Agomelatine, Ketamine and Vortioxetine Attenuate Energy Cell Metabolism-In Vitro Study.

This determination of the mitochondrial effect of pharmacologically different antidepressants (agomelatine, ketamine and vortioxetine) was evaluated and quantified in vitro in pig brain-isolated mitochondria. We measured the activity of mitochondrial complexes, citrate synthase, malate dehydrogenase and monoamine oxidase, and the mitochondrial respiratory rate. Total hydrogen peroxide production and ATP production were assayed. The most potent inhibitor of all mitochondrial complexes and complex I-linked respiration was vortioxetine. Agomelatine and ketamine inhibited only complex IV activity. None of the drugs affected complex II-linked respiration, citrate synthase or malate dehydrogenase activity. Hydrogen peroxide production was mildly increased by agomelatine, which might contribute to increased oxidative damage and adverse effects at high drug concentrations. Vortioxetine significantly reduced hydrogen peroxide concentrations, which might suggest antioxidant mechanism activation. All tested antidepressants were partial MAO-A inhibitors, which might contribute to their antidepressant effect. We observed vortioxetine-induced MAO-B inhibition, which might be linked to decreased hydrogen peroxide formation and contribute to its procognitive and neuroprotective effects. Mitochondrial dysfunction could be linked to the adverse effects of vortioxetine, as vortioxetine is the most potent inhibitor of mitochondrial complexes and complex I-linked respiration. Clarifying the molecular interaction between drugs and mitochondria is important to fully understand their mechanism of action and the connection between their mechanisms and their therapeutic and/or adverse effects.

Interactions Among Polymorphisms of Susceptibility Loci for Alzheimer's Disease or Depressive Disorder.

BACKGROUND Several genetic susceptibility loci for major depressive disorder (MDD) or Alzheimer's disease (AD) have been described. Interactions among polymorphisms are thought to explain the differences between low- and high-risk groups. We tested for the contribution of interactions between multiple functional polymorphisms in the risk of MDD or AD. MATERIAL AND METHODS A genetic association case-control study was performed in 68 MDD cases, 84 AD cases (35 of them with comorbid depression), and 90 controls. The contribution of 7 polymorphisms from 5 genes (APOE, HSPA1A, SLC6A4, HTR2A, and BDNF) related to risk of MDD or AD development was analyzed. RESULTS Significant associations were found between MDD and interactions among polymorphisms in HSPA1A, SLC6A4, and BDNF or HSPA1A, BDNF, and APOE genes. For polymorphisms in the APOE gene in AD, significant differences were confirmed on the distributions of alleles and genotype rates compared to the control or MDD. Increased probability of comorbid depression was found in patients with AD who do not carry the ε4 allele of APOE. CONCLUSIONS Assessment of the interactions among polymorphisms of susceptibility loci in both MDD and AD confirmed a synergistic effect of genetic factors influencing inflammatory, serotonergic, and neurotrophic pathways at these heterogenous complex diseases. The effect of interactions was greater in MDD than in AD. A presence of the ε4 allele was confirmed as a genetic susceptibility factor in AD. Our findings indicate a role of APOE genotype in onset of comorbid depression in a subgroup of patients with AD who are not carriers of the APOE ε4 allele.

1-(Benzo[d]thiazol-2-yl)-3-phenylureas as dual inhibitors of casein kinase 1 and ABAD enzymes for treatment of neurodegenerative disorders.

Several neurodegenerative disorders including Alzheimer's disease (AD) have been connected with deregulation of casein kinase 1 (CK1) activity. Inhibition of CK1 therefore presents a potential therapeutic strategy against such pathologies. Recently, novel class of CK1-specific inhibitors with N-(benzo[d]thiazol-2-yl)-2-phenylacetamide structural scaffold has been discovered. 1-(benzo[d]thiazol-2-yl)-3-phenylureas, on the other hand, are known inhibitors amyloid-beta binding alcohol dehydrogenase (ABAD), an enzyme also involved in pathophysiology of AD. Based on their tight structural similarity, we decided to evaluate series of previously published benzothiazolylphenylureas, originally designed as ABAD inhibitors, for their inhibitory activity towards CK1. Several compounds were found to be submicromolar CK1 inhibitors. Moreover, two compounds were found to inhibit both, ABAD and CK1. Such dual-activity could be of advantage for AD treatment, as it would simultaneously target two distinct pathological processes involved in disease's progression. Based on PAMPA testing both compounds were suggested to permeate the blood-brain barrier, which makes them, together with their unique dual activity, interesting lead compounds for further development.

