Dopamine toxicity involves mitochondrial complex I inhibition: implications to dopamine-related neuropsychiatric disorders.

Dopamine, which is suggested as a prominent etiological factor in several neuropsychiatric disorders such as Parkinson's disease and schizophrenia, demonstrates neurotoxic properties. In such dopamine-related diseases mitochondrial dysfunction has been reported. Dopamine oxidized metabolites were shown to inhibit the mitochondrial respiratory system both in vivo and in vitro. In the present study, we suggest an additional mechanism for dopamine toxicity, which involves mitochondrial complex I inhibition by dopamine. In human neuroblastoma SH-SY5Y cells dopamine induced a reduction in ATP concentrations, which was negatively correlated to intracellular dopamine levels (r = - 0.96, P = 0.012), and was already evident at non-toxic dopamine doses. In disrupted mitochondria dopamine inhibited complex I activity with IC50 = 11.87 +/- 1.45 microm or 8.12 +/- 0.75 microM in the presence of CoQ or ferricyanide, respectively, with no effect on complexes IV and V activities. The catechol moiety, but not the amine group, of dopamine is essential for complex I inhibition, as is indicated by comparing the inhibitory potential of functionally and structurally dopamine-related compounds. In line with the latter is the finding that chelatable FeCl2 prevented dopamine-induced inhibition of complex I. Monoamine oxidase A and B inhibitors, as well as the antioxidant butylated hydroxytoluene (BHT), did not prevent dopamine-induced inhibition, suggesting that dopamine oxidation was not involved in this process. The present study suggests that dopamine toxicity involves, or is initiated by, its interaction with the mitochondrial oxidative phosphorylation system. We further hypothesize that this interaction between dopamine and mitochondria is associated with mitochondrial dysfunction observed in dopamine-related neuropsychiatric disorders, such as schizophrenia and Parkinson's disease.

Telomerase activity in HPV-associated vulvar vestibulitis.

OBJECTIVE: To find a possible correlation between telomerase activity, mean telomere length and human papillomavirus (HPV) presence and type in vulvar vestibulitis. STUDY DESIGN: Twenty-two tissues excised during surgery for the treatment of severe vulvar vestibulitis and nine control tissue samples were tested for telomerase activity, mean telomere length, and HPV presence and type. RESULTS: Thirty-six percent of the tissues from vestibulitis patients were infected with HPV, mainly type 16/18, and none of the control tissue samples showed presence of HPV DNA (P < .02). Telomerase activity was detected in all tissues harboring HPV DNA, whereas only 64% of tissues without HPV DNA exhibited telomerase activity (P < .02). The mean telomere length was unchanged as compared to control samples. CONCLUSION: Telomerase activity in vestibulitis may be increased as a result of HPV infection, suggesting that HPV infection may play a role in the etiology of some cases of vulvar vestibulitis.

The effects of bile acids on beta-adrenoceptors, fluidity, and the extent of lipid peroxidation in rat cardiac membranes.

Bile acids have been proposed as a causative factor for the cardiomyopathy of cholestatic liver disease, since they cause negative inotropism and chronotropism and attenuate cardiac responsiveness to sympathetic stimulation. Bile acids can also modify membrane fluidity and generate reactive oxygen species (ROS). The effects of 10(-6)-10(-3) M deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA) and their taurine conjugates, TDCA and TCDCA, on (1) the binding characteristics of beta-adrenoceptors, (2) membrane fluidity, and (3) the extent of lipid peroxidation in rat cardiac membranes were assessed. The results were compared to the effects of the oxidant, 10(-4)-10(-3) M hydrogen peroxide (H(2)O(2)), and the membrane-fluidizing compound, 5 x 10(-5) M 2-(2-methoxyethoxy)ethyl 8-(cis-2-n-octylcyclopropyl)octanoate (A(2)C). Cardiac beta-adrenoceptor density alone was reduced at 10(-4) M bile acid concentration while, at 10(-3) M bile acids, reductions in both receptor density and affinity were seen. At 10(-4) M H(2)O(2), receptor number and affinity were reduced, whereas A(2)C increased receptor affinity without affecting receptor density. Bile acids (10(-3) M) and 10(-4) M H(2)O(2) reduced membrane fluidity. H(2)O(2) caused a concentration-dependent increase in the extent of lipid peroxidation, whereas the bile acids and A(2)C had no effect. Bile acids (10(-4) M) reduced beta-adrenoceptor density in the absence of variations in membrane fluidity and in the extent of membrane lipid peroxidation. This result suggests that bile acids, at concentrations equivalent to the plasma/serum total or estimated free bile acid concentration, may have a possible role in the etiology of cardiomyopathy of cholestatic liver disease. At 10(-3) M bile acid concentration, beta-adrenoceptor number and affinity were adversely affected, accompanied by a decrease in membrane fluidity but without any significant increase in the extent of membrane lipid peroxidation. Although cardiac beta-adrenoceptor density and affinity and membrane fluidity were adversely affected by bile acids, the relevance of these findings to our understanding of the etiological basis of hepatic cardiomyopathy is questionable, since such concentrations exceeded the highest concentrations seen in the plasma and/or tissues of patients with cholestatic liver disease.

