Multi-target drugs for the treatment of cognitive impairment and fatigue in post-COVID syndrome: focus on Ginkgo biloba and Rhodiola rosea.

Cognitive impairment, depression and (mental) fatigue represent the most frequent neuropsychiatric symptoms of the post-COVID syndrome. Neuroinflammation, oxidative stress and mitochondrial dysfunction have been identified as common pathophysiological mechanisms underlying these symptoms. Attempts to treat post-COVID-associated cognitive impairment and fatigue with different drugs available for other diseases have not yet been successful. One probable explanation could be that these drugs work by one specific mechanism of action only and not in a broad multi-target way. Therefore, they will not address the broad pathophysiological spectrum possibly responsible for cognitive impairment, depression and fatigue in post-COVID syndrome. Notably, nearly all drugs currently under investigation for fatigue in post-COVID syndrome are rather addressing one single target instead of the several pathomechanisms underlying this condition. Contrary to this approach, herbal drugs often consist of many different ingredients with different pharmacological properties and pharmacological targets. Therefore, these drugs might be a promising approach for the treatment of the broad symptomatic presentation and the pathophysiological mechanisms of cognitive impairment and fatigue following a SARS-CoV-2 infection. Of these herbal drugs, extracts of Ginkgo biloba and Rhodiola rosea probably are the best investigated candidates. Their broad pharmacological spectrum in vitro and in vivo includes anti-oxidative, anti-inflammatory, antidepressant as well as properties reducing cognitive impairment and fatigue. In several studies, both drugs showed positive effects on physical and mental fatigue and impaired cognition. Moreover, depressive symptoms were also reduced in some studies. However, even if these results are promising, the data are still preliminary and require additional proof by further studies.

Effect of anxiolytic drug silexan on sleep - a narrative review.

OBJECTIVES: Silexan is an orally administered, proprietary essential oil from Lavandula angustifolia with significant anxiolytic and sleep improving properties. Here we present a narrative review that provides an overview of the available evidence of the effects of silexan on sleep. METHODS: We start with a summary of the pharmacological background and continue with presenting sleep-related results from controlled clinical trials with silexan. Then we report on a meta-analysis of item 'insomnia' from the Hamilton Anxiety Scale, which includes data from all randomised, placebo-controlled clinical trials with silexan in which the scale was administered. Finally, we summarise the results of a mediation analysis that was performed to elucidate the pathway of the effect of silexan on sleep. RESULTS: In randomised, placebo-controlled trials in patients suffering from anxiety disorders silexan had a significant anxiolytic effect and improved sleep along with recovery from anxiety. Mediation analysis demonstrates that more than 98% of the effect of silexan on sleep was mediated by its anxiolytic effect while the direct effect on sleep was marginal. CONCLUSIONS: Silexan improves sleep as a result of its anxiolytic effect.

Neuropsychiatric Drugs Against COVID-19: What is the Clinical Evidence?

Since the beginning of the coronavirus disease (COVID)-19 pandemic, the need for effective treatments for COVID-19 led to the idea of "repurposing" drugs for antiviral treatment. Several antipsychotics and antidepressants have been tested for in vitro activity against the severe acute respiratory syndrome coronavirus 2. Chlorpromazine, other phenothiazine antipsychotics, and the antidepressant fluoxetine were found to be rather potent in these studies. However, whether effective plasma concentrations can be obtained with clinically accepted doses of these drugs is not clear. Data of COVID-19 patients are not yet available but several clinical studies are currently underway.The specific serotonin reuptake inhibitor fluvoxamine is a potent Sigma-1 receptor agonist and reduces inflammation in animal models of cytokine-stress. Accordingly, fluvoxamine treatment was superior to placebo in reducing impaired respiratory function and other symptoms of inflammation in COVID-19 patients in a placebo-controlled clinical study and another open clinical trial. The beneficial effects of fluvoxamine on the course of COVID-19 were recently confirmed in a large placebo-controlled double-blind trial with several hundred patients.Inflammation represents a major risk factor for many psychiatric disorders which explains the high susceptibilitiy of COVID-19 patients for psychiatric diseases. Many antidepressants and antipsychotics possess anti-inflammatory properties independent of sigma-1 activity which might be important to reduce psychiatric symptoms of COVID-19 patients and to improve respiratory dysfunction and other consequences of inflammation. This might explain the rather unspecific benefit which has been reported for several cohorts of COVID-19 patients treated with different psychotropic drugs.