Biological hypotheses and biomarkers of bipolar disorder.

The most common mood disorders are major depressive disorders and bipolar disorders (BD). The pathophysiology of BD is complex, multifactorial, and not fully understood. Creation of new hypotheses in the field gives impetus for studies and for finding new biomarkers for BD. Conversely, new biomarkers facilitate not only diagnosis of a disorder and monitoring of biological effects of treatment, but also formulation of new hypotheses about the causes and pathophysiology of the BD. BD is characterized by multiple associations between disturbed brain development, neuroplasticity, and chronobiology, caused by: genetic and environmental factors; defects in apoptotic, immune-inflammatory, neurotransmitter, neurotrophin, and calcium-signaling pathways; oxidative and nitrosative stress; cellular bioenergetics; and membrane or vesicular transport. Current biological hypotheses of BD are summarized, including related pathophysiological processes and key biomarkers, which have been associated with changes in genetics, systems of neurotransmitter and neurotrophic factors, neuroinflammation, autoimmunity, cytokines, stress axis activity, chronobiology, oxidative stress, and mitochondrial dysfunctions. Here we also discuss the therapeutic hypotheses and mechanisms of the switch between depressive and manic state.

Plasma homocysteine in Alzheimer's disease with or without co-morbid depressive symptoms.

OBJECTIVE: Elevated homocysteine is associated with a variety of diseases, including Alzheimer's disease (AD) and depressive disorder. This study was designed to detect an association between plasma homocysteine and AD with or without co-morbid depressive symptoms. METHODS: Plasma homocysteine concentrations were measured in 85 AD patients (36 of them with depressive symptoms), 33 non-AD patients with a depression diagnosis and 44 healthy controls, all aged above 50 years. RESULTS: Positive correlation between age and homocysteine was confirmed. Significantly higher mean plasma homocysteine was found in AD patients, but not in depressive patients, when compared with controls. We confirmed significant correlation between homocysteine concentration and the degree of cognitive impairment in AD patients. There was no incremental effect of concurrent depressive symptoms on homocysteine concentration in AD patients. CONCLUSION: The association of high homocysteine with degree of cognitive impairment or stage of dementia in AD indicate potential role of high plasma homocysteine as a biomarker of the disease and/or indicator of brain damage during the progression of AD dementia.

Alzheimer's disease approaches - Focusing on pathology, biomarkers and clinical trial candidates.

The strategy for the development of new drugs for Alzheimer's disease (AD) recognizes that an effective therapy requires early therapeutic intervention and a multifactorial approach that considers the individual initiators of AD development. Current knowledge of AD includes the understanding of pathophysiology, risk factors, biomarkers, and the evolving patterns of biomarker abnormalities. This knowledge is essential in identifying potential molecular targets for new drug development. This review summarizes promising AD drug candidates, many of which are currently in phase 2 or 3 clinical trials. New agents are classified according to the Common Alzheimer's Disease Research Ontology (CADRO). The main targets of new drugs for AD are processes related to amyloid beta and tau neurotoxicity, neurotransmission, inflammation, metabolism and bioenergetics, synaptic plasticity, and oxidative stress. These interventions are aimed at preventing disease onset and slowing or eliminating disease progression. The efficacy of pharmacotherapy may be enhanced by combining these drugs with other treatments, antioxidants, and dietary supplements. Ongoing research into AD pathophysiology, risk factors, biomarkers, and the dynamics of biomarker abnormalities may contribute to the understanding of AD and offer hope for effective therapeutic strategies in the near future.

CoQ10 and Mitochondrial Dysfunction in Alzheimer's Disease.

