Preclinical Evaluation of Sodium Butyrate's Potential to Reduce Alcohol Consumption: A Dose-Escalation Study in C57BL/6J Mice in Antibiotic-Enhanced Binge-Like Drinking Model.

Introduction: In our earlier efforts to establish gut-brain axis during alcohol use disorder (AUD), we have demonstrated that supplementation of C57BL/6J male mice with 8 mg/mL sodium butyrate, a major short-chain fatty acid, in drinking water reduced ethanol intake and neuroinflammatory response in antibiotic (ABX)-enhanced voluntary binge-like alcohol consumption model, drinking in the dark (DID).

Methods: To further evaluate the preclinical potential of SB, we have set a dose-escalation study in C57BL/6J male mice to test effects of ad libitum 20 mg/mL SB and 50 mg/mL SB and their combinations with ABX in the DID procedure for 4 weeks. Effects of these SB concentrations on ethanol consumption and bodily parameters were determined for the duration of the treatments.

Dihydromyricetin supplementation improves ethanol-induced lipid accumulation and inflammation.

Introduction: Excessive alcohol consumption leads to a myriad of detrimental health effects, including alcohol-associated liver disease (ALD). Unfortunately, no available treatments exist to combat the progression of ALD beyond corticosteroid administration and/or liver transplants. Dihydromyricetin (DHM) is a bioactive polyphenol and flavonoid that has traditionally been used in Chinese herbal medicine for its robust antioxidant and anti-inflammatory properties.

Sodium Butyrate Supplementation Modulates Neuroinflammatory Response Aggravated by Antibiotic Treatment in a Mouse Model of Binge-like Ethanol Drinking.

Growing evidence supports the pivotal role of the bidirectional interplay between the gut microbiota and the central nervous system during the progression of alcohol use disorder (AUD). In our previous study, supplementation with sodium butyrate (SB) in C57BL/6J mice prevented increased ethanol consumption in a binge-like drinking paradigm (DID) as a result of treatment with a non-absorbable antibiotic cocktail (ABX). In this study, we tested the hypothesis that SB protection against enhanced ABX-induced ethanol consumption in mice is partially due to modulation of neuroinflammatory responses.

Cross-Talk between P2X and NMDA Receptors.

Purinergic P2X receptors (P2X) are ATP-gated ion channels widely expressed in the CNS. While the direct contribution of P2X to synaptic transmission is uncertain, P2X reportedly affect N-methyl-D-aspartate receptor (NMDAR) activity, which has given rise to competing theories on the role of P2X in the modulation of synapses. However, P2X have also been shown to participate in receptor cross-talk: an interaction where one receptor (e.

Antibiotic-induced disruption of commensal microbiome linked to increases in binge-like ethanol consumption behavior.

Research focusing on the gut-brain axis is growing, but the interplay of ethanol (alcohol molecule), the gut microbiome, the brain and behavior is poorly understood. In the current study, we remodeled the gut microbiota by providing adult male C57BL/6J mice with a non-absorbable antibiotic cocktail (ABX) in the drinking water and tested ethanol consumption behavior in a binge-like "Drinking in the Dark" model. Notably, 2 weeks of ABX pre-treatment significantly increased ethanol consumption during the 6 weeks of ethanol exposure in the DID paradigm.

A novel pharmacotherapy approach using P-glycoprotein (PGP/ABCB1) efflux inhibitor combined with ivermectin to reduce alcohol drinking and preference in mice.

Alcohol use disorder (AUD) has a major national impact, affecting over 18 million people, causing approximately 88,000 deaths, and costing upward of $250 billion annually in the United States. Unfortunately, FDA-approved AUD pharmaceuticals are few, and clinical benefits are mostly ineffective in patients suffering from AUD. Therefore, the identification of novel targets and/or innovative methods for the development of safe and effective medications represents a critical public health need.

Residues in Transmembrane Segments of the P2X4 Receptor Contribute to Channel Function and Ethanol Sensitivity.

Mouse models of alcohol use disorder (AUD) revealed purinergic P2X4 receptors (P2X4Rs) as a promising target for AUD drug development. We have previously demonstrated that residues at the transmembrane (TM)-ectodomain interface and within the TM1 segment contribute to the formation of an ethanol action pocket in P2X4Rs. In the present study, we tested the hypothesis that there are more residues in TM1 and TM2 segments that are important for the ethanol sensitivity of P2X4Rs.

Dopamine Receptor Blockade Attenuates Purinergic P2X4 Receptor-Mediated Prepulse Inhibition Deficits and Underlying Molecular Mechanisms.

