The Probiotic Lactobacillus reuteri Preferentially Synthesizes Kynurenic Acid from Kynurenine.

The gut-brain axis is increasingly understood to play a role in neuropsychiatric disorders. The probiotic bacterium Lactobacillus (L.) reuteri 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 L. reuteri by incubating the bacteria in Hank's Balanced Salt solution in vitro. Kynurenine readily entered the bacterial cells and was preferentially converted to KYNA, which was promptly released into the extracellular milieu. De novo production of KYNA increased linearly with increasing concentrations of kynurenine (up to 1 mM) and bacteria (107 to 109 CFU/mL) and with incubation time (1-3 h). KYNA neosynthesis was blocked by two selective inhibitors of mammalian kynurenine aminotransferase II (PF-048559989 and BFF-122). In contrast to mammals, however, kynurenine uptake was not influenced by other substrates of the mammalian large neutral amino acid transporter, and KYNA production was not affected by the presumed competitive enzyme substrates (glutamine and α-aminoadipate). Taken together, these results reveal substantive qualitative differences between bacterial and mammalian KP metabolism.

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. We also showed that neurotoxic kynurenine pathway metabolites are correlated with increased frailty score. For the present study, we sought to further examine the neurobiology of these neurotoxic intermediates by utilizing a mouse model that has a deletion of the quinolinate phosphoribosyltransferase (QPRT) gene, a rate-limiting step of the kynurenine pathway. QPRT-/- mice have elevated neurotoxic quinolinic acid level in the nervous system throughout their lifespan. We found that QPRT-/- mice have accelerated declines in neuromuscular function in an age- and sex-specific manner compared to control strains. In addition, the QPRT-/- mice show premature signs of frailty and body composition changes that are typical for metabolic syndrome. Our findings suggest that the kynurenine pathway may play an important role in frailty and age-associated muscle weakness.

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. To examine whether KYNA plays a role in the pathophysiology of schizophrenia, we compared the acute effects of a single oral dose of TRYP (6 g) in 32 healthy controls (HC) and 37 people with either schizophrenia (Sz), schizoaffective or schizophreniform disorder, in a placebo-controlled, randomized crossover study. We examined plasma levels of KYNA and its precursor kynurenine; selected cognitive measures from the MATRICS Consensus Cognitive Battery; and resting cerebral blood flow (CBF) using arterial spin labeling imaging. In both cohorts, the TRYP challenge produced significant, time-dependent elevations in plasma kynurenine and KYNA. The resting CBF signal (averaged across all gray matter) was affected differentially, such that TRYP was associated with higher CBF in HC, but not in participants with a Sz-related disorder. While TRYP did not significantly impair cognitive test performance, there was a trend for TRYP to worsen visuospatial memory task performance in HC. Our results demonstrate that oral TRYP challenge substantially increases plasma levels of kynurenine and KYNA in both groups, but exerts differential group effects on CBF. Future studies are required to investigate the mechanisms underlying these CBF findings, and to evaluate the impact of KYNA fluctuations on brain function and behavior. (Clinicaltrials.gov: NCT02067975).

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., a neuroactive metabolite of tryptophan degradation) and cognition has not been investigated in adolescence. Early exposure to delta 9-tetrahydrocannabinol (THC; i.e., the main psychotropic component of cannabis) causes enduring cognitive deficits, which critically involve impaired glutamatergic function in the prefrontal cortex (PFC). In addition, prenatal cannabis exposure results in enduring increases in PFC KYNA levels. Based on these findings, the effects of chronic THC exposure in rats, during another critical period of neurodevelopment particularly sensitive to perturbation by exogenous stimuli, such as adolescence, have been investigated. Methods: Male Wistar rats were chronically treated with vehicle or ascending intraperitoneal (i.p.) doses of THC starting on postnatal day (PND) 35 until PND 45. In adulthood (PND 75), cognitive assessment (Y-maze) and extracellular KYNA/glutamate levels were measured in the PFC by in vivo microdialysis, before and after a challenge with KYN (5 mg/kg i.p., the biological precursor of KYNA). By using the selective, brain-penetrable KAT II inhibitor PF-04859989, we then examined whether blockade of KYNA neosynthesis prevents the cognitive impairment. Results: Compared to vehicle-treated controls, extracellular basal KYNA levels were higher in the PFC of adult rats chronically exposed to THC in adolescence (p < 0.01). No changes were observed in extracellular glutamate levels. Following a challenge with KYN, extracellular KYNA levels similarly increased in both groups (i.e., vehicle- and THC-treated; p < 0.001 and p < 0.01, respectively). Chronic adolescent THC exposure negatively affected short-term memory (reduced spontaneous alternation), in adult animals (p < 0.001), while PF-04859989 (30 mg/kg i.p.) restored the cognitive impairment (p < 0.05). Discussion: We propose that the observed alterations in PFC KYNA signaling might be involved in the cognitive dysfunction induced by the exposure to THC during the adolescence. In the translational realm, these experiments raise the prospect of prevention of KYNA neosynthesis as a possible novel approach to counteract some of the detrimental long-term effects of adolescence cannabis use.