The progress in understanding the pathogenesis and treatment of Alzheimer's disease (AD) is based on the recognition of the primary causes of the disease, which can be deduced from the knowledge of risk factors and biomarkers measurable in the early stages of the disease. Insights into the risk factors and the time course of biomarker abnormalities point to a role for the connection of amyloid beta (Aß) pathology, tau pathology, mitochondrial dysfunction, and oxidative stress in the onset and development of AD. Coenzyme Q10 (CoQ10) is a lipid antioxidant and electron transporter in the mitochondrial electron transport system. The availability and activity of CoQ10 is crucial for proper mitochondrial function and cellular bioenergetics. Based on the mitochondrial hypothesis of AD and the hypothesis of oxidative stress, the regulation of the efficiency of the oxidative phosphorylation system by means of CoQ10 can be considered promising in restoring the mitochondrial function impaired in AD, or in preventing the onset of mitochondrial dysfunction and the development of amyloid and tau pathology in AD. This review summarizes the knowledge on the pathophysiology of AD, in which CoQ10 may play a significant role, with the aim of evaluating the perspective of the pharmacotherapy of AD with CoQ10 and its analogues.

Plasma cortisol in Alzheimer's disease with or without depressive symptoms.

BACKGROUND: Cortisol is presumed to be a risk factor for stress- and age-related disorders, such as depressive disorder and Alzheimer's disease (AD). The aim of this study was to investigate the association of plasma cortisol concentration with AD in presence or absence of comorbid depressive symptoms. MATERIAL AND METHODS: Plasma cortisol concentration was measured in 80 AD patients (35 of them with depressive symptoms), 27 elderly depressive patients without AD, and 37 elderly controls. RESULTS: Compared to controls, a significant increase of mean plasma cortisol was found in AD patients but not in depressive patients. Plasma cortisol was positively correlated with cognitive impairment in AD patients. We confirmed a U-shaped association between plasma cortisol and major depression and a linear association between plasma cortisol and AD without depressive symptoms. Significantly increased relative risk of disease in people with high plasma cortisol was found for AD with depressive symptoms and for AD with mild dementia. CONCLUSIONS: Plasma cortisol reflects the degree of cognitive impairment in AD rather than the severity of comorbid depression. We confirmed that both hypercortisolemia and hypocortisolemia are associated with depressive disorder. Significant association between high plasma cortisol and AD was found, supporting the use of high plasma cortisol as a component of a panel of biochemical markers for AD with depressive symptoms as well as AD in the early stage of dementia development.

Biological hypotheses, risk factors, and biomarkers of schizophrenia.

Both the discovery of biomarkers of schizophrenia and the verification of biological hypotheses of schizophrenia are an essential part of the process of understanding the etiology of this mental disorder. Schizophrenia has long been considered a neurodevelopmental disease whose symptoms are caused by impaired synaptic signal transduction and brain neuroplasticity. Both the onset and chronic course of schizophrenia are associated with risk factors-induced disruption of brain function and the establishment of a new homeostatic setpoint characterized by biomarkers. Different risk factors and biomarkers can converge to the same symptoms of schizophrenia, suggesting that the primary cause of the disease can be highly individual. Schizophrenia-related biomarkers include measurable biochemical changes induced by stress (elevated allostatic load), mitochondrial dysfunction, neuroinflammation, oxidative and nitrosative stress, and circadian rhythm disturbances. Here is a summary of selected valid biological hypotheses of schizophrenia formulated based on risk factors and biomarkers, neurodevelopment, neuroplasticity, brain chemistry, and antipsychotic medication. The integrative neurodevelopmental-vulnerability-neurochemical model is based on current knowledge of the neurobiology of the onset and progression of the disease and the effects of antipsychotics and psychotomimetics and reflects the complex and multifactorial nature of schizophrenia.

Different Effects of SSRIs, Bupropion, and Trazodone on Mitochondrial Functions and Monoamine Oxidase Isoform Activity.

