Inhibition of brain retinoic acid catabolism: a mechanism for minocycline's pleiotropic actions?

OBJECTIVES: Minocycline is a tetracycline antibiotic increasingly recognized in psychiatry for its pleiotropic anti-inflammatory and neuroprotective potential. While underlying mechanisms are still incompletely understood, several lines of evidence suggest a relevant functional overlap with retinoic acid (RA), a highly potent small molecule exhibiting a great variety of anti-inflammatory and neuroprotective properties in the adult central nervous system (CNS). RA homeostasis in the adult CNS is tightly controlled through local RA synthesis and cytochrome P450 (CYP450)-mediated inactivation of RA. Here, we hypothesized that minocycline may directly affect RA homeostasis in the CNS via altering local RA degradation. METHODS: We used in vitro RA metabolism assays with metabolically competent synaptosomal preparations from murine brain and human SH-SY5Y neuronal cells as well as viable human SH-SY5Y neuroblastoma cell cultures. RESULTS: We revealed that minocycline potently blocks RA degradation as measured by reversed-phase high-performance liquid chromatography and in a viable RA reporter cell line, even at low micromolar levels of minocycline. CONCLUSIONS: Our findings provide evidence for enhanced RA signalling to be involved in minocycline's pleiotropic mode of action in the CNS. This novel mode of action of minocycline may help in developing more specific and effective strategies in the treatment of neuroinflammatory or neurodegenerative disorders.

The effects of donepezil on postlearning sleep EEG of healthy older adults.

INTRODUCTION: Aging is associated with cholinergic hypofunction and memory decline. Cholinergic activity also plays a crucial role in sleep-dependent memory consolidation. The acetylcholinesterase inhibitor (AChE-I) donepezil has been found to increase sleep-related procedural memory consolidation in healthy older adults in a previous study. METHODS: Data of the former study were reanalyzed with regard to the effects of donepezil on the sleep EEG of healthy older adults. This analysis was conducted with a special focus on spectral parameters of sleep, which have previously been linked to plasticity-related processes during sleep, i.e., sigma and delta activity. Forty-two participants (aged: 60-77 years) received 5 mg of the AChE-I donepezil orally 30 min before bedtime in a placebo-controlled, double-blind design. Power values for EEG delta, theta, alpha1, alpha 2, sigma, beta and gamma frequency bands were calculated for stage 2 NREM sleep, SWS and REM sleep. RESULTS: In line with our hypotheses, the AChE-I donepezil led to an increase in sigma activity during stage 2 NREM sleep and delta activity during slow wave sleep. CONCLUSION: These results suggest that an AChE-I facilitates processes of sleep-dependent memory consolidation in older adults.

[Mixed episodes in bipolar disorder: a review]. / Affektive Mischzustände bei Bipolaren Störungen: ein Uberblick.

Affective mixed states in bipolar disorders are a current matter of scientific debate and represent a complex clinical picture with coexisting manic and depressive symptoms. Treatment of mixed states is regarded as an important challenge. As diagnostic uncertainties complicate systematic clinical evaluations of this patient group, generally accepted clinical treatment guidelines are lacking yet. In this review the significance as well as the problems and risks of new treatment options are discussed.

The effect of donepezil on sleep in elderly, healthy persons: a double-blind placebo-controlled study.

INTRODUCTION: Previous research in younger individuals has shown that acetylcholinesterase inhibitors tend to enhance REM sleep. METHODS: Forty-two healthy elderly persons participated in a double-blind placebo-controlled polysomnographic study (parallel group design). RESULTS: The present study indicates that in the elderly persons, donepezil, an acetylcholinesterase inhibitor also exerts a marked effect on REM sleep parameters: REM density was increased whereas REM latency was reduced, thus, confirming the findings of our pilot study described earlier. CONCLUSION: Whether the cholinergic stimulation measured by polysomnography is related to treatment efficacy is a very interesting but an open question. Based on the findings that REM sleep is associated with memory consolidation, the question whether REM sleep augmentation enhances memory performance-as suggested by the findings of the pilot study-seems to be an interesting topic for future research.

[Diabetes and depression]. / Diabetes und Depression.

Cohort studies indicate a high prevalence of depression in patients with diabetes mellitus. Despite numerous investigations, the underlying pathophysiologies of the metabolic abnormalities are poorly understood. A possible role play the increased counter-regulatory hormone release involved in glucose homeostasis, alterations in the glucose transport function and increased inflammatory activation triggered by depression. The diagnose of "depression" in diabetic patients might be hampered by similar symptoms of both conditions as fatigue, psychomotor inhibition, reduced appetite or sexual dysfunction. In treating depressive patients with diabetes one should consider potential induction or worsening of diabetes-like metabolic alterations. Selective serotonin-reuptake-inhibitors, venlafaxin and MAO-Inhibitors constitute a beneficial choice. Atypical antipsychotics like clozapine, olanzapine, quetiapine and risperidone should be given with precaution due to potential effects on glucose homeostasis.