in PANSS total, positive subscale score, and CGI-S score, compared with recurrent patients. Slightly increased akathisia (+0.32 from baseline score of Barnes Akathisia Rating Scale, p=0.033) and weight gain (1.15+/-3.44 kg, p<0.001) were observed by aripiprazole during 8-week acute treatment phase. CONCLUSION: The present study demonstrated that aripiprazole was effective in acute treatment of positive and negative symptoms of schizophrenia, schizophreniform disorder, and schizoaffective disorder. In general, aripiprazole showed favorable safety and tolerability profiles, although clinicians needed to pay attention to the possibility of akathisia and weight gain by aripiprazole in first-episode patients during acute treatment phase.
Humans ; Piperazines ; Prospective Studies ; Psychomotor Agitation ; Psychotic Disorders ; Quinolones ; Schizophrenia ; Vital Signs ; Weight Gain ; Aripiprazole