Mitochondrial Dysfunction as a Causative Factor in Alzheimer's Disease-Spectrum Disorders: Lymphocytes as a Window to the Brain.

Alzheimer's disease (AD) is the most common progressive neurodegenerative disease. Today, AD affects millions of people worldwide and the number of AD cases will further increase with longer life expectancy. The AD brain is marked by severe neurodegeneration, such as the loss of synapses and neurons, atrophy and depletion of neurotransmitter systems, especially in the hippocampus and cerebral cortex. Recent findings highlight the important role of mitochondrial dysfunction and increased oxidative stress in the pathophysiology of late-onset alzheimer's disease (LOAD). These alterations are not only observed in the brain of AD patients but also in the periphery. In this review, we discuss the potential role of elevated apoptosis, increased oxidative stress and mitochondrial dysfunction as peripheral markers for the detection of AD in blood cells e.g. lymphocytes. We evaluate recent findings regarding impaired mitochondrial function comprising mitochondrial respiration, reduced complex activities of the respiratory chain and altered Mitochondrial Membrane Potential (MMP) in lymphocytes as well as in neurons. Finally, we will question whether these mitochondrial parameters might be suitable as an early peripheral marker for the detection of LOAD but also for the transitional stage between normal aging and Dementia, "Mild Cognitive Impairment" (MCI).

Control and Diagnostics System Generator for Complex FPGA-Based Measurement Systems.

FPGA-based data acquisition and processing systems play an important role in modern high-speed, multichannel measurement systems, especially in High-Energy and Plasma Physics. Such FPGA-based systems require an extended control and diagnostics part corresponding to the complexity of the controlled system. Managing the complex structure of registers while keeping the tight coupling between hardware and software is a tedious and potentially error-prone process. Various existing solutions aimed at helping that task do not perfectly match all specific requirements of that application area. The paper presents a new solution based on the XML system description, facilitating the automated generation of the control system's HDL code and software components and enabling easy integration with the control software. The emphasis is put on reusability, ease of maintenance in the case of system modification, easy detection of mistakes, and the possibility of use in modern FPGAs. The presented system has been successfully used in data acquisition and preprocessing projects in high-energy physics experiments. It enables easy creation and modification of the control system definition and convenient access to the control and diagnostic blocks. The presented system is an open-source solution and may be adopted by the user for particular needs.

Effects of 7,8-Dihydroxyflavone on Lipid Isoprenoid and Rho Protein Levels in Brains of Aged C57BL/6 Mice.

Synaptic impairment may be the main cause of cognitive dysfunction in brain aging that is probably due to a reduction in synaptic contact between the axonal buttons and dendritic spines. Rho proteins including the small GTPase Rac1 have become key regulators of neuronal morphogenesis that supports synaptic plasticity. Small Rho- and Ras-GTPases are post-translationally modified by the isoprenoids geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP), respectively. For all GTPases, anchoring in the plasma membrane is essential for their activation by guanine nucleotide exchange factors (GEFs). Rac1-specific GEFs include the protein T lymphoma invasion and metastasis 1 (Tiam1). Tiam1 interacts with the TrkB receptor to mediate the brain-derived neurotrophic factor (BDNF)-induced activation of Rac1, resulting in cytoskeletal rearrangement and changes in cellular morphology. The flavonoid 7,8-dihydroxyflavone (7,8-DHF) acts as a highly affine-selective TrkB receptor agonist and causes the dimerization and autophosphorylation of the TrkB receptor and thus the activation of downstream signaling pathways. In the current study, we investigated the effects of 7,8-DHF on cerebral lipid isoprenoid and Rho protein levels in male C57BL/6 mice aged 3 and 23 months. Aged mice were daily treated with 100 mg/kg b.w. 7,8-DHF by oral gavage for 21 days. FPP, GGPP, and cholesterol levels were determined in brain tissue. In the same tissue, the protein content of Tiam1 and TrkB in was measured. The cellular localization of the small Rho-GTPase Rac1 and small Rab-GTPase Rab3A was studied in total brain homogenates and membrane preparations. We report the novel finding that 7,8-DHF restored levels of the Rho proteins Rac1 and Rab3A in membrane preparations isolated from brains of treated aged mice. The selective TrkB agonist 7,8-DHF did not affect BDNF and TrkB levels, but restored Tiam1 levels that were found to be reduced in brains of aged mice. FPP, GGPP, and cholesterol levels were significantly elevated in brains of aged mice but not changed by 7,8-DHF treatment. Hence, 7,8-DHF may be useful as pharmacological tool to treat age-related cognitive dysfunction although the underlying mechanisms need to be elucidated in detail.

