Neuroactive Kynurenines as Pharmacological Targets: New Experimental Tools and Exciting Therapeutic Opportunities.

Both preclinical and clinical studies implicate functional impairments of several neuroactive metabolites of the kynurenine pathway (KP), the major degradative cascade of the essential amino acid tryptophan in mammals, in the pathophysiology of neurologic and psychiatric diseases. A number of KP enzymes, such as tryptophan 2,3-dioxygenase (TDO2), indoleamine 2,3-dioxygenases (IDO1 and IDO2), kynurenine aminotransferases (KATs), kynurenine 3-monooxygenase (KMO), 3-hydroxyanthranilic acid oxygenase (3-HAO), and quinolinic acid phosphoribosyltransferase (QPRT), control brain KP metabolism in health and disease and are therefore increasingly considered to be promising targets for the treatment of disorders of the nervous system. Understanding the distribution, cellular expression, and regulation of KP enzymes and KP metabolites in the brain is therefore critical for the conceptualization and implementation of successful therapeutic strategies.

White matter and latency of visual evoked potentials during maturation: A miniature pig model of adolescent development.

Background: Continuous myelination of cerebral white matter (WM) during adolescence overlaps with the formation of higher cognitive skills and the onset of many neuropsychiatric disorders. We developed a miniature-pig model of adolescent brain development for neuroimaging and neurophysiological assessment during this critical period. Minipigs have gyroencephalic brains with a large cerebral WM compartment and a well-defined adolescence period.

The Tryptophan Metabolite Indole-3-Propionic Acid Raises Kynurenic Acid Levels in the Rat Brain In Vivo.

Alterations in the composition of the gut microbiota may be causally associated with several brain diseases. Indole-3-propionic acid (IPrA) is a tryptophan-derived metabolite, which is produced by intestinal commensal microbes, rapidly enters the circulation, and crosses the blood-brain barrier. IPrA has neuroprotective properties, which have been attributed to its antioxidant and bioenergetic effects.

Adrenalectomy exacerbates stress-induced impairment in fear discrimination: A causal role for kynurenic acid?

Impaired activity of the hypothalamic-pituitary axis and reduced blood levels of glucocorticoids (GCs) are signature features of stress-related maladies. Recent evidence suggests a possible role of the tryptophan metabolite kynurenic acid (KYNA) in this context. Here we investigated possible causal relationships in adult male rats, using stress-induced fear discrimination as a translationally relevant behavioral outcome measure.

The Probiotic Preferentially Synthesizes Kynurenic Acid from Kynurenine.

The gut-brain axis is increasingly understood to play a role in neuropsychiatric disorders. The probiotic bacterium and products of tryptophan degradation, specifically the neuroactive kynurenine pathway (KP) metabolite kynurenic acid (KYNA), have received special attention in this context. We, therefore, assessed relevant features of KP metabolism, namely, the cellular uptake of the pivotal metabolite kynurenine and its conversion to its primary products KYNA, 3-hydroxykynurenine and anthranilic acid in by incubating the bacteria in Hank's Balanced Salt solution in vitro.

Tryptophan challenge in individuals with schizophrenia and healthy controls: acute effects on circulating kynurenine and kynurenic acid, cognition and cerebral blood flow.

Cognitive impairments predict poor functional outcomes in people with schizophrenia. These impairments may be causally related to increased levels of kynurenic acid (KYNA), a major metabolic product of tryptophan (TRYP). In the brain, KYNA acts as an antagonist of the of α7-nicotinic acetylcholine and NMDA receptors, both of which are involved in cognitive processes.

Deletion of quinolinate phosphoribosyltransferase gene accelerates frailty phenotypes and neuromuscular decline with aging in a sex-specific pattern.

Decline in neuromuscular function with aging is known to be a major determinant of disability and all-cause mortality in late life. Despite the importance of the problem, the neurobiology of age-associated muscle weakness is poorly understood. In a previous report, we performed untargeted metabolomics on frail older adults and discovered prominent alteration in the kynurenine pathway, the major route of dietary tryptophan degradation that produces neurotoxic intermediate metabolites.

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.

Kynurenine 3-Monooxygenase Interacts with Huntingtin at the Outer Mitochondrial Membrane.

