Kynurenic Acid Synthesis from D-Kynurenine in the Cerebellum: A Distinct Role of D-Amino Acid Oxidase.

The enzymatic formation of kynurenic acid (KYNA), a neuromodulator metabolite of the kynurenine pathway (KP) of tryptophan metabolism, in the mammalian brain is widely attributed to kynurenine aminotransferase II (KATII). However, an alternative biosynthetic route, involving the conversion of D-kynurenine (D-KYN) to KYNA by D-amino acid oxidase (D-AAO), may play a role as well. In the present study, we first confirmed that purified D-AAO efficiently converted D-KYN-but not L-KYN-to KYNA.

Functional Impairments in Learning and Signal Propagation Following Prenatal Kynurenine Treatment in Mice.

The levels of kynurenic acid (KYNA), a metabolite of the kynurenine pathway (KP) of tryptophan degradation, are elevated in the brain of persons with schizophrenia (SZ) and may be linked to cognitive dysfunctions in the disease. Studies in rats indicate that abnormally high fetal brain KYNA may play a pathophysiologically significant role in this context ("EKyn model"). Here, we fed pregnant C57Bl/6J mice with the immediate KYNA precursor kynurenine (10 mg or 30 mg/day; EKyn) or with control chow (ECon) from embryonic day (ED) 11 to ED 18 and assessed offspring postnatally both functionally and biochemically.

Parental kynurenine 3-monooxygenase genotype in mice directs sex-specific behavioral outcomes in offspring.

Background: Disruptions in brain development can impact behavioral traits and increase the risk of neurodevelopmental conditions such as autism spectrum disorder, attention-deficit/hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder, often in sex-specific ways. Dysregulation of the kynurenine pathway (KP) of tryptophan metabolism has been implicated in cognitive and neurodevelopmental disorders. Increased brain kynurenic acid (KYNA), a neuroactive metabolite implicated in cognition and sleep homeostasis, and variations in the Kmo gene, which encodes kynurenine 3-monooxygenase (KMO), have been identified in these patients.

Nasal Administration of a Nanoemulsion Based on Methyl Ferulate and Eugenol Encapsulated in Chitosan Oleate: Uptake Studies in the Central Nervous System.

: The phytochemicals ferulic acid (Fer) and eugenol display neuroprotective effects for their anti-oxidative properties; moreover, eugenol can induce dopamine (DA) release from dopaminergic neuronal cells. However, poor bioavailability and/or fast elimination rate limit their clinical benefits. We therefore propose a new nasal formulation based on a nanoemulsion (NE) for the jointed brain-targeting of eugenol and methyl ferulate (Fer-Me, i.

Kynurenine amplifies tetrahydrocannabinol-induced sensorimotor impairment and classic "tetrad" effects in mice.

Background: L-kynurenine (KYN), a kynurenine pathway (KP) metabolite, is the main precursor for the neuroactive metabolite kynurenic acid (KYNA). Several studies suggest a patho-physiologically relevant association between increased brain KYNA levels and cognitive dysfunctions in individuals with schizophrenia. Δ-tetrahydrocannabinol (Δ-THC; i.

Clove Essential Oil as a Source of Antitumoral Compounds Capable of Crossing the Blood-Brain Barrier: A Focus on the Effects of β-Caryophyllene and Eugenol in a Glioblastoma Cell Line.

This study aimed to investigate β-Caryophyllene (BCA) pharmacokinetics as well as the potential antitumor activity and mechanism of action of BCA and eugenol (EU), alone or in combination, in U87 glioblastoma (GB) cells. The BCA pharmacokinetic was studied by evaluating its concentration profiles in rat blood and cerebrospinal fluid after oral and intravenous administration. EU and BCA antitumor mechanisms were assessed by comparing their effects in U87 GB cells and non-tumoral HMC3 cells.

GET73 modulates lipopolysaccharide- and ethanol-induced increase in cytokine/chemokine levels in primary cultures of microglia of rat cerebral cortex.

Background: - Alcohol-induced pro-inflammatory activation might influence cellular and synaptic pathology, thus contributing to the behavioral phenotypes associated with alcohol use disorders. In the present study, the possible anti-inflammatory properties of N-[(4-trifluoromethyl)-benzyl]4-methoxybutyramide (GET73), a promising therapeutic agent for alcohol use disorder treatment, were evaluated in primary cultures of rat cortical microglia.

Methods: - Primary cultures of cerebral cortex microglial cells were treated with 100 ng/ml lipopolysaccharide (LPS; 8 h, 37 °C) or 75 mM ethanol (EtOH; 4 days, 37 °C) alone or in the presence of GET73 (1-30 µM).

Supramolecular eutectogel as new oral paediatric delivery system to enhance benznidazole bioavailability.