Pharmacological basis of the anxiolytic and antidepressant properties of Silexan®, an essential oil from the flowers of lavender.

Silexan®, a proprietary essential oil manufactured by steam distillation from Lavandula angustifolia flowers showed pronounced anxiolytic effects in patients with subthreshold anxiety disorders and was also efficacious in patients with Generalized Anxiety disorder (GAD). Moreover, evidences for antidepressant-like properties of Silexan® have been observed in anxious patients suffering from comorbid depressive symptoms and in patients with mixed anxiety-depression disorder (ICD-10 F41.2). In accordance with the clinical data Silexan® is active in several behavioral models in rodents at rather low concentrations indicating potent anxiolytic and antidepressive properties. As possible mechanism of action a moderate inhibition of voltage dependent calcium channels (VDCC) has been found showing some similarities to the anxiolytic drug pregabalin. However, while pregabalin mainly inhibits P/Q-type channels by binding to a modulatory subunit, Silexan® moderately inhibits mainly T-type and N-type channels and to some extent P/Q-type channels. Unlike pregabalin Silexan® is free of hypnotic or sedative side effects and seems to be devoid of any abuse potential. With respect to its specific antidepressant like properties Silexan® improves several aspects of neuroplasticity which seems to be the common final pathway of all antidepressant drugs. As a potential mechanism of its effects on neuroplasticity an activation of the transcription factor CREB via activation of intracellular signaling kinases like PKA and MAPK has been found. Since the concentrations of Silexan® needed to inhibit VDCC function and to improve neuroplasticity are quite similar, the effects of Silexan® on PKA or MAPK could constitute a common intracellular signaling cascade leading to VDCC modulation as well as CREB activation and improved neuroplasticity.

Neurotrophic Properties of Silexan, an Essential Oil from the Flowers of Lavender-Preclinical Evidence for Antidepressant-Like Properties.

BACKGROUND: Silexan, a special essential oil from flowering tops of lavandula angustifolia, is used to treat subsyndromal anxiety disorders. In a recent clinical trial, Silexan also showed antidepressant effects in patients suffering from mixed anxiety-depression (ICD-10 F41.2). Since preclinical data explaining antidepressant properties of Silexan are missing, we decided to investigate if Silexan also shows antidepressant-like effects in vitro as well as in vivo models. METHODS: We used the forced swimming test (FST) in rats as a simple behavioral test indicative of antidepressant activity in vivo. As environmental events and other risk factors contribute to depression through converging molecular and cellular mechanisms that disrupt neuronal function and morphology-resulting in dysfunction of the circuitry that is essential for mood regulation and cognitive function-we investigated the neurotrophic properties of Silexan in neuronal cell lines and primary hippocampal neurons. RESULTS: The antidepressant activity of Silexan (30 mg/kg BW) in the FST was comparable to the tricyclic antidepressant imipramine (20 mg/kg BW) after 9-day treatment. Silexan triggered neurite outgrowth and synaptogenesis in 2 different neuronal cell models and led to a significant increase in synaptogenesis in primary hippocampal neurons. Silexan led to a significant phosphorylation of protein kinase A and subsequent CREB phosphorylation. CONCLUSION: Taken together, Silexan demonstrates antidepressant-like effects in cellular as well as animal models for antidepressant activity. Therefore, our data provides preclinical evidence for the clinical antidepressant effects of Silexan in patients with mixed depression and anxiety.

No Abuse Potential of Silexan in Healthy Recreational Drug Users: A Randomized Controlled Trial.