Mitochondrial dysfunction is involved in the pathophysiology of psychiatric and neurodegenerative disorders and can be used as a modulator and/or predictor of treatment responsiveness. Understanding the mitochondrial effects of antidepressants is important to connect mitochondria with their therapeutic and/or adverse effects. Pig brain-isolated mitochondria were used to evaluate antidepressant-induced changes in the activity of electron transport chain (ETC) complexes, monoamine oxidase (MAO), mitochondrial respiratory rate, and ATP. Bupropion, escitalopram, fluvoxamine, sertraline, paroxetine, and trazodone were tested. All tested antidepressants showed significant inhibition of complex I and IV activities at high concentrations (50 and 100 µmol/L); complex II + III activity was reduced by all antidepressants except bupropion. Complex I-linked respiration was reduced by escitalopram >> trazodone >> sertraline. Complex II-linked respiration was reduced only by bupropion. Significant positive correlations were confirmed between complex I-linked respiration and the activities of individual ETC complexes. MAO activity was inhibited by all tested antidepressants, with SSRIs causing a greater effect than trazodone and bupropion. The results indicate a probable association between the adverse effects of high doses of antidepressants and drug-induced changes in the activity of ETC complexes and the respiratory rate of mitochondria. In contrast, MAO inhibition could be linked to the antidepressant, procognitive, and neuroprotective effects of the tested antidepressants.

Age-Dependent Alterations in Platelet Mitochondrial Respiration.

Mitochondrial dysfunction is an important cellular hallmark of aging and neurodegeneration. Platelets are a useful model to study the systemic manifestations of mitochondrial dysfunction. To evaluate the age dependence of mitochondrial parameters, citrate synthase activity, respiratory chain complex activity, and oxygen consumption kinetics were assessed. The effect of cognitive impairment was examined by comparing the age dependence of mitochondrial parameters in healthy individuals and those with neuropsychiatric disease. The study found a significant negative slope of age-dependence for both the activity of individual mitochondrial enzymes (citrate synthase and complex II) and parameters of mitochondrial respiration in intact platelets (routine respiration, maximum capacity of electron transport system, and respiratory rate after complex I inhibition). However, there was no significant difference in the age-related changes of mitochondrial parameters between individuals with and without cognitive impairment. These findings highlight the potential of measuring mitochondrial respiration in intact platelets as a means to assess age-related mitochondrial dysfunction. The results indicate that drugs and interventions targeting mitochondrial respiration may have the potential to slow down or eliminate certain aging and neurodegenerative processes. Mitochondrial respiration in platelets holds promise as a biomarker of aging, irrespective of the degree of cognitive impairment.

Development of submicromolar 17ß-HSD10 inhibitors and their in vitro and in vivo evaluation.

17ß-hydroxysteroid dehydrogenase type 10 (17ß-HSD10) is a multifunctional mitochondrial enzyme and putative drug target for the treatment of various pathologies including Alzheimer's disease or some types of hormone-dependent cancer. In this study, a series of new benzothiazolylurea-based inhibitors were developed based on the structure-activity relationship (SAR) study of previously published compounds and predictions of their physico-chemical properties. This led to the identification of several submicromolar inhibitors (IC50 ∼0.3 µM), the most potent compounds within the benzothiazolylurea class known to date. The positive interaction with 17ß-HSD10 was further confirmed by differential scanning fluorimetry and the best molecules were found to be cell penetrable. In addition, the best compounds weren't found to have additional effects for mitochondrial off-targets and cytotoxic or neurotoxic effects. The two most potent inhibitors 9 and 11 were selected for in vivo pharmacokinetic study after intravenous and peroral administration. Although the pharmacokinetic results were not fully conclusive, it seemed that compound 9 was bioavailable after peroral administration and could penetrate into the brain (brain-plasma ratio 0.56).

Core/shell nanofibers with embedded liposomes as a drug delivery system.