Benznidazole (BNZ) serves as the primary drug for treating Chagas Disease and is listed in the WHO Model List of Essential Medicines for Children. Herein, a new child-friendly oral BNZ delivery platform is developed in the form of supramolecular eutectogels (EGs). EGs address BNZ's poor oral bioavailability and provide a flexible twice-daily dose in stick-pack format.

Prenatal MAM exposure raises kynurenic acid levels in the prefrontal cortex of adult rats.

Background: Elevated brain levels of kynurenic acid (KYNA), a metabolite in the kynurenine pathway, are associated with cognitive dysfunctions, which are nowadays often considered as fundamental characteristics of several psychopathologies; however, the role of KYNA in mental illnesses, such as schizophrenia, is not fully elucidated. This study aimed to assess KYNA levels in the prefrontal cortex (PFC) of rats prenatally treated with methylazoxymethanol (MAM) acetate, i.e.

Signature of paraoxonases in the altered redox homeostasis in Alzheimer's disease.

Paraoxonase (PON) enzymes (PON1, PON2 and PON3) exert antioxidant properties through arylesterase, lactonase and paraoxonase activities. Increasing findings suggested their potential involvement, particularly PON1 and PON2, in Alzheimer's disease (AD), a neurodegenerative pathology characterized by early oxidative stress. Specifically, decreased serum PON1-arylesterase and lactonase activities seem to be associated with an increased brain oxidative damage in early AD, leading to hypothesize that PON activity alterations might be an early event in AD.

Dimeric ferulic acid conjugate as a prodrug for brain targeting after nasal administration of loaded solid lipid microparticles.

Objective: Ferulic acid (Fer) displays antioxidant/anti-inflammatory properties useful against neurodegenerative diseases. To increase Fer uptake and its central nervous system residence time, a dimeric prodrug, optimizing the Fer loading on nasally administrable solid lipid microparticles (SLMs), was developed.

Methods: The prodrug was synthesized as Fer dimeric conjugate methylated on the carboxylic moiety.

Cognitive dysfunction and impaired neuroplasticity following repeated exposure to the synthetic cannabinoid JWH-018 in male mice.

Background And Purpose: Psychotic disorders have been reported in long-term users of synthetic cannabinoids. This study aims at investigating the long-lasting effects of repeated JWH-018 exposure.

Experimental Approach: Male CD-1 mice were injected with vehicle, JWH-018 (6 mg·kg ), the CB -antagonist NESS-0327 (1 mg·kg ) or co-administration of NESS-0327 and JWH-018, every day for 7 days.

Alterations in rat prefrontal cortex kynurenic acid levels are involved in the enduring cognitive dysfunctions induced by tetrahydrocannabinol exposure during the adolescence.

Introduction: Cannabis abuse during adolescence is a risk factor for cognitive impairments in psychiatric disorders later in life. To date, the possible causal relationship between cannabinoids, kynurenic acid (KYNA; i.e.

Biological activity of new bioactive steroids deriving from biotransformation of cortisone.

Cortisone is a metabolite belonging to the corticosteroid class that is used pharmaceutically directly as a drug or prodrug. In addition to its large consumption, its use is linked to several side effects, so pharmaceutical research aims to develop effective drugs with low or no side effects, alternative compounds to cortisone are part of an active investment in ongoing research on drug discovery. Since biotransformation can be considered a source of new molecules with potential therapeutic use, the present work focuses on a preliminary in vitro study aimed at evaluating the mutagenic, anti-inflammatory, antioxidant and neuroprotective activity of SCA and SCB molecules obtained from the biotransformation of cortisone using Rh.

Effects of Ultramicronized Palmitoylethanolamide on Mitochondrial Bioenergetics, Cerebral Metabolism, and Glutamatergic Transmission: An Integrated Approach in a Triple Transgenic Mouse Model of Alzheimer's Disease.

The therapeutic potential of ultramicronized palmitoylethanolamide (um-PEA) was investigated in young (6-month-old) and adult (12-month-old) 3 × Tg-AD mice, which received um-PEA for 3 months a subcutaneous delivery system. Mitochondrial bioenergetics, ATP homeostasis, and magnetic resonance imaging/magnetic resonance spectroscopy were evaluated in the frontal cortex (FC) and hippocampus (HIPP) at the end of um-PEA treatment. Glutamate release was investigated by microdialysis in the ventral HIPP (vHIPP).

Pros and Cons of Pharmacological Manipulation of cGMP-PDEs in the Prevention and Treatment of Breast Cancer.

The cyclic nucleotides, cAMP and cGMP, are ubiquitous second messengers responsible for translating extracellular signals to intracellular biological responses in both normal and tumor cells. When these signals are aberrant or missing, cells may undergo neoplastic transformation or become resistant to chemotherapy. cGMP-hydrolyzing phosphodiesterases (PDEs) are attracting tremendous interest as drug targets for many diseases, including cancer, where they regulate cell growth, apoptosis and sensitization to radio- and chemotherapy.