BACKGROUND: Silexan is a lavender essential oil with established anxiolytic and calming efficacy. Here we asked whether there is a potential for abuse in human patients. METHODS: We carried out a phase I abuse liability single-center, double-blind, 5-way crossover study in healthy users of recreational central nervous system depressants. They received single oral doses of 80 mg (therapeutic dose) and 640 mg Silexan, 2 mg and 4 mg lorazepam (active control) and placebo in randomized order, with 4- to 14-day washout periods between treatments. Pharmacodynamic measures included validated visual analogue scales assessing positive, negative, and sedative drug effects and balance of effects; a short form of the Addiction Research Center Inventory; and a drug similarity assessment. The primary outcome measure was the individual maximum value on the drug liking visual analogue scale during 24 hours post-dose. RESULTS: Forty participants were randomized and 34 were evaluable for pharmacodynamic outcomes. In intraindividual head-to-head comparisons of the drug liking visual analogue scale maximum value, both doses of Silexan were rated similar to placebo whereas differences were observed between Silexan and lorazepam and between placebo and lorazepam (P < .001). These data were supported by all secondary measures of positive drug effects and of balance of effects. Differences between placebo and both doses of Silexan were always negligible in magnitude. Moreover, Silexan showed no sedative effects and was not perceived to be similar to commonly used drugs that participants had used in the past. CONCLUSIONS: Silexan did not exhibit any abuse potential in a standard abuse potential detection screen study and is unlikely to be recreationally abused.

Olesoxime improves cerebral mitochondrial dysfunction and enhances Aß levels in preclinical models of Alzheimer's disease.

BACKGROUND: Approved drugs for Alzheimer's disease (AD) only have a symptomatic effects and do not intervene causally in the course of the disease. Olesoxime (TRO19622) has been tested in AD disease models characterized by improved amyloid precursor protein processing (AßPP) and mitochondrial dysfunction. METHODS: Three months old Thy-1-AßPPSL (tg) and wild type mice (wt) received TRO19622 (100 mg/kg b.w.) in supplemented food pellets for 15 weeks (tg TRO19622). Mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) levels were determined in dissociated brain cells (DBC). Respiration was analyzed in mitochondria isolated from brain tissue. Citrate synthase (CS) activity and beta-amyloid peptide (Aß1-40) levels were determined in brain tissue. Malondialdehyde (MDA) levels were determined as an indicator for lipid peroxidation. DBC and brain homogenates were additionally stressed with Rotenone and FeCl2, respectively. Mitochondrial respiration and Aß1-40 levels were also determined in HEK-AßPPsw-cells. RESULTS: Treatment of mice did not affect the body weight. TRO19622 was absorbed after oral treatment (plasma levels: 6,2 µg/ml). Mitochondrial respiration was significantly reduced in brains of tg-mice. Subsequently, DBC isolated from brains of tg-mice showed significantly lower MMP but not ATP levels. TRO19622 increased the activity of respiratory chain complexes and reversed complex IV (CIV) activity and MMP. Moreover, DBC isolated from brains of tg TRO19622 mice were protected from Rotenone induced inhibition of complex I activity. TRO19622 also increased the respiratory activity in HEKsw-cells. MDA basal levels were significantly higher in brain homogenates isolated from tg-mice. TRO19622 treatment had no effects on lipid peroxidation. TRO19622 increased cholesterol levels but did not change membrane fluidity of synaptosomal plasma and mitochondrial membranes isolated from brain of mice. TRO19622 significantly increased levels of Aß1-40 in both, in brains of tg TRO19622 mice and in HEKsw cells. CONCLUSIONS: TRO19622 improves mitochondrial dysfunction but enhances Aß levels in disease models of AD. Further studies must evaluate whether TRO19622 offers benefits at the mitochondrial level despite the increased formation of Aß, which could be harmful.

Aerobic and anaerobic enrichment cultures highlight the pivotal role of facultative anaerobes in soil hydrocarbon degradation.

