IntroductionLithium is the agent that has shown more efficacy for the treatment of Bipolar Disorder (BD), anyway a single agent isn’t effective to control all aspects of the syndrome.The mood-stabilizer frequently used, in combination with Lithium, is Valproate which presents different methabolism and side effects. Further both molecules are glycogen synthase kinase-3 (GSK-3b) inhibitors and have synergistic neuroprotective action.ObjectivesWe underline the need to better investigate Lithium and Valproate combination therapy in BD.AimsObservation of Lithium and Valproate combination therapy in a sample of patients with BD, considering doses and serum levels.Methods56 patients with BD (mean age 38 ± 0,02), followed at the day hospital of the Psychiatric Clinic, University of Pisa, were studied. Serum levels evaluated at the Section of Pharmacology, Department of Neuroscience, University of Pisa.ResultsWe identified 5 comparison groups depending on the dose intake of Lithium (11 subjects: 300 mg /die, 9: 450 mg/die, 19: 600 mg/die, 7: 750 mg/die, 10: 900 mg/die) with increased serum levels of the medication (0.27 mEq/l, 0.37 mEq/l, 0.50 mEq/l, 0.52 mEq/l, 0,70 mEq/l). There are not significant differences between groups related to both, the mean dose intake of Valproate (772 mg/die, 744.4 mg/die, 867.5 mg/die, 821.4 mg/die, 845 mg/die) and its serum levels (45.2 mg/L, 46.6 mg/L, 53.2 mg/L, 47.4 mg/L, 48.4 mg/L).ConclusionsThis study aims to identify the effective dose of Lithium in combination with Valproate able to determine the prevention of relapse in BD patients. The use of the lower dose of Lithium maintaining therapeutic effectivness, means reducing side effects, toxicity and the need for constant monitoring.

Evidence for involvement of cytochrome P450 2E1 in the MPTP-induced mouse model of PD has been reported [Vaglini, F, Pardini, C., Viaggi, C., Bartoli, C., Dinucci, D., Corsini, G.U., 2004. Involvement of cytochrome P450 2E1 in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease. J. Neurochem. 91, 285-298]. We studied the sensitivity of Cyp2e1(-/-) mice to the acute administration of MPTP in comparison with their wild-type counterparts. in Cyp2e1(-/-) mice, the reduction of striatal DA content was less pronounced 7 days after MPTP treatment compared to treated wild-type mice. Similarly, TH immuno reactivity analysis of the substantia nigra of Cyp2e1(-/-) mice did not show any neuronal lesions after MPTP treatment. In contrast to this, wild-type animals showed a minimal but significant lesioning by the toxin as evaluated also by means of non-stereologic computerized assisted analysis of this brain area. Striatal levels of DA metabolites after 7 days were variably affected by the toxin, but consistent differences between the two animal strains were not observed.We evaluated short-term changes in the levels of striatal DA and its metabolites, and we monitored striatal MPP+ levels. Striatal MPPI was cleared more rapidly in Cyp2e1(-/-) mice than in wild-type animals and, consistently, striatal DA content decreased faster in Cyp2e1(-/-) mice than in wild-type animals, and 3-methoxytyramine and HVA levels showed an early and sharp rise. Our findings suggest that Cyp2e1(-/-) mice are weakly sensitive to MPTP-induced brain lesions, markedly in contrast with a protective role of the enzyme as suggested previously. The differences observed between the knockout mice and their wild-type counterparts are modest and may be due to an efficient compensatory mechanism or genetic drift in the colonies. (C) 2009 Elsevier Ltd. All rights reserved.

The mechanism by which the dopamine neurons of the substantia nigra pars compacta degenerate in Parkinson's disease, is partly unknown. Dopamine could be implicated in this phenomenon, and in order to explain its toxicity several hypotheses have been suggested. The similarity between apomorphine and dopamine as regards their chemical, pharmacological and toxicological properties provided a basis for investigating the nature of the toxicity of the former agent. In this study we describe some effects of apomorphine on mouse mesencephalic cell cultures at relatively low concentrations (from 0.5 to 2.5microM), apomorphine produced a neurotrophic effect, consisting of a 60% increase in dopaminergic neuron survival as measured by [(3)H] dopamine uptake. At high concentrations (over 20microM), however, apomorphine induced an increasing cytotoxic effect, as measured by the marked decrease in [(3)H] dopamine uptake, and by the direct observation of the dopaminergic neurons after TH immunostaining. This study may offer a new strategy for investigating the mechanisms underlying DA neuron vulnerability.

It has been shown that diethyldithiocarbamate (DDC) potentiates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice as a result of increased levels of 1-methyl-4-phenylpyridinium ion (MPP+) in the striatum. Brain CYP2E1 inhibition by DDC in C57Bl mice was responsible for increased toxicity and striatal MPP+ accumulation. However, CYP2E1-null mice did not show any enhanced sensitivity to MPTP or any MPP+ accumulation. This unexpected finding suggested that the CYP2E1-null mice compensate with other isozymes as already described for acetaminophen-induced liver damage. MPP+ intoxication of mesencephalic cell cultures from CYP2E1-null mice indicated a reduced sensitivity of dopaminergic (DA) neurons from knockout animals. Surprisingly, MPP+ cell distribution under these conditions indicated that the toxin accumulates more intracellularly in knockout cultures, suggesting further that CYP2E1 has a role in MPP+ storage and efflux.

In order to reach a deeper insight into the mechanism of diethyldithiocarbamate (DDC)-induced enhancement of MPTP toxicity in mice, we showed that CYP450 (2E1) inhibitors, such as diallyl sulfide (DAS) or phenylethylisothiocyanate (PIC), also potentiate the selective DA neuron degeneration in C57/bl mice. Furthermore we showed that CYP 2E1 is present in the brain and in the basal ganglia of mice (Vaglini et al., 2004). However, because DAS and PIC are not selective CYP 2E1 inhibitors and in order to provide direct evidence for CYP 2E1 involvement in the enhancement of MPTP toxicity, CYP 2E1 knockout mice (GONZ) and wild type animals (SVI) of the same genetic background were treated with MPTP or the combined DDC + MPTP treatment. In CYP 2E1 knockout mice, DDC pretreatment completely fails to enhance MPTP toxicity, although enhancement of MPTP toxicity was regularly present in the SVI control animals. The immunohistochemical study confirms our results and suggests that CYP 2E1 may have a detoxifying role.