scholarly journals Brain-specific inhibition of mTORC1 eliminates side effects resulting from mTORC1 blockade in the periphery and reduces alcohol intake in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yann Ehinger ◽  
Ziyang Zhang ◽  
Khanhky Phamluong ◽  
Drishti Soneja ◽  
Kevan M. Shokat ◽  
...  
Keyword(s):  
Side Effects ◽  
Inhibitory Action ◽  
Alcohol Use Disorder ◽  
Alcohol Intake ◽  
Therapeutic Agents ◽  
Adverse Side Effects ◽  
Mtorc1 Activation ◽  
Potential Use ◽  
Heavy Alcohol Intake ◽  
Alcohol Dependent

AbstractAlcohol Use Disorder (AUD) affects a large portion of the population. Unfortunately, efficacious medications to treat the disease are limited. Studies in rodents suggest that mTORC1 plays a crucial role in mechanisms underlying phenotypes such as heavy alcohol intake, habit, and relapse. Thus, mTORC1 inhibitors, which are used in the clinic, are promising therapeutic agents to treat AUD. However, chronic inhibition of mTORC1 in the periphery produces undesirable side effects, which limit their potential use for the treatment of AUD. To overcome these limitations, we designed a binary drug strategy in which male mice were treated with the mTORC1 inhibitor RapaLink-1 together with a small molecule (RapaBlock) to protect mTORC1 activity in the periphery. We show that whereas RapaLink-1 administration blocked mTORC1 activation in the liver, RapaBlock abolished the inhibitory action of Rapalink-1. RapaBlock also prevented the adverse side effects produced by chronic inhibition of mTORC1. Importantly, co-administration of RapaLink-1 and RapaBlock inhibited alcohol-dependent mTORC1 activation in the nucleus accumbens and attenuated alcohol seeking and drinking.

scholarly journals Brain-Specific Inhibition of mTORC1 by a Dual Drug Strategy: A Novel Approach for the Treatment of Alcohol Use Disorder

2020 ◽  
Author(s):  
Yann Ehinger ◽  
Ziyang Zhang ◽  
Khanhky Phamluong ◽  
Drishti Soneja ◽  
Kevan M. Shokat ◽  
...  
Keyword(s):  
Side Effects ◽  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Liver Toxicity ◽  
Body Weight Loss ◽  
Novel Approach ◽  
Medical Need ◽  
Dual Administration ◽  
Mtorc1 Activation ◽  
Dual Drug

AbstractAlcohol Use Disorder (AUD) is a devastating psychiatric disorder affecting a large portion of the population. Unfortunately, efficacious medications to treat the disease are limited and thus AUD represents an area of unmet medical need. mTORC1 plays a crucial role in neuroadaptations underlying alcohol use. mTORC1 also contributes to alcohol craving, habit, and relapse. Thus, mTORC1 inhibitors are promising therapeutic agents to treat AUD. However, chronic inhibition of mTORC1 in the periphery produces undesirable side effects in humans, which limit their potential clinical use for the treatment of AUD. To overcome these limitations, we utilized a binary drug strategy in which mice were co-administered the mTORC1 inhibitor RapaLink-1 together with a novel small molecule (RapaBlock) to protect mTORC1 activity in the periphery. We show that the dual administration of RapaLink-1 with RapaBlock, abolishes RapaLink-1-dependent mTORC1 inhibition in the liver and blocks adverse side effects detected in humans including body weight loss, glucose intolerance and liver toxicity. Importantly, we show that co-administration of RapaLink-1 and RapaBlock inhibits alcohol-dependent mTORC1 activation in the Nucleus Accumbens and robustly moderates the level of alcohol use. Our data present a novel approach that could be used to treat individuals suffering from AUD.

Nalmefene effectiveness in reducing alcohol consumption and prevention of craving: A case report

2017 ◽  
Vol 41 (S1) ◽  
pp. S873-S873
Author(s):  
G. Pardo de Santayana ◽  
R. Landera ◽  
M. Juncal ◽  
O. Porta ◽  
L. Sánchez ◽  
...  
Keyword(s):  
Side Effects ◽  
Alcohol Consumption ◽  
Alcohol Use ◽  
Opioid Receptors ◽  
Alcohol Withdrawal ◽  
Alcohol Use Disorder ◽  
Alcohol Intake ◽  
Therapeutic Option ◽  
Observation Time ◽  
Psychiatric Consultation