Increased telomerase activity and decreased telomere length in genital condylomata acuminata.

Our objective was to find a possible correlation between telomerase activity, mean telomere length and human papillomavirus (HPV) presence and type in genital condylomata acuminata. Fifteen biopsies from women with genital condylomata acuminata and nine control tissue samples were tested for telomerase activity, mean telomere length, and HPV presence and type. All condylomata exhibited telomerase activity, compared to 78% of the control samples. The mean telomere length of condylomata was significantly (P<0.002) shorter compared to telomere length in control tissue samples. All condylomata lesions were infected with HPV types 6/11, and more than half had additional infection with HPV 16/18. Mixed HPV 6/11 with 16/18 infection correlated with shorter telomeres than presence of HPV 6/11 alone in the lesions (4.68 +/- 0.44 kb vs 4.97 +/- 0.57 kb). None of the control tissue samples showed presence of HPV DNA. Telomerase activity may be a marker of proliferation rather than malignancy, whereas the mean telomere length could better serve as a marker for the progression of HPV lesions toward malignancy.

Telomerase activity in patients with transitional cell carcinoma: a preliminary study.

BACKGROUND: Telomerase activity is not detectable in normal cells, and their telomers shorten until the chromosome is unable to replicate. Immortal cells have short but stable chromosomes and increased telomerase activity. Transitional cell carcinoma (TCC) has only a few useful markers of diagnostic or prognostic importance. The objective of this study was to determine whether there was a correlation between telomerase activity and the grade or stage of TCC, and whether the enzyme's activity could serve as a biochemical marker of this tumor. METHODS: The study included 29 patients with TCC. From each patient, samples of urine cells were obtained, and a cup biopsy was taken from an apparently normal area as well as from a part of the bladder tumor resected transurethrally. Control uroepithelial biopsies were taken from normal transitional cell sites from non-TCC patients. Biopsies or cells were subjected to either histologic examination or telomerase activity determination. RESULTS: Twenty-six of 29 (90%) of the tumor biopsies exhibited telomerase activity. Most of the cup biopsies were categorized as metaplastic or dysplastic, and 20 of 29 (69%) of these exhibited telomerase activity. Telomerase activity was found in 17 of 21 (81%) of the urine cells but in only 3 of 14 (21%) of control urine cells. All (10 of 10) of the uroepithelial biopsies taken from non-TCC patients did not show any telomerase activity. CONCLUSIONS: In this study, almost all tumor biopsies exhibited telomerase activity. The high incidence of telomerase activity found in cup biopsies of the malignant field uroepithelial cells from cup biopsies of TCC patients may suggest that telomerase could be activated early in carcinogenesis. A high incidence of telomerase activity was found in voided uroepithelial cells of TCC patients; however, no correlation between this activity and the histologic determination of grading and staging of the tumor was found.

Chronic repetitive transcranial magnetic stimulation alters beta-adrenergic and 5-HT2 receptor characteristics in rat brain.

Repetitive transcranial magnetic stimulation (rTMS) has been shown to affect mood in health and disease. Evidence to date has demonstrated an antidepressant potential for low- and high-frequency rTMS treatment. In animal behavioral models of depression magnetic stimulation of the brain induced similar effects to those of electroconvulsive shock (ECS). In this study the effects of repeated rTMS on rat brain noradrenaline, dopamine, serotonin and their metabolites levels, as well as on beta-adrenergic and 5-HT2 receptor characteristics were studied. After 10 days of treatment, beta-adrenergic receptors were significantly up regulated in the frontal cortex, down regulated in the striatum and were unchanged in the hippocampus. 5-HT2 receptors were down regulated in the frontal cortex and were not changed in the other brain areas. No change in benzodiazepine receptors in the frontal cortex and cerebellum were demonstrated. These findings demonstrate specific and selective alterations induced by repeated rTMS, which are distinct from those induced by other antidepressant treatments. TMS therapeutic effects in humans and behavioral and biochemical effects in animal, suggest that TMS has a unique mechanism of action which requires further investigation.

Rat brain monoamines after acute and chronic myo-inositol treatment.

Inositol was reported to have effects in depression, panic disorder and OCD, and in animal models of depression and anxiety. The present study tested whether inositol treatment alters monoamine systems. Brain areas of rats pre-treated with acute or chronic inositol were analysed by HPLC for monoamines and their metabolites and compared to control animals. Inositol treatment had no significant effect on levels of monoamines, their metabolites, or turnover rates compared to controls.