Omega-3 Fatty Acids as Druggable Therapeutics for Neurodegenerative Disorders.

Neurodegenerative disorders are commonly associated with a complex pattern of pathophysiological hallmarks, including increased oxidative stress and neuroinflammation, which makes their treatment challenging. Omega-3 Fatty Acids (O3FA) are natural products with reported neuroprotective, anti-inflammatory, and antioxidant effects. These effects have been attributed to their incorporation into neuronal membranes or through the activation of intracellular or recently discovered cell-surface receptors (i.

The β2-adrenergic receptor-ROS signaling axis: An overlooked component of β2AR function?

β2-Adrenergic receptor (β2AR) agonists are clinically used to elicit rapid bronchodilation for the treatment of bronchospasms in pulmonary diseases such as asthma and COPD, both of which exhibit characteristically high levels of reactive oxygen species (ROS); likely secondary to over-expression of ROS generating enzymes and chronically heightened inflammation. Interestingly, β2AR has long-been linked to ROS, yet the involvement of ROS in β2AR function has not been as vigorously studied as other aspects of β2AR signaling. Herein, we discuss the existing body of evidence linking β2AR activation to intracellular ROS generation and importantly, the role of ROS in regulating β2AR function.

The pharmacokinetics of 3-fluoroamphetamine following delivery using clinically relevant routes of administration.

3-Fluoroamphetamine (also called PAL-353) is a synthetic amphetamine analog that has been investigated for cocaine use disorder (CUD), yet no studies have characterized its pharmacokinetics (PK). In the present study, we determined the PK of PAL-353 in male Sprague Dawley rats following intravenous bolus injection (5 mg/kg). Plasma samples were analyzed using a novel bioanalytical method that coupled liquid-liquid extraction and LC-MS/MS.

Effects of the synthetic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) on ethanol consumption and place conditioning in male mice.

Rationale: Approximately 20 million adults in the USA have an alcohol use disorder (AUD). There are clinical and preclinical data suggesting that psychedelics may have benefits for AUD.

Objective: To investigate the effects of the synthetic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) on the behavioral effects of ethanol.

Reintroduction of quazepam: an update on comparative hypnotic and adverse effects.

Insomnia is a prevalent disorder that affects over one-third of the U.S. population to varying degrees and is highly disruptive towards quality of life.

The sesquiterpene beta-caryophyllene oxide attenuates ethanol drinking and place conditioning in mice.

Approximately 20 million adults in the United States have an alcohol use disorder. In recent years, modulation of the behavioral effects of ethanol by phytochemicals has been explored. In this study, we used the ethanol-induced loss of righting reflex (LORR) assay to assess potency differences between the sesquiterpene phytochemical beta-caryophyllene (BCP) and its derivative caryophyllene oxide (BCPO).

The cannabinoid receptor 2 agonist, β-caryophyllene, improves working memory and reduces circulating levels of specific proinflammatory cytokines in aged male mice.

Age-related cognitive decline has been associated with proinflammatory cytokines, yet the precise relationship between cognitive decline and cytokine load remains to be elucidated. β-caryophyllene (BCP) is a cannabinoid receptor 2 (CB) agonist with established anti-inflammatory effects that is known to improve memory and increase lifespan. It is of interest to explore the potential of BCP to reduce age-related cognitive decline and proinflammatory cytokine load.

M100907 and BD 1047 attenuate the acute toxic effects of methamphetamine.

There are no Food and Drug Administration approved pharmacotherapies for methamphetamine (METH) overdose, thus identifying novel drug targets to prevent this devastating adverse event is a public-health imperative. Previous research suggests that serotonin and sigma receptors may contribute to the adverse effects of METH. The present study assessed whether pretreatment with the 5-HT receptor antagonist M100907 or the sigma 1 (σ) receptor antagonist BD 1047 attenuated METH-induced lethality, hyperthermia, convulsions, and seizures.

The adrenergic receptor antagonist carvedilol interacts with serotonin 2A receptors both in vitro and in vivo.

There is increasing support for the potential clinical use of compounds that interact with serotonin 2A (5-HT) receptors. It is therefore of interest to discover novel compounds that interact with 5-HT receptors. In the present study, we used computational chemistry to identify critical ligand structural features of 5-HT receptor binding and function.

Serotonin 2A receptors are a stress response system: implications for post-traumatic stress disorder.

Serotonin, one of the first neurotransmitters to be identified, is an evolutionarily old molecule that is highly conserved across the animal kingdom, and widely used throughout the brain. Despite this, ascribing a specific set of functions to brain serotonin and its receptors has been difficult and controversial. The 2A subtype of serotonin receptors (5-HT2A receptor) is the major excitatory serotonin receptor in the brain and has been linked to the effects of drugs that produce profound sensory and cognitive changes.