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. In order to test this hypothesis, we employed bimolecular fluorescence complementation (BiFC) and found that KMO physically interacts with soluble HTT exon 1 protein fragment in living cells. Notably, expansion of the disease-causing polyglutamine tract in HTT leads to the formation of proteinaceous intracellular inclusions that disrupt this interaction with KMO, markedly decreasing BiFC efficiency. Using confocal microscopy and ultrastructural analysis, we determined KMO and HTT localisation within the cell and found that the KMO-HTT interaction is localized to the outer mitochondrial membrane. These data suggest that KMO may interact with a pool of HTT at the mitochondrial membrane, highlighting a possible physiological role for mitochondrial HTT. The KMO-HTT interaction is abrogated upon polyglutamine expansion, which may indicate a heretofore unrecognized relevance in the pathogenesis of this disorder.

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. Here, we assessed the acute effects of an oral TRP challenge (6 g) on peripheral concentrations of kynurenine, KYNA and 5-HIAA, as well as the cytokines interferon-γ, TNF-α and interleukin-6, in 22 participants with SZ and 16 healthy controls (HCs) using a double-blind, placebo-controlled, crossover design. TRP raised the levels of kynurenine, KYNA and 5-HIAA in a time-dependent manner, causing >20-fold, >130-fold and 1.5-fold increases in kynurenine, KYNA and 5-HIAA concentrations, respectively, after 240 min. According to multivariate analyses, neither baseline levels nor the stimulating effects of TRP differed between participants with SZ and HC. Basal cytokine levels did not vary between groups, and remained unaffected by TRP. Although unlikely to be useful diagnostically, measurements of circulating metabolites following an acute TRP challenge may be informative for assessing the in vivo efficacy of drugs that modulate the neosynthesis of KYNA and other products of TRP degradation.

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. This paper reflects the recommendations of an interdisciplinary expert panel for the use of Restylane in correcting tear trough deformity, including patient selection, dosing, injection technique, and post-treatment care. Recommendations were discussed and agreed as a consensus, according to cross-sectional expertise and clinical experience. J Drugs Dermatol. 2022;21(4):387-392. doi:10.36849/JDD.6597.

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. Here, we examined KP metabolism in the brain after depleting microglial cells pharmacologically with the colony stimulating factor 1 receptor inhibitor PLX5622. Young adult mice were fed PLX5622 for 21 days and were euthanized either on the next day or after receiving normal chow for an additional 21 days. Expression of microglial marker genes was dramatically reduced on day 22 but had fully recovered by day 43. In both groups, PLX5622 treatment failed to affect Kmo expression, KMO activity or tissue levels of 3-HK and KYNA in the brain. In a parallel experiment, PLX5622 treatment also did not reduce KMO activity, 3-HK and KYNA in the brain of R6/2 mice (a model of HD with activated microglia). Finally, using freshly isolated mouse cells ex vivo, we found KMO only in microglia and neurons but not in astrocytes. Taken together, these data unexpectedly revealed that neurons contain a large proportion of functional KMO in the adult mouse brain under both physiological and pathological conditions.

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. To this end, LPS (100 µg/kg, i.p.) was administered on gestational day 15, and KP metabolites were measured 4 and 24 h later or in adulthood. After 4 h, kynurenine, KYNA and 3-HK levels were elevated in the fetal brain, 3-HK and KYNA levels were increased in the maternal plasma, and kynurenine was increased in the maternal brain, whereas no changes were seen in the placenta. These effects were less prominent after 24 h, and prenatal LPS did not affect the basal levels of KP metabolites in the forebrain of adult animals. In addition, a second LPS injection (1 mg/kg) in adulthood in the offspring of prenatally saline- and LPS-treated mice caused a similar elevation in 3-HK levels in both groups after 24 h, but the effect was significantly more pronounced in male mice. Thus, acute immune activation during pregnancy has only short-lasting effects on KP metabolism and does not cause cerebral KP metabolites to be disproportionally affected by a second immune challenge in adulthood. However, prenatal KYNA elevations still contribute to functional abnormalities in the offspring.