Aliphatic and aromatic hydrocarbons are ubiquitous in the environment due to natural and anthropogenic processes. Under aerobic conditions hydrocarbons can be rapidly biodegraded but oxygenated environments often quickly become anaerobic when microbial respiration is coupled to contaminant oxidation. Most studies in literature usually focus on the initial microbial diversity of the hydrocarbon impacted environment and examine either aerobic or anaerobic conditions for enrichment. Hence, the aim of the present study was to enrich bacterial consortiums from two diesel impacted soil samples under both these conditions to assess the enrichment diversities and hydrocarbon degradation potentials. This would shed light upon how an environmental population shift would correlate to oxygen intrusion and depletion and still continue hydrocarbon degradation. Analysis of the 16S rRNA gene sequences showcases the different microbial populations that could emerge as the environmental factors change, resulting in different populations that are still capable of hydrocarbon degradation. Microbial diversity analysis also highlights the role of facultative anaerobic bacteria like Pseudomonas spp. and Citrobacter spp. in maintaining hydrocarbon degradation. This study shows that microorganisms capable of surviving under both oxic and anoxic (aerobic and anaerobic) conditions are the most crucial to the long term degradation of hydrocarbons in the environment.

Therapeutic efficacy of the Ginkgo special extract EGb761® within the framework of the mitochondrial cascade hypothesis of Alzheimer's disease.

OBJECTIVES: The mitochondrial cascade hypothesis of dementia assumes mitochondrial dysfunction as an important common pathomechanism for the whole spectrum of age-associated memory disorders from cognitive symptoms in the elderly over mild cognitive impairment to Alzheimer's dementia. Thus, a drug such as the Ginkgo special extract EGb 761® which improves mitochondrial function should be able to ameliorate cognitive deficits over the whole aging spectrum. METHODS: We review the most relevant publications about effects of EGb 761® on cognition and synaptic deficits in preclinical studies as well as on cognitive deficits in man from aging to dementia. RESULTS: EGb 761® improves mitochondrial dysfunction and cognitive impairment over the whole spectrum of age-associated cognitive disorders in relevant animal models and in vitro experiments, and also shows clinical efficacy in improving cognition over the whole range from aging to Alzheimer's or even vascular dementia. CONCLUSIONS: EGb 761® shows clinical efficacy in the treatment of cognitive deficits over the whole spectrum of age-associated memory disorders. Thus, EGb 761® can serve as an important pharmacological argument for the mitochondrial cascade hypothesis of dementia.

Optimizing medical care for geriatric patients in Austria: defining a top five list of "Choosing Wisely" recommendations using the Delphi technique.

PURPOSE: Inappropriate use of diagnostic and therapeutic medical procedures is common and potentially harmful for older patients. The Austrian Society of Geriatrics and Gerontology defined a consensus of five recommendations to avoid overuse of medical interventions and to improve care of geriatric patients. METHODS: From an initial pool of 147 reliable recommendations, 20 were chosen by a structured selection process for inclusion in a Delphi process to define a list of five top recommendations for geriatric medicine. 12 experts in the field of geriatric medicine scored the recommendations in two Delphi rounds. RESULTS: The final five recommendations are concerning urinary catheters in elderly patients, percutaneous feeding tubes in patients with advanced dementia, antipsychotics as the first choice to treat behavioral and psychological symptoms of dementia, and screening for breast, colorectal, prostate, or lung cancer, and the use of antimicrobials to treat asymptomatic bacteriuria. CONCLUSIONS: The selected recommendations have the potential to improve medical care for older patients, to reduce side effects caused by unnecessary medical procedures, and to save costs in the health care system.

Complex Effects of Cytochrome P450 Monooxygenase on Purple Membrane and Bacterioruberin Production in an Extremely Halophilic Archaeon: Genetic, Phenotypic, and Transcriptomic Analyses.

Halophilic archaea are known to produce a diverse array of pigments for phototrophy and photoprotection. The aim of this paper was to determine the role of a Halobacterium gene encoding the predicted cytochrome P450 monooxygenase (CYP174A1) in pigment synthesis through a combined genetic, phenotypic, and transcriptomic approach. We report on the observed phenotype changes [increased bacterioruberin levels and the loss of purple membrane (PM)] between the Halobacterium salinarum R1 and its CYP174A1-deletion mutant. In addition, we report on the whole-genome DNA microarray analysis, which supports the phenotype of PM loss. This work expands our understanding of the bop-gene regulon, and its relation to carotenoid biosynthesis, and sheds light on our broader understanding of the role (s) of CYP174A1 in archaeal pigment synthesis. To date, this is the first study in which the physiological role of any cytochrome P450 monooxygenase (CYP450) in extremely halophilic archaea has been reported.

Automated distinction of shearing and distortion artefacts in structured illumination microscopy.