Nanoparticle encapsulation increases the brain penetrance and duration of action of intranasal oxytocin.

The blood-brain barrier (BBB) limits the therapeutic use of large molecules as it prevents them from passively entering the brain following administration by conventional routes. It also limits the capacity of researchers to study the role of large molecules in behavior, as it often necessitates intracerebroventricular administration. Oxytocin is a large-molecule neuropeptide with pro-social behavioral effects and therapeutic promise for social-deficit disorders.

The renaissance in psychedelic research: What do preclinical models have to offer.

Human research with psychedelics is making groundbreaking discoveries. Psychedelics modify enduring elements of personality and seemingly reduce anxiety, depression, and substance dependence in small but well-designed clinical studies. Psychedelics are advancing through pharmaceutical regulatory systems, and neuroimaging studies have related their extraordinary effects to select brain networks.

The serotonin 2C receptor agonist WAY-163909 attenuates ketamine-induced hypothermia in mice.

Anesthesia-Induced Hypothermia (AIH) has been reported to be the cause of many postoperative adverse effects, including increased mortality, decreased immune responses, cardiac events, and a greater prevalence of postoperative surgical wound infections. AIH can in some cases be minimized with pre-warming fluids and gases and forced-air heating systems, but such techniques are not always effective and can result in patient burns or other adverse effects. Stimulation of 5-HT receptors has been reported to increase body temperature through a variety of mechanisms, and as such, may be a viable target for pharmacologically minimizing AIH.

Effects of the second-generation "bath salt" cathinone alpha-pyrrolidinopropiophenone (α-PPP) on behavior and monoamine neurochemistry in male mice.

Rationale: Synthetic cathinones ("bath salts") are β-ketone analogs of amphetamines, yet few studies have examined their potential neurotoxic effects.

Objective: In the current study, we assessed the persistent behavioral and neurochemical effects of exposure to the second-generation synthetic cathinone α-pyrrolidinopropiophenone (α-PPP).

Methods: Male, Swiss-Webster mice were exposed to α-PPP (80 mg/kg) using a binge-like dosing regimen (QID, q2h).

Nanoparticle formulations that allow for sustained delivery and brain targeting of the neuropeptide oxytocin.

Oxytocin is a promising candidate for the treatment of social-deficit disorders such as Autism Spectrum Disorder, but oxytocin cannot readily pass the blood-brain barrier. Moreover, oxytocin requires frequent dosing as it is rapidly metabolized in blood. We fabricated four polymeric nanoparticle formulations using poly(lactic-co-glycolic acid) (PLGA) or bovine serum albumin (BSA) as the base material.

The role of free-fatty acid receptor-4 (FFA4) in human cancers and cancer cell lines.

A dietary influence on cancer progression has been evident for many decades, and dietary fatty acids, particularly long chain mono- and polyunsaturated fatty acids, have been shown to play significant roles in influencing growth of a variety of human cancers. The discovery of the family of cell-surface free-fatty acid receptors, which include the long-chain fatty acid receptors FFA1 and FFA4, suggest that many of the effects of dietary fats could be receptor-mediated. FFA4 is ubiquitously expressed and has recently been shown to modulate a variety of important anti-inflammatory and metabolic processes.

Free-fatty acid receptor-4 (FFA4) modulates ROS generation and COX-2 expression via the C-terminal β-arrestin phosphosensor in Raw 264.7 macrophages.

Agonism of the G protein-coupled free-fatty acid receptor-4 (FFA4) has been shown to promote numerous anti-inflammatory effects in macrophages that arise due to interaction with β-arrestin partner proteins. Humans express functionally distinct short and long FFA4 splice variants, such that FFA4-S signals through Gαq/11 and β-arrestin, while FFA4-L is intrinsically biased solely towards β-arrestin signaling. Recently, we and others have shown that phosphorylation of the FFA4 C-terminal tail is responsible for β-arrestin interactability and signaling.

The serotonin 5-HT receptor and the non-addictive nature of classic hallucinogens.

Classic hallucinogens share pharmacology as serotonin 5-HT, 5-HT, and 5-HT receptor agonists. Unique among most other Schedule 1 drugs, they are generally non-addictive and can be effective tools in the treatment of addiction. Mechanisms underlying these attributes are largely unknown.

Free-fatty acid receptor-4 (GPR120): Cellular and molecular function and its role in metabolic disorders.

Over the last decade, a subfamily of G protein-coupled receptors that are agonized by endogenous and dietary free-fatty acids (FFA) has been discovered. These free-fatty acid receptors include FFA2 and FFA3, which are agonized by short-chained FFA, as well as FFA1 and FFA4, which are agonized by medium-to-long chained FFA. Ligands for FFA1 and FFA4 comprise the family of long chain polyunsaturated omega-3 fatty acids including α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), suggesting that many of the long-known beneficial effects of these fats may be receptor mediated.