Sensorimotor gating refers to the ability to filter incoming sensory information in a stimulus-laden environment and disruption of this physiological process has been documented in psychiatric disorders characterized by cognitive aberrations. The effectiveness of current pharmacotherapies for treatment of sensorimotor gating deficits in the patient population still remains controversial. These challenges emphasize the need to better understand the biological underpinnings of sensorimotor gating which could lead to discovery of novel drug targets for therapeutic intervention.

Murine Drinking Models in the Development of Pharmacotherapies for Alcoholism: Drinking in the Dark and Two-bottle Choice.

Alcohol Use Disorder (AUD) is a major problem with more than an estimated 76 million people worldwide meeting the diagnostic criteria. Current treatments are limited to three FDA-approved medications that are largely ineffective even when combined with psychosocial intervention, as is evident by the high relapse rate. As such, the search for more novel treatments represents an important public health goal.

Similarities in Blood Mononuclear Cell Membrane Phospholipid Profiles During Malignancy.

Phospholipids (PLs), key elements of cellular membranes, are regulated reciprocally with membrane proteins and can act as sensors for alterations in physiological or pathological states of cells including initiation and development of cancer. On the other hand, peripheral blood mononuclear cells (MNCs) play an important role in antitumor immune response by reacting to cancerous modifications in distant organs. In the current study, we tested the hypothesis that tumor initiation and development are reflected in the alteration pattern of the MNC PL component.

P2X7 Receptor Antagonist A804598 Inhibits Inflammation in Brain and Liver in C57BL/6J Mice Exposed to Chronic Ethanol and High Fat Diet.

Chronic low-grade neuroinflammation is increasingly implicated in organ damage caused by alcohol abuse. Purinergic P2X7 receptors (P2X7Rs) play an important role in the generation of inflammatory responses during a number of CNS pathologies as evidenced from studies using pharmacological inhibition approach. P2X7Rs antagonism has not been tested during chronic alcohol abuse.

Preclinical evaluation of avermectins as novel therapeutic agents for alcohol use disorders.

The deleterious effects of alcohol use disorders (AUDs) on human health have been documented worldwide. The enormous socioeconomic burden coupled with lack of efficacious pharmacotherapies underlies the need for improved treatment strategies. At present, there is a growing body of preclinical evidence that demonstrates the potential of avermectins [ivermectin (IVM), selamectin (SEL), abamectin (ABM), and moxidectin (MOX)] in treatment of AUDs.

Reduced expression of purinergic P2X4 receptors increases voluntary ethanol intake in C57BL/6J mice.

Purinergic P2X4 receptors (P2X4Rs) belong to the P2X superfamily of ionotropic receptors that are gated by adenosine 5'-triphosphate (ATP). Accumulating evidence indicates that P2X4Rs play an important role in regulation of ethanol intake. At the molecular level, ethanol's inhibitory effects on P2X4Rs are antagonized by ivermectin (IVM), in part, via action on P2X4Rs.

Ethanol differentially modulates P2X4 and P2X7 receptor activity and function in BV2 microglial cells.

Neuroinflammation is one of the mechanisms leading to neurodegenerative brain damage induced by chronic alcohol (ethanol) exposure. Microglia play a major role in the development of innate immune responses to environmental injuries including ethanol. Adenosine 5″-triphosphate (ATP)-activated purinergic P2X receptor (P2XR) subtypes, P2X4Rs and P2X7Rs, are endogenously expressed in microglia and can modulate their activity.

Preclinical development of moxidectin as a novel therapeutic for alcohol use disorder.

Current pharmacotherapies for alcohol used disorder (AUD) are few and relatively ineffective illustrating the need for the development of new, effective medications. Using a translational approach, our laboratory reported that ivermectin, an FDA-approved, human and animal anti-parasitic agent, can significantly reduce ethanol intake in male and female mice across different drinking paradigms. Extending this line of investigation, the current paper investigated the utility of moxidectin (MOX), an analogue of ivermectin, to reduce ethanol intake.

Role of purinergic P2X4 receptors in regulating striatal dopamine homeostasis and dependent behaviors.

Purinergic P2X4 receptors (P2X4Rs) belong to the P2X superfamily of ion channels regulated by ATP. We recently demonstrated that P2X4R knockout (KO) mice exhibited deficits in sensorimotor gating, social interaction, and ethanol drinking behavior. Dopamine (DA) dysfunction may underlie these behavioral changes, but there is no direct evidence for P2X4Rs' role in DA neurotransmission.

Utilizing an Orally Dissolving Strip for Pharmacological and Toxicological Studies: A Simple and Humane Alternative to Oral Gavage for Animals.

Prior to testing novel therapeutics in humans, short and long term preclinical (i.e., animal), repetitive pharmacological and toxicological testing is required.