IntroductionAlcohol use disorder is a pressing problem in our society. However, only a small percentage of patients with alcohol use disorder are ever treated. Nalmefene acts as an antagonist of mu opioid receptors preventing the pleasurable sensation that often accompanies alcohol consumption, while its modulation of kappa opioid receptors can decrease the dysphoria associated with alcohol withdrawal.AimStudying the effect of nalmefene on patients with alcohol use disorder who are trying to reduce their daily alcohol consumption.MethodsThis is a descriptive study that pretends to assess the effect of nalmefene 18 mg/day on alcohol intake in a sample of five patients (3 men and 2 women) that came to our psychiatric consultation from March to September 2016. They all had tried in the past to stop or reduce their alcohol consumption but were unable to do so. We initiate follow-up with the patients in psychiatric consultation for the next three months with a monthly frequency.ResultsOut of the 5 patients, 4 reported to have reduced their alcohol consumption over the observation time, going from 32 drinks per week to 18 drinks per week on average. The fifth patient abandoned prematurely the treatment due to the appearance of side effects (nausea). No other relevant side effects were detected.ConclusionsNalmefene appears to be effective and safe reducing abusive alcohol intake and avoiding alcohol withdrawal syndrome. Therefore, nalmefene can be considered a good therapeutic option helping reduce alcohol consumption in patients with alcohol use disorder.Disclosure of interestThe authors have not supplied their declaration of competing interest.

scholarly journals Obesity – Can Allium fistulosum L. be a remedy?

2021 ◽  
Vol 5 (4) ◽  
pp. 01-05
Author(s):  
Mohammed Rahmatullah ◽  
Rownak Jahan
Keyword(s):  
Side Effects ◽  
Allium Sativum ◽  
Sedentary Lifestyle ◽  
Cardiovascular Complications ◽  
Office Workers ◽  
Allium Fistulosum ◽  
Human Beings ◽  
Adverse Side Effects ◽  
Medicinal Properties ◽  
Potential Use

Obesity is one of the major problems facing human beings at present. Because of the consumption of refined sugar and foods rich in carbohydrates, as well as adoption of a more sedentary lifestyle (often by necessity as is the case with most office workers), people in all countries are increasingly getting obese, which in turn is leading to other disorders like diabetes and cardiovascular complications. Existing conventional drugs have adverse side-effects, which is the major cause for scientists to look towards the plant kingdom for discovery of newer drugs with less or no side-effects. The Allium genera of plants are widely known for their medicinal properties, in particular Allium cepa (onion) and Allium sativum (garlic), whose beneficial actions include anti-obesity effects. In this mini review, we examine a lesser known plant of the Allium genera, namely Allium fistulosum L. and review its anti-obesity potential. The conclusion of the present study is that the plant contains phytochemicals like ferulic acid and quercetin, which possess anti-obesity mechanisms of action thus rendering the plant to be of potential use against obesity.

mTORC and PKCε in Regulation of Alcohol Use Disorder

2020 ◽  
Vol 20 (17) ◽  
pp. 1696-1708 ◽  
Author(s):  
Athirah Hanim ◽  
Isa Naina Mohamed ◽  
Rashidi M. Pakri Mohamed ◽  
Srijit Das ◽  
Norefrina Shafinaz Md Nor ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Alcohol Intake ◽  
Potential Role ◽  
Synaptic Proteins ◽  
Cellular Mechanisms ◽  
Kinase C ◽  
Protein Kinase C Epsilon ◽  
Seeking Behavior

Alcohol use disorder (AUD) is characterized by compulsive binge alcohol intake, leading to various health and social harms. Protein Kinase C epsilon (PKCε), a specific family of PKC isoenzyme, regulates binge alcohol intake, and potentiates alcohol-related cues. Alcohol via upstream kinases like the mammalian target to rapamycin complex 1 (mTORC1) or 2 (mTORC2), may affect the activities of PKCε or vice versa in AUD. mTORC2 phosphorylates PKCε at hydrophobic and turn motif, and was recently reported to be associated with alcohol-seeking behavior, suggesting the potential role of mTORC2-PKCε interactions in the pathophysiology of AUD. mTORC1 regulates translation of synaptic proteins involved in alcohol-induced plasticity. Hence, in this article, we aimed to review the molecular composition of mTORC1 and mTORC2, drugs targeting PKCε, mTORC1, and mTORC2 in AUD, upstream regulation of mTORC1 and mTORC2 in AUD and downstream cellular mechanisms of mTORCs in the pathogenesis of AUD.