The broader application of liposomes in regenerative medicine is hampered by their short half-life and inefficient retention at the site of application. These disadvantages could be significantly reduced by their combination with nanofibers. We produced 2 different nanofiber-liposome systems in the present study, that is, liposomes blended within nanofibers and core/shell nanofibers with embedded liposomes. Herein, we demonstrate that blend electrospinning does not conserve intact liposomes. In contrast, coaxial electrospinning enables the incorporation of liposomes into nanofibers. We report polyvinyl alcohol-core/poly-ε-caprolactone-shell nanofibers with embedded liposomes and show that they preserve the enzymatic activity of encapsulated horseradish peroxidase. The potential of this system was also demonstrated by the enhancement of mesenchymal stem cell proliferation. In conclusion, intact liposomes incorporated into nanofibers by coaxial electrospinning are very promising as a drug delivery system.

Can chiroptical spectroscopy be used for the analysis of blood plasma?

As an improvement on currently used methods of molecular spectroscopy, we used chiroptical techniques (electronic circular dichroism, fluorescence detected circular dichroism, and Raman optical activity [ROA]) to investigate the human blood plasma. To avoid the degradation of plasma samples, we measured them directly without any further preparation. We also tested cutoff weight filters (Amicon Ultra 100, 30, 10, and 3 kDa by Merck Millipore) to reduce undesirable fluorescence in the ROA and Raman spectra and also to remove the most abundant protein in the plasma-human serum albumin. The obtained spectra show that the ultrafiltration has a positive effect on undesirable fluorescence in ROA and Raman and also could reduce the amount of albumin in the plasma. Our results suggest that blood plasma can be successfully measured by the aforementioned methods. Therefore, these methods can potentially be useful for following research in the development of new, noninvasive, and reliable screening methods of clinical diagnostics.

New drug targets in depression: inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And new drug candidates--Nrf2 activators and GSK-3 inhibitors.

This paper reviews new drug targets in the treatment of depression and new drug candidates to treat depression. Depression is characterized by aberrations in six intertwined pathways: (1) inflammatory pathways as indicated by increased levels of proinflammatory cytokines, e.g. interleukin-1 (IL-1), IL-6, and tumour necrosis factor α. (2) Activation of cell-mediated immune pathways as indicated by an increased production of interferon γ and neopterin. (3) Increased reactive oxygen and nitrogen species and damage by oxidative and nitrosative stress (O&NS), including lipid peroxidation, damage to DNA, proteins and mitochondria. (4) Lowered levels of key antioxidants, such as coenzyme Q10, zinc, vitamin E, glutathione, and glutathione peroxidase. (5) Damage to mitochondria and mitochondrial DNA and reduced activity of respiratory chain enzymes and adenosine triphosphate production. (6) Neuroprogression, which is the progressive process of neurodegeneration, apoptosis, and reduced neurogenesis and neuronal plasticity, phenomena that are probably caused by inflammation and O&NS. Antidepressants tend to normalize the above six pathways. Targeting these pathways has the potential to yield antidepressant effects, e.g. using cytokine antagonists, minocycline, Cox-2 inhibitors, statins, acetylsalicylic acid, ketamine, ω3 poly-unsaturated fatty acids, antioxidants, and neurotrophic factors. These six pathways offer new, pathophysiologically guided drug targets suggesting that novel therapies could be developed that target these six pathways simultaneously. Both nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activators and glycogen synthase kinase-3 (GSK-3) inhibitors target the six above-mentioned pathways. GSK-3 inhibitors have antidepressant effects in animal models of depression. Nrf2 activators and GSK-3 inhibitors have the potential to be advanced to phase-2 clinical trials to examine whether they augment the efficacy of antidepressants or are useful as monotherapy.

Linking the Amyloid, Tau, and Mitochondrial Hypotheses of Alzheimer's Disease and Identifying Promising Drug Targets.