Epigenetic control of group V phospholipase A2 expression in human malignant cells.

Secreted phospholipases A2 (sPLA2) are suggested to play an important role in inflammation and tumorigenesis. Different mechanisms of epigenetic regulation are involved in the control of group IIA, III and X sPLA2s expression in cancer cells, but group V sPLA2 (GV-PLA2) in this respect has not been studied. Here, we demonstrate the role of epigenetic mechanisms in regulation of GV-PLA2 expression in different cell lines originating from leukaemia and solid cancers.

Chronic ethanol exposure combined with high fat diet up-regulates P2X7 receptors that parallels neuroinflammation and neuronal loss in C57BL/6J mice.

The present investigation tested the role of ATP-activated P2X7 receptors (P2X7Rs) in alcohol-induced brain damage using a model that combines intragastric (iG) ethanol feeding and high fat diet in C57BL/6J mice (Hybrid). The Hybrid paradigm caused increased levels of pro-inflammatory markers, changes in microglia and astrocytes, reduced levels of neuronal marker NeuN and increased P2X7R expression in ethanol-sensitive brain regions. Observed changes in P2X7R and NeuN expression were more pronounced in Hybrid paradigm with inclusion of additional weekly binges.

Glycine and GABA(A) ultra-sensitive ethanol receptors as novel tools for alcohol and brain research.

A critical obstacle to developing effective medications to prevent and/or treat alcohol use disorders is the lack of specific knowledge regarding the plethora of molecular targets and mechanisms underlying alcohol (ethanol) action in the brain. To identify the role of individual receptor subunits in ethanol-induced behaviors, we developed a novel class of ultra-sensitive ethanol receptors (USERs) that allow activation of a single receptor subunit population sensitized to extremely low ethanol concentrations. USERs were created by mutating as few as four residues in the extracellular loop 2 region of glycine receptors (GlyRs) or γ-aminobutyric acid type A receptors (GABA(A)Rs), which are implicated in causing many behavioral effects linked to ethanol abuse.

P2X4 receptors (P2X4Rs) represent a novel target for the development of drugs to prevent and/or treat alcohol use disorders.

Alcohol use disorders (AUDs) have a staggering socioeconomic impact. Few therapeutic options are available, and they are largely inadequate. These shortcomings highlight the urgent need to develop effective medications to prevent and/or treat AUDs.

Multiday administration of ivermectin is effective in reducing alcohol intake in mice at doses shown to be safe in humans.

Ivermectin (IVM), an FDA approved anthelmintic agent, can significantly reduce ethanol intake in mice following acute administration. The current study evaluates the sustainability and safety of multiday IVM administration in reducing 10% v/v ethyl alcohol (10E) intake in mice at a dose shown to be safe in humans. We tested the effect of 10-day administration of IVM (3.

Contribution of P2X4 receptors to ethanol intake in male C57BL/6 mice.

P2X receptors (P2XRs) are a family of cation-permeable ligand-gated ion channels activated by synaptically released extracellular adenosine 5'-triphosphate. The P2X4 subtype is abundantly expressed in the central nervous system and is sensitive to low intoxicating ethanol concentrations. Genetic meta-analyses identified the p2rx4 gene as a candidate gene for innate alcohol intake and/or preference.

Avermectins differentially affect ethanol intake and receptor function: implications for developing new therapeutics for alcohol use disorders.

Our laboratory is investigating ivermectin (IVM) and other members of the avermectin family as new pharmaco-therapeutics to prevent and/or treat alcohol use disorders (AUDs). Earlier work found that IVM significantly reduced ethanol intake in mice and that this effect likely reflects IVM's ability to modulate ligand-gated ion channels. We hypothesized that structural modifications that enhance IVM's effects on key receptors and/or increase its brain concentration should improve its anti-alcohol efficacy.

Serum amyloid A, phospholipase A₂-IIA and C-reactive protein as inflammatory biomarkers for prostate diseases.

Introduction: Serum amyloid A (SAA), secreted group IIA phospholipase A₂ (sPLA₂-IIA), and C-reactive protein (CRP) are acute-phase proteins whose serum concentrations increase not only during inflammatory disorders, but also in the course of malignant diseases.

Materials And Methods: In this study we analyzed serum levels of these inflammatory markers along with prostate-specific antigens (PSA) in patients with benign prostatic hyperplasia (BPH, n = 55), localized prostate cancers (PCa, n = 55), and metastatic prostate cancers (mPCa, n = 27) using immunological assays.

Results: We found that in comparison to healthy individuals (n = 55), patients with BPH, PCa and mPCa have elevated serum levels of SAA, sPLA₂-IIA, and CRP, in addition to elevated levels of PSA.