Subchronic N-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 N-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 N-acetylcysteine (NAC) inhibits kynurenine aminotransferase II (KAT II), KYNA's key biosynthetic enzyme, and reduces KYNA neosynthesis in rats in vivo. In this study, we examined if repeated systemic administration of NAC influences brain KYNA and cognitive performance in mice. Animals received NAC (100 mg/kg, i.p.) daily for 7 days. Redox markers, KYNA levels, and KAT II activity were determined in the brain. We also assessed the effect of repeated NAC treatment on Trp catabolism using brain tissue slices ex vivo. Finally, learning and memory was evaluated with and without an acute challenge with KYNA's bioprecursor L-kynurenine (Kyn; 100 mg/kg). Subchronic NAC administration protected against an acute pro-oxidant challenge, decreased KYNA levels, and lowered KAT II activity and improved memory both under basal conditions and after acute Kyn treatment. In tissue slices from these mice, KYNA neosynthesis from Trp or Kyn was reduced. Together, our data indicate that prolonged treatment with NAC may enhance memory at least in part by reducing brain KYNA levels.

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. The Coyle laboratory showed that direct injection of the potent glutamate receptor agonist, kainic acid, into the rat striatum caused a rapid degeneration of intrinsic neurons while sparing axons of passage or termination including the unmyelinated dopaminergic terminals. Kainic acid also exhibited this perikaryal-specific and axon-sparing profile when injected into the cerebellum, hippocampus and eye. However, neuronal vulnerability was highly variable, with hippocampal CA3, pyriform cortex and amygdala neurons exhibiting great sensitivity due to kainate's high convulsive activity. In a comparison study, ibotenic acid, a potent glutamatergic agonist isolated from the amanita muscaria mushroom, was found to have excitotoxic potency comparable to kainate but was far less epileptogenic. Ibotenate produced spherical, perikaryal-specific lesions regardless of the site of injection, and experiments with specific glutamate receptor antagonists showed that its effects were mediated by the N-methyl-D-aspartate receptor. Because of this uniform neurotoxicity and near ubiquitous efficacy, ibotenic acid became the excitotoxic lesioning agent of choice. The discovery of the excitotoxic properties of the tryptophan metabolite quinolinic acid and of the anti-excitotoxic, neuroprotective effects of the related metabolite kynurenic acid in the Schwarcz laboratory then gave rise to the concept that these endogenous compounds may play causative roles in the neuropathology of a wide range of neurological and psychiatric disorders.

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. OBJECTIVES: The aim of the present study was to examine, using pharmacological tools, the respective roles of these two receptor sites on performance in a delayed non-match-to-position working memory (WM) task (DNMTP). METHODS: DNMTP consisted of 120 trials/session (5, 10, and 15 s delays). Rats received two doses (25 or 100 mg/kg, i.p.) of L-kynurenine (KYN; bioprecursor of KYNA) or L-4-chlorokynurenine (4-Cl-KYN; bioprecursor of the selective glycineB site antagonist 7-Cl-kynurenic acid). Attenuation of KYN- or 4-Cl-KYN-induced deficits was assessed by co-administration of galantamine (GAL, 3 mg/kg) or PAM-2 (1 mg/kg), two positive modulators of α7nAChR function. Reversal of 4-Cl-KYN-induced deficits was examined using D-cycloserine (DCS; 30 mg/kg), a partial agonist at the glycineB site. RESULTS: Both KYN and 4-Cl-KYN administration produced dose-related deficits in DNMTP accuracy that were more severe at the longer delays. In KYN-treated rats, these deficits were reversed to control levels by GAL or PAM-2 but not by DCS. In contrast, DCS eliminated performance deficits in 4-Cl-KYN-treated animals. CONCLUSIONS: These experiments reveal that both α7nAChR and NMDAR activity are necessary for normal WM accuracy. They provide substantive new support for the therapeutic potential of positive modulators at these two receptor sites in SZ and other major brain diseases.

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. OBJECTIVES: To investigate a possible causal relationship between acute stress, KYNA, and fear discrimination. METHODS: Adult rats were exposed to one of three acute stressors-predator odor, restraint, or inescapable foot shocks (ISS)-and KYNA in the prefrontal cortex was measured using microdialysis. Corticosterone was analyzed in a subset of rats. Another cohort underwent a fear discrimination procedure immediately after experiencing stress. Different auditory conditioned stimuli (CSs) were either paired with foot shock (CS+) or were non-reinforced (CS-). One week later, fear was assessed by re-exposing rats to each CS. Finally, to test whether stress-induced changes in KYNA causally impacted fear discrimination, a group of rats that received ISS were pre-treated with the selective KYNA synthesis inhibitor PF-04859989. RESULTS: ISS caused the greatest increase in circulating corticosterone levels and raised extracellular KYNA levels by ~ 85%. The two other stressors affected KYNA much less (< 25% increase). Moreover, only rats that received ISS were unable to discriminate between CS+ and CS-. PF-04859989 abolished the stress-induced KYNA increase and also prevented the impairment in fear discrimination in animals that experienced ISS. CONCLUSIONS: These findings demonstrate a causal connection between stress-induced KYNA increases and cognitive deficits. Pharmacological manipulation of KYNA synthesis therefore offers a novel approach to modulate cognitive processes in stress-related disorders.