The flavoprotein kynurenine 3-monooxygenase (KMO) is localised to the outer mitochondrial membrane and catalyses the synthesis of 3-hydroxykynurenine from L-kynurenine, a key step in the kynurenine pathway (KP) of tryptophan degradation. Perturbation of KP metabolism due to inflammation has long been associated with the pathogenesis of several neurodegenerative disorders, including Huntington's disease (HD)-which is caused by the expansion of a polyglutamine stretch in the huntingtin (HTT) protein. While HTT is primarily localised to the cytoplasm, it also associates with mitochondria, where it may physically interact with KMO.

Tryptophan Challenge in Healthy Controls and People with Schizophrenia: Acute Effects on Plasma Levels of Kynurenine, Kynurenic Acid and 5-Hydroxyindoleacetic Acid.

The pivotal tryptophan (TRP) metabolite kynurenine is converted to several neuroactive compounds, including kynurenic acid (KYNA), which is elevated in the brain and cerebrospinal fluid of people with schizophrenia (SZ) and may contribute to cognitive abnormalities in patients. A small proportion of TRP is metabolized to serotonin and further to 5-hydroxyindoleacetic acid (5-HIAA). Notably, KP metabolism is readily affected by immune stimulation.

Expert Recommendations on the Use of Hyaluronic Acid Filler for Tear Trough Rejuvenation.

Restylane® Lidocaine is one of the most widely used hyaluronic acid (HA) fillers to replace lost or displaced volume during tear trough correction. Patient goals for tear trough correction include looking less tired or removing dark circles and this may be achieved by administering HA filler into the infraorbital region to correct the lower eyelid relative to the volume deficit, thereby smoothing the transition from the lower eyelid to the cheek. To achieve patient satisfaction and consistent results with Restylane, optimal application is essential; however, clinical guidance based on experience is limited.

Cellular Localization of Kynurenine 3-Monooxygenase in the Brain: Challenging the Dogma.

Kynurenine 3-monooxygenase (KMO), a key player in the kynurenine pathway (KP) of tryptophan degradation, regulates the synthesis of the neuroactive metabolites 3-hydroxykynurenine (3-HK) and kynurenic acid (KYNA). KMO activity has been implicated in several major brain diseases including Huntington's disease (HD) and schizophrenia. In the brain, KMO is widely believed to be predominantly localized in microglial cells, but verification in vivo has not been provided so far.

A single prenatal lipopolysaccharide injection has acute, but not long-lasting, effects on cerebral kynurenine pathway metabolism in mice.

In rodents, a single injection of lipopolysaccharide (LPS) during gestation causes chemical and functional abnormalities in the offspring. These effects may involve changes in the kynurenine pathway (KP) of tryptophan degradation and may provide insights into the pathophysiology of psychiatric diseases. Using CD1 mice, we examined acute and long-term effects of prenatal LPS treatment on the levels of kynurenine and its neuroactive downstream products kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK) and quinolinic acid.

Subchronic -acetylcysteine Treatment Decreases Brain Kynurenic Acid Levels and Improves Cognitive Performance in Mice.

The tryptophan (Trp) metabolite kynurenic acid (KYNA) is an α7-nicotinic and -methyl-d-aspartate receptor antagonist. Elevated brain KYNA levels are commonly seen in psychiatric disorders and neurodegenerative diseases and may be related to cognitive impairments. Recently, we showed that -acetylcysteine (NAC) inhibits kynurenine aminotransferase II (KAT II), KYNA's key biosynthetic enzyme, and reduces KYNA neosynthesis in rats .

The Discovery and Characterization of Targeted Perikaryal-Specific Brain Lesions With Excitotoxins.

The neurotoxic action of glutamic acid was first described by Lucas and Newhouse, who demonstrated neural degeneration in the inner layers of the neonatal mouse retina after systemic treatment with L-glutamate. Olney extended these findings by showing that neuronal degeneration affected other brain structures including neurons within the arcuate nucleus of the hypothalamus and the area postrema, that the lesion spared axons passing through these areas, and that the neurotoxic potency of glutamate analogs correlated with their excitatory potency, resulting in the designation "excitotoxins." As this method affected only a small number of brain regions, it was not suitable for targeted brain lesions.

Stress-induced impairment in fear discrimination is causally related to increased kynurenic acid formation in the prefrontal cortex.

