Routine exercise ameliorates the metabolic side-effects of treatment with the atypical antipsychotic drug olanzapine in rats.

Second generation antipsychotic (SGA) drugs are effective treatments for psychosis. Common side-effects of SGAs include metabolic dysregulation and risk of cardiometabolic disorders. Metabolic side-effects, including glucose intolerance, can be accurately modelled in rodents. The benefits of interventions used for treating metabolic side-effects of SGAs are mostly unknown. In a 9 wk longitudinal study, female rats were given daily olanzapine (10 mg/kg s.c.) or vehicle. Animals were either sedentary or allowed 1 or 3 h daily access to a running wheel, with total wheel revolutions electronically quantified to reflect exercise intensity. Glucose tolerance tests were performed once weekly to measure glycemic control. Drug levels were measured at week 4. At week 9, abdominal fat and skeletal muscle levels of Glucose Transporter 4 (GLUT4) were measured. Exercise intensity progressively increased over time in all groups given access to running wheels; however, rats treated with olanzapine consistently exercised less than those given the vehicle. Olanzapine caused acute and persistent glucose intolerance throughout the study, which was markedly, though incompletely, ameliorated by exercise. Exercise did not affect glycemic regulation in vehicle-treated rats. Olanzapine-treated rats showed greater central adiposity. Levels of GLUT4 in skeletal muscle were higher in both groups of exercising than in sedentary rats, and GLUT4 values were negatively correlated with glucose intolerance. Routine exercise reduced olanzapine-induced glucose intolerance and increased skeletal muscle levels of GLUT 4, the insulin-responsive transporter that mediates glucose uptake into cells. The current animal model is suitable for evaluating physiological pathways involved with glucose intolerance.

Substrate specificity of Myriococcum thermophilum cellobiose dehydrogenase on mono-, oligo-, and polysaccharides related to in situ production of H2O2.

Cellobiose dehydrogenase from the ascomycete fungus Myriococcum thermophilum (MtCDH) was tested for the ability to generate bleaching species at a pH suitable for liquid detergents. The catalytic properties of MtCDH were investigated for a large variety of carbohydrate substrates using oxygen as an electron receptor. MtCDH produces H2O2 with all substrates tested (except fructose) but only in the presence of a chelant. Insoluble substrates like cellulose and cotton could as well be oxidized by MtCDH. To enhance the amount of cello-oligosaccharides in solution, different cellulases on cotton were used and in combination with MtCDH an increased H2O2 concentration could be measured. Additionally, the degradation of pure anthocyanins in solution (as model substrates for bleaching) was investigated in the absence and presence of a horseradish peroxidase. MtCDH was able to produce a sufficient amount of H2O2 to decolorize the anthocyanins within 2 h.

Synthesis and anti-melanoma activity of analogues of N-acetyl-4-S-cysteaminylphenol substituted with two methyl groups alpha to the nitrogen.

N-Acetyl-4-S-cysteaminylphenol 1 is an analogue of a biosynthetic intermediate in the pathway to melanin. It is probably oxidized to an o-quinone which can alkylate cellular nucleophiles resulting in interference with cell growth and proliferation. It is reported to have useful anti-melanoma activity. We previously synthesized a range of analogues of 1 by varying the acyl portion of the amide. A modest increase in melanoma activity against six melanoma cell lines for these analogues could be correlated with increased lipophilicity. Thirteen new analogues of 1 containing two methyl groups at the alpha-position of the amino component and various acyl groups have now been prepared and assessed for anti-melanoma activity against six human melanoma cell lines. Most of the new compounds displayed greater cytotoxicity than the lead compound 1. The highest cytotoxicity against the cell lines was observed for the cyclohexylacetamide 11 followed by the cyclohexylcarboxamide 10 and the 2,2-dimethylpropanamide 6. The IC50 values of the most cytotoxic compound 11 against the cell lines were comparable with those of cisplatin. Small variations in the acyl components of these analogues, such as reducing the ring size, lengthening the carbon chain and reducing the amount of chain branching, resulted in a considerable loss of cytotoxicity. The moderate activity of 6, 10 and 11 against SK-Mel-24 cells (non-tyrosinase containing) and an ovarian cell line suggests that interference with the melanin pathway may not be their only mode of action.

Synthesis and antimelanoma activity of analogues of N-acetyl-4-S-cysteaminylphenol.

N-Acetyl-4-S-cysteaminylphenol (1) has been shown by Jimbow and co-workers to possess useful antimelanoma activity. It is an analogue of a biosynthetic intermediate in the pathway to melanin and probably acts as a prodrug, being oxidized to an o-quinone which reacts with essential enzymes containing sulphydryl groups resulting in interference with cell growth and proliferation. We have synthesized a range of analogues of 1 by varying the acyl portion of the amide with the intention of increasing the lipophilicity of the compounds. A modest increase in melanoma activity against six melanoma cell lines for these analogues could be correlated with increased lipophilicity. The most active of these compounds, N-[2-[(4-hydroxyphenyl)thiol]ethyl]cyclohexanecarboxamide (9), showed promising selectivity (lack of cytotoxicity) on the non-melanotic cell line SK-Mel-24 and on an ovarian cell line. A significant improvement in antimelanoma activity was observed with a new type of analogue containing three carbon atoms between the sulphur and nitrogen. The most active of these new analogues, N-[3-[(4-hydroxyphenyl)-thiolpropyl]-1-cyclohexanecarboxamide (15), had activity comparable to cisplatin against several cell lines and low cytotoxicity towards the non-melanotic cell line.