Damage or loss of brain cells and impaired neurochemistry, neurogenesis, and synaptic and nonsynaptic plasticity of the brain lead to dementia in neurodegenerative diseases, such as Alzheimer's disease (AD). Injury to synapses and neurons and accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles are considered the main morphological and neuropathological features of AD. Age, genetic and epigenetic factors, environmental stressors, and lifestyle contribute to the risk of AD onset and progression. These risk factors are associated with structural and functional changes in the brain, leading to cognitive decline. Biomarkers of AD reflect or cause specific changes in brain function, especially changes in pathways associated with neurotransmission, neuroinflammation, bioenergetics, apoptosis, and oxidative and nitrosative stress. Even in the initial stages, AD is associated with Aß neurotoxicity, mitochondrial dysfunction, and tau neurotoxicity. The integrative amyloid-tau-mitochondrial hypothesis assumes that the primary cause of AD is the neurotoxicity of Aß oligomers and tau oligomers, mitochondrial dysfunction, and their mutual synergy. For the development of new efficient AD drugs, targeting the elimination of neurotoxicity, mutual potentiation of effects, and unwanted protein interactions of risk factors and biomarkers (mainly Aß oligomers, tau oligomers, and mitochondrial dysfunction) in the early stage of the disease seems promising.

Synthesis and in vitro evaluation of 7-methoxy-N-(pent-4-enyl)-1,2,3,4-tetrahydroacridin-9-amine-new tacrine derivate with cholinergic properties.

Cholinesterase inhibitors are, so far, the only successful strategy for the symptomatic treatment of Alzheimer's disease. Tacrine (THA) is a potent acetylcholinesterase inhibitor that was used in the treatment of Alzheimer's disease for a long time. However, the clinical use of THA was hampered by its low therapeutic index, short half-life and liver toxicity. 7-Methoxytacrine (7-MEOTA) is equally pharmacological active compound with lower toxicity compared to THA. In this Letter, the synthesis, biological activity and molecular modelling of elimination by-product isolated during synthesis of 7-MEOTA based bis-alkylene linked compound is described.

Connectivity between mitochondrial functions and psychiatric disorders.

Mitochondria provide most of the energy production in cells. They are involved in the regulation of free radicals, calcium buffering, and redox signaling and take part in the intrinsic pathway of apoptosis. Mutations or polymorphisms of mitochondrial DNA, mitochondria-mediated oxidative stress, decrease of adenosine triphosphate production, changes of intracellular calcium and oxidative stress are concerned in various diseases. There is increasing evidence that impaired functions of mitochondria are associated with mood disorders. It is suggested that disturbed energetic metabolism and/or reactive oxygen species production take part in the pathophysiology of mood disorders and could participate in the therapeutic effects or side-effects of antidepressants and mood stabilizers.

In vitro effects of acetylcholinesterase inhibitors and reactivators on Complex I of electron transport chain.

OBJECTIVES: Inhibition of the enzyme acetylcholinesterase (AChE) is the main mechanism both of therapeutic action of drugs for the treatment of Alzheimer's disease and toxic action of organophosphorus compounds. Various types of oximes reactivate AChE and are commonly used as antidotes against organophosphates (pesticides, nerve agents). METHODS: Effects both of AChE inhibitors (tacrine, 7-methoxytacrine) and oximes (pralidoxime, trimedoxime, obidoxime, methoxime, HI-6) on Complex I of electron transport chain (ETC) were examined. The enzyme activity was measured spectrophotometrically in crude mitochondrial fraction isolated from pig brain. RESULTS: Our results showed statistically significant Complex I inhibition by tacrine, other drugs did not affect the enzyme activity significantly. CONCLUSIONS: These observations suggest the possibility of tacrine-induced side effects related to disturbance in ETC. On the contrary, it seems that oximes do not affect cellular energetic metabolism.

[Biochemical mechanisms of action of antidepressants]. / Biochemicé mechanismy úcinku antidepresiv.

The findings regarding direct, early and long-term biochemical effects of antidepressants are summarized in this review. Mechanisms of action of other drugs showing antidepressant activity are mentioned as well as alternative possibilities of adjuvants. Psychotropic drugs used in the therapy of mood disorders show neurotrophic or neuroprotective effects after long-term treatment. Thus, next to adenylate cyclase, guanylate cyclase, phosphoinositide and calcium systems, attention has been paid to tyrosine kinase pathway and Wnt pathway. Knowledge about biological markers of mood disorders and predictors of efficiency of pharmacotherapy is included also in relation to importance, potentialities and perspectives in the development of new antidepressants.