Any motion during an image acquisition leads to an artefact in the final image. Structured illumination microscopy (SIM) combines several raw images into one high-resolution image and is thus particularly prone to these motion artefacts. Their unpredictable shape cannot easily be distinguished from real high-resolution content. We previously implemented a motion detection specifically for SIM, which had two shortcomings which are solved here. First, the brightness dependency of the motion signal is removed. Second, the empirical threshold of the calculated motion signal was not a threshold at a maximum allowed artefact. Here we investigate which artefacts are still acceptable and which linear movement creates them. Thus, the motion signal is linked with the maximal strength of the expected artefact. A signal-to-noise analysis including classification successfully distinguishes between artefact-free imaging, shearing and distortion artefacts in biological specimens. A shearing, as in wide-field microscopy, is the dominant reconstruction artefact, while distortions arise not until surprisingly fast movements.

Mitochondrial Pharmacology of Dimebon (Latrepirdine) Calls for a New Look at its Possible Therapeutic Potential in Alzheimer's Disease.

Dimebon (latrepirdine), an old antihistaminic drug, showed divergent results in two large clinical trials in Alzheimer disease (AD), which according to our review might be related to the specific pharmacological properties of the drug and the different patient populations included in both studies. Out of the many pharmacological effects of Dimebon, improvement of impaired mitochondrial function seeems to be most relevant for the substantial effects on cognition and behaviour reported in one of the studies, as these effects are already present at the low concentrations of dimebon measured in plasma and tissues of patients and experimental animals. Since impaired mitochondrial function seems to be the major driving force for the progression of the clinical symptoms and since most of the clinical benefits of dimebon originate from an effect on the symptomatic deterioration, mitochondrial improvement can also explain the lack of efficacy of this drug in another clinical trial where symptoms of the patiets remained stable for the time of the study. Accordingly, it seems worthwhile to reevaluate the clinical data to proof that clinical response is correlated with high levels of Neuropsychiatric Symptoms as these show a good relationship to the individual speed of symptomatic decline in AD patients related to mitochondrial dysfunction.

Changes in prescribed medicines in older patients with multimorbidity and polypharmacy in general practice.

BACKGROUND: Treatment complexity rises in line with the number of drugs, single doses, and administration methods, thereby threatening patient adherence. Patients with multimorbidity often need flexible, individualised treatment regimens, but alterations during the course of treatment may further increase complexity. The objective of our study was to explore medication changes in older patients with multimorbidity and polypharmacy in general practice. METHODS: We retrospectively analysed data from the cluster-randomised PRIMUM trial (PRIoritisation of MUltimedication in Multimorbidity) conducted in 72 general practices. We developed an algorithm for active pharmaceutical ingredients (API), strength, dosage, and administration method to assess changes in physician-reported medication data during two intervals (baseline to six-months: ∆1; six- to nine-months: ∆2), analysed them descriptively at prescription and patient levels, and checked for intervention effects. RESULTS: Of 502 patients (median age 72 years, 52% female), 464 completed the study. Changes occurred in 98.6% of patients (changes were 19% more likely in the intervention group): API changes during ∆1 and ∆2 occurred in 414 (82.5%) and 338 (67.3%) of patients, dosage alterations in 372 (74.1%) and 296 (59.2%), and changes in API strength in 158 (31.5%) and 138 (27.5%) respectively. Administration method changed in 79 (16%) of patients in both ∆1 and ∆2. Simvastatin, metformin and aspirin were most frequently subject to alterations. CONCLUSION: Medication regimens in older patients with multimorbidity and polypharmacy changed frequently. These are mostly due to discontinuations and dosage alterations, followed by additions and restarts. These findings cast doubt on the effectiveness of cross-sectional assessments of medication and support longitudinal assessments where possible. TRIAL REGISTRATION: 1. Prospective registration: Trial registration number: NCT01171339 ; Name of registry: ClinicalTrials.gov; Date of registration: July 27, 2010; Date of enrolment of the first participant to the trial: August 12, 2010. 2. Peer reviewed trial registration: Trial registration number: ISRCTN99526053 ; Name of registry: Controlled Trials; Date of registration: August 31, 2010; Date of enrolment of the first participant to the trial: August 12, 2010.

Mitochondrial Function, Dynamics, and Permeability Transition: A Complex Love Triangle as A Possible Target for the Treatment of Brain Aging and Alzheimer's Disease.