Rationale: Stress is related to cognitive impairments which are observed in most major brain diseases. Prior studies showed that the brain concentration of the tryptophan metabolite kynurenic acid (KYNA) is modulated by stress, and that changes in cerebral KYNA levels impact cognition. However, the link between these phenomena has not been tested directly so far.

Activation of alpha7 nicotinic and NMDA receptors is necessary for performance in a working memory task.

Rationale: Working memory deficits are present in schizophrenia (SZ) but remain insufficiently resolved by medications. Similar cognitive dysfunctions can be produced acutely in animals by elevating brain levels of kynurenic acid (KYNA). KYNA's effects may reflect interference with the function of both the α7 nicotinic acetylcholine receptor (α7nAChR) and the glycineB site of the NMDA receptor.

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

Cannabis remains one of the most widely used illicit drugs during pregnancy. The main psychoactive component of marijuana (Δ-tetrahydrocannabinol, THC) is correlated with untoward physiological effects in the offspring. Neurobehavioral and cognitive impairments have been reported in longitudinal studies on children and adolescents prenatally exposed to marijuana, and a link to psychiatric disorders has been proposed.

The Impact of Submental Deoxycholic Acid Injections on Neck Surgery.

Non-invasive procedures targeting the submental fat or “double chin” have undergone a surge in popularity. Injections of deoxycholic acid, a secondary bile acid, have recently received FDA-approval for fat reduction in this area. With appropriate patient selection, this preparation of 10 mg/mL of sodium deoxycholate (Kybella®, Kythera Biopharmaceuticals, Westlake Village, CA) leads to aesthetic improvement of moderate-to-severe convexity or fullness associated with submental fat in adults.

A brain-permeable inhibitor of the neurodegenerative disease target kynurenine 3-monooxygenase prevents accumulation of neurotoxic metabolites.

Dysregulation of the kynurenine pathway (KP) leads to imbalances in neuroactive metabolites associated with the pathogenesis of several neurodegenerative disorders, including Huntington's disease (HD). Inhibition of the enzyme kynurenine 3-monooxygenase (KMO) in the KP normalises these metabolic imbalances and ameliorates neurodegeneration and related phenotypes in several neurodegenerative disease models. KMO is thus a promising candidate drug target for these disorders, but known inhibitors are not brain permeable.

Demographic Differences Among Patients Undergoing Blepharoplasty Based on Surgeon Training in New York State.

Purpose: To evaluate whether patient demographics and surgical metrics varied among differently trained surgeons performing blepharoplasty.

Methods: The Statewide Planning and Research Cooperative System database was used to identify patients who underwent blepharoplasty in New York State. Surgeons were grouped based on residency training as listed in the New York State Physician Profile.

Assessment of Prenatal Kynurenine Metabolism Using Tissue Slices: Focus on the Neosynthesis of Kynurenic Acid in Mice.

Several lines of evidence support the hypothesis that abnormally elevated brain levels of kynurenic acid (KYNA), a metabolite of the kynurenine pathway (KP) of tryptophan degradation, play a pathophysiologically significant role in schizophrenia and other major neurodevelopmental disorders. Studies in experimental animal models suggest that KP impairments in these diseases may originate already in utero since prenatal administration of KYNA's bioprecursor, kynurenine, leads to biochemical and structural abnormalities as well as distinct cognitive impairments in adulthood. As KP metabolism during pregnancy is still insufficiently understood, we designed this study to examine the de novo synthesis of KYNA and 3-hydroxykynurenine (3-HK), an alternative biologically active product of kynurenine degradation, in tissue slices obtained from pregnant mice on gestational day (GD) 18.

The Aesthetic Oculoplastic Surgery Video Teleconference Consult.

Background: Skype video telemedicine consults are gaining popularity to evaluate patients from distant locations. No study has analyzed the utility of this means of patient evaluation in a cosmetic oculoplastic patient population.

Objectives: The authors sought to provide an evidence-based analysis of the utility of Skype video consults in a cosmetic oculoplastic surgery patient population with regards to patient demographics, reasons for consult, and procedural conversion rate.

In Vitro Evaluation of Preinjection Aspiration for Hyaluronic Fillers as a Safety Checkpoint.

Background: Hyaluronic acid (HA) fillers have increased in popularity. Although complications are rare, knowledge regarding their prevention and management are crucial. The utility of preinjection aspiration has become controversial.