Time of Day-Dependent Alterations in Hippocampal Kynurenic Acid, Glutamate, and GABA in Adult Rats Exposed to Elevated Kynurenic Acid During Neurodevelopment.

Hypofunction of glutamatergic signaling is causally linked to neurodevelopmental disorders, including psychotic disorders like schizophrenia and bipolar disorder. Kynurenic acid (KYNA) has been found to be elevated in postmortem brain tissue and cerebrospinal fluid of patients with psychotic illnesses and may be involved in the hypoglutamatergia and cognitive dysfunction experienced by these patients. As insults during the prenatal period are hypothesized to be linked to the pathophysiology of psychotic disorders, we presently utilized the embryonic kynurenine (EKyn) paradigm to induce a prenatal hit.

Serotonin Heteroreceptor Complexes and Their Integration of Signals in Neurons and Astroglia-Relevance for Mental Diseases.

The heteroreceptor complexes present a novel biological principle for signal integration. These complexes and their allosteric receptor-receptor interactions are bidirectional and novel targets for treatment of CNS diseases including mental diseases. The existence of D2R-5-HT2AR heterocomplexes can help explain the anti-schizophrenic effects of atypical antipsychotic drugs not only based on blockade of 5-HT2AR and of D2R in higher doses but also based on blocking the allosteric enhancement of D2R protomer signaling by 5-HT2AR protomer activation.

The coming together of allosteric and phosphorylation mechanisms in the molecular integration of A2A heteroreceptor complexes in the dorsal and ventral striatal-pallidal GABA neurons.

The role of adenosine A2A receptor (A2AR) and striatal-enriched protein tyrosine phosphatase (STEP) interactions in the striatal-pallidal GABA neurons was recently discussed in relation to A2AR overexpression and cocaine-induced increases of brain adenosine levels. As to phosphorylation, combined activation of A2AR and metabotropic glutamate receptor 5 (mGluR5) in the striatal-pallidal GABA neurons appears necessary for phosphorylation of the GluA1 unit of the AMPA receptor to take place. Robert Yasuda (J Neurochem 152: 270-272, 2020) focused on finding a general mechanism by which STEP activation is enhanced by increased A2AR transmission in striatal-pallidal GABA neurons expressing A2AR and dopamine D2 receptor.

Nasal biocompatible powder of Geraniol oil complexed with cyclodextrins for neurodegenerative diseases: physicochemical characterization and in vivo evidences of nose to brain delivery.

Recently, many studies have shown that plant metabolites, such as geraniol (GER), may exert anti-inflammatory effects in neurodegenerative diseases and, in particular, Parkinson's disease (PD) models. Unfortunately, delivering GER to the CNS via nose-to-brain is not feasible due to its irritant effects on the mucosae. Therefore, in the present study β-cyclodextrin (βCD) and its hydrophilic derivative hydroxypropyl-beta-cyclodextrin (HPβCD) were selected as potential carriers for GER nose-to-brain delivery.

COR758, a negative allosteric modulator of GABA receptors.

Allosteric modulators of G protein coupled receptors (GPCRs), including GABARs (GABARs), are promising therapeutic candidates. While several positive allosteric modulators (PAM) of GABARs have been characterized, only recently the first negative allosteric modulator (NAM) has been described. In the present study, we report the characterization of COR758, which acts as GABAR NAM in rat cortical membranes and CHO cells stably expressing GABARs (CHO-GABA).

The Balance of MU-Opioid, Dopamine D2 and Adenosine A2A Heteroreceptor Complexes in the Ventral Striatal-Pallidal GABA Antireward Neurons May Have a Significant Role in Morphine and Cocaine Use Disorders.

The widespread distribution of heteroreceptor complexes with allosteric receptor-receptor interactions in the CNS represents a novel integrative molecular mechanism in the plasma membrane of neurons and glial cells. It was proposed that they form the molecular basis for learning and short-and long-term memories. This is also true for drug memories formed during the development of substance use disorders like morphine and cocaine use disorders.

The Dual Role of Glutamatergic Neurotransmission in Alzheimer's Disease: From Pathophysiology to Pharmacotherapy.

Alzheimer's disease (AD) is an age-related dementia and neurodegenerative disorder, characterized by Aβ and tau protein deposition impairing learning, memory and suppressing synaptic plasticity of neurons. Increasing evidence suggests that there is a link between the glucose and glutamate alterations with age that down-regulates glucose utilization reducing glutamate levels in AD patients. Deviations in brain energy metabolism reinforce the development of AD by hampering glutamate levels in the brain.