Because of the failure of all amyloid-ß directed treatment strategies for Alzheimer's disease (AD), the concept of mitochondrial dysfunction as a major pathomechanism of the cognitive decline in aging and AD has received substantial support. Accordingly, improving mitochondrial function as an alternative strategy for new drug development became of increasing interest and many different compounds have been identified which improve mitochondrial function in preclinical in vitro and in vivo experiments. However, very few if any have been investigated in clinical trials, representing a major drawback of the mitochondria directed drug development. To overcome these problems, we used a top-down approach by investigating several older antidementia drugs with clinical evidence of therapeutic efficacy. These include EGb761® (standardized ginkgo biloba extract), piracetam, and Dimebon. All improve experimentally many aspects of mitochondrial dysfunction including mitochondrial dynamics and also improve cognition and impaired neuronal plasticity, the functionally most relevant consequences of mitochondrial dysfunction. All partially inhibit opening events of the mitochondrial permeability transition pore (mPTP) which previously has mainly been discussed as a mechanism relevant for the induction of apoptosis. However, as more recent work suggests the mPTP as a master regulator of many mitochondrial functions, our data suggest the mPTP as a possible relevant drug target within the love triangle between mPTP regulation, mitochondrial dynamics, and mitochondrial function including regulation of neuronal plasticity. Drugs interfering with mPTP function will improve not only mitochondrial impairment in aging and AD but also will have beneficial effects on impaired neuronal plasticity, the pathomechanism which correlates best with functional deficits (cognition, behavior) in aging and AD.

Silexan in anxiety disorders: Clinical data and pharmacological background.

OBJECTIVES: Silexan is a lavender oil preparation available in 80-mg capsules. Here we review clinical trials investigating its anxiolytic efficacy, safety and tolerability in humans, as well as preclinical investigations supporting this therapeutic use. METHODS: Besides three selected publications reporting preclinical investigations, seven clinical trials are included, of which five had a treatment duration of 6 or 10 weeks. Primary outcome measure was the HAM-A total score reduction, while single items were assessed with regard to effects on concomitant depressive symptoms and on quality of sleep. RESULTS: In patients with subthreshold (subsyndromal) anxiety or generalised anxiety disorder (GAD), an anxiolytic effect of Silexan was evident after 2 weeks. HAM-A total score reductions between baseline and end of treatment were significantly superior to placebo in patients with subthreshold anxiety and comparable with those achieved under lorazepam or paroxetine in patients with GAD. In addition, Silexan had beneficial effects on typical concomitant symptoms of anxiety disorders, such as impaired sleep, somatic complaints, co-morbid depression or decreased quality of life. Except for mild gastrointestinal symptoms, Silexan did not induce any adverse effects and did not cause drug interactions, sedation or withdrawal symptoms at daily doses of 80 or 160 mg. CONCLUSIONS: Silexan is a safe and effective treatment in anxiety disorders.

Enhanced Neuroplasticity by the Metabolic Enhancer Piracetam Associated with Improved Mitochondrial Dynamics and Altered Permeability Transition Pore Function.

The mitochondrial cascade hypothesis of dementia assumes mitochondrial dysfunction leading to reduced energy supply, impaired neuroplasticity, and finally cell death as one major pathomechanism underlying the continuum from brain aging over mild cognitive impairment to initial and advanced late onset Alzheimer's disease. Accordingly, improving mitochondrial function has become an important strategy to treat the early stages of this continuum. The metabolic enhancer piracetam has been proposed as possible prototype for those compounds by increasing impaired mitochondrial function and related aspects like mechanisms of neuroplasticity. We here report that piracetam at therapeutically relevant concentrations improves neuritogenesis in the human cell line SH-SY5Y over conditions mirroring the whole spectrum of age-associated cognitive decline. These effects go parallel with improvement of impaired mitochondrial dynamics shifting back fission and fusion balance to the energetically more favorable fusion site. Impaired fission and fusion balance can also be induced by a reduction of the mitochondrial permeability transition pore (mPTP) function as atractyloside which indicates the mPTP has similar effects on mitochondrial dynamics. These changes are also reduced by piracetam. These findings suggest the mPTP as an important target for the beneficial effects of piracetam on mitochondrial function.