SARS-CoV-2 Biology Insights, Part I. Genome-wide structure and druggability: literature review (Preprint)

2020 ◽  
Author(s):  
Laura Lafon-Hughes
Keyword(s):  
Side Effects ◽  
Literature Review ◽  
Host Cell ◽  
Nucleoside Analogs ◽  
Viral Proteins ◽  
Therapeutic Strategies ◽  
Adverse Side Effects ◽  
Viral Proteases ◽  
Genome Wide ◽  
Therapeutic Alternatives

BACKGROUND COVID-19 pandemic prompts the study of coronavirus biology and search of putative therapeutic strategies. OBJECTIVE To compare SARS-CoV-2 genome-wide structure and proteins with other coronaviruses, focusing on putative coronavirus-specific or SARS-CoV-2 specific therapeutic designs. METHODS The genome-wide structure of SARS-CoV-2 was compared to that of SARS and other coronaviruses in order to gain insights, doing a literature review through Google searches. RESULTS There are promising therapeutic alternatives. Host cell targets could be modulated to hamper viral replication, but targeting viral proteins directly would be a better therapeutic design, since fewer adverse side effects would be expected. CONCLUSIONS Therapeutic strategies (Figure 1) could include the modulation of host targets (PARPs, kinases) , competition with G-quadruplexes or nucleoside analogs to hamper RDRP. The nicest anti-CoV options include inhibitors of the conserved essential viral proteases and drugs that interfere ribosome slippage at the -1 PRF site.

scholarly journals In VitroActivities of Hexaazatrinaphthylenes against Leishmania spp.

2015 ◽  
Vol 59 (5) ◽  
pp. 2867-2874 ◽  
Author(s):  
Atteneri López-Arencibia ◽  
Daniel García-Velázquez ◽  
Carmen M. Martín-Navarro ◽  
Ines Sifaoui ◽  
María Reyes-Batlle ◽  
...  
Keyword(s):  
Therapeutic Agents ◽  
Content Type ◽  
Inhibition Effect ◽  
Intracellular Amastigotes ◽  
Dependent Inhibition ◽  
Leishmania Spp ◽  
Dose Dependent Inhibition ◽  
Dose Dependent ◽  
Potential Use

ABSTRACTThein vitroactivity of a novel group of compounds, hexaazatrinaphthylene derivatives, against two species ofLeishmaniais described in this study. These compounds showed a significant dose-dependent inhibition effect on the proliferation of the parasites, with 50% inhibitory concentrations (IC50s) ranging from 1.23 to 25.05 μM against the promastigote stage and 0.5 to 0.7 μM against intracellular amastigotes. Also, a cytotoxicity assay was carried out to in order to evaluate the possible toxic effects of these compounds. Moreover, different assays were performed to determine the type of cell death induced after incubation with these compounds. The obtained results highlight the potential use of hexaazatrinaphthylene derivatives againstLeishmaniaspecies, and further studies should be undertaken to establish them as novel leishmanicidal therapeutic agents.

scholarly journals Ketogenic diet reduces alcohol withdrawal symptoms in humans and alcohol intake in rodents

2021 ◽  
Vol 7 (15) ◽  
pp. eabf6780
Author(s):  
Corinde E. Wiers ◽  
Leandro F. Vendruscolo ◽  
Jan-Willem van der Veen ◽  
Peter Manza ◽  
Ehsan Shokri-Kojori ◽  
...  
Keyword(s):  
Ketogenic Diet ◽  
Alcohol Withdrawal ◽  
Alcohol Use Disorder ◽  
Alcohol Intake ◽  
Anterior Cingulate ◽  
Dorsal Anterior Cingulate Cortex ◽  
Beneficial Effects ◽  
Alcohol Cues ◽  
History Of ◽  
To Receive

Individuals with alcohol use disorder (AUD) show elevated brain metabolism of acetate at the expense of glucose. We hypothesized that a shift in energy substrates during withdrawal may contribute to withdrawal severity and neurotoxicity in AUD and that a ketogenic diet (KD) may mitigate these effects. We found that inpatients with AUD randomized to receive KD (n = 19) required fewer benzodiazepines during the first week of detoxification, in comparison to those receiving a standard American (SA) diet (n = 14). Over a 3-week treatment, KD compared to SA showed lower “wanting” and increased dorsal anterior cingulate cortex (dACC) reactivity to alcohol cues and altered dACC bioenergetics (i.e., elevated ketones and glutamate and lower neuroinflammatory markers). In a rat model of alcohol dependence, a history of KD reduced alcohol consumption. We provide clinical and preclinical evidence for beneficial effects of KD on managing alcohol withdrawal and on reducing alcohol drinking.

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