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 (Δ9-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. Interestingly, the deleterious effects of prenatal cannabis use are similar to those observed in adult rats prenatally exposed to (L)-kynurenine, the direct bioprecursor of the neuroactive metabolite kynurenic acid (KYNA). We therefore investigated whether alterations in KYNA levels in the rat brain might play a role in the long-term consequences of prenatal cannabinoid exposure. Pregnant Wistar rats were treated daily with THC [5 mg/kg, p.o.] from gestational day (GD)5 through GD20. Using in vivo microdialysis in the medial prefrontal cortex, adult animals were then used to determine the extracellular levels of KYNA and glutamate. Compared to controls, extracellular basal KYNA levels were higher, and basal glutamate levels were lower, in prenatally THC-exposed rats. These rats also showed abnormal short-term memory. Following an additional acute challenge with a low dose of kynurenine (5 mg/kg i.p.) in adulthood, the increase in extracellular KYNA levels in the mPFC was more pronounced in in prenatally THC-exposed rats. These effects could be causally related to the cognitive dysfunction seen in prenatally THC-exposed rats. In the translational realm, these experiments raise the prospect of prevention of KYNA neosynthesis as a promising novel approach to combat some of the detrimental long-term effects of prenatal cannabis use.

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. Multivariate regression analysis was used to determine predictors of patient characteristics based on surgeon training. RESULTS: There were 361 surgeons who performed 39,932 cases of blepharoplasty in New York State from 2008 to 2016. When aggregated by surgeon training, there were significant differences among procedure times and total charges for blepharoplasty. On average, cases performed by ophthalmologists took 66.7 minutes and patients were charged $6,860; cases performed by otolaryngologists took 158.2 minutes and patients were charged $9,084; and cases performed by plastic surgeons took 131.8 minutes and patients were charged $11,028. Unlike plastic surgeons or otolaryngologists, ophthalmologists tended to have older patients and more male patients. Ophthalmologists were more likely to operate on patients with comorbidities as well as non-white patients (p < 0.0001). They were also significantly more likely to have patients with insurance coverage than self-pay (p < 0.0001). CONCLUSIONS: Demographic and surgical metrics of blepharoplasty cases performed by surgeons trained in otolaryngology and plastic surgery are similar. Ophthalmology-trained surgeons performed blepharoplasty on patients that were more likely to be older, male, non-white, and had insurance coverage. Ophthalmologist procedure time for blepharoplasty was also less than half of the procedure time of otolaryngologists and plastic surgeons.Blepharoplasty is a surgical procedure commonly performed by ophthalmologists, otolaryngologists, and plastic surgeons to address cosmetic concerns or visual impairment related to the eyelids.

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. Here, 19 new KMO inhibitors have been identified. One of these (1) is neuroprotective in a Drosophila HD model but is minimally brain penetrant in mice. The prodrug variant (1b) crosses the blood-brain barrier, releases 1 in the brain, thereby lowering levels of 3-hydroxykynurenine, a toxic KP metabolite linked to neurodegeneration. Prodrug 1b will advance development of targeted therapies against multiple neurodegenerative and neuroinflammatory diseases in which KP likely plays a role, including HD, Alzheimer's disease, and Parkinson's disease.

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. Fetal brain and liver, placenta, and maternal brain and liver were collected, and the tissues were incubated in vitroin the absence or presence of micromolar concentrations of kynurenine. KYNA and 3-HK were measured in the extracellular milieu. Basal and newly produced KYNA was detected in all cases. As KYNA formation exceeded 3-HK production by 2-3 orders of magnitude in the placenta and maternal brain, and as very little 3-HK neosynthesis was detectable in fetal brain tissue, detailed follow-up experiments focused on KYNA only. The fetal brain produced 3-4 times more KYNA than the maternal brain and placenta, though less than the maternal and fetal liver. No significant differences were observed when using tissues obtained on GD 14 and GD 18. Pharmacological inhibition of KYNA's main biosynthetic enzymes, kynurenine aminotransferase (KAT) I and KAT II, revealed qualitative and quantitative differences between the tissues, with a preferential role of KAT I in the fetal and maternal brain and of KAT II in the fetal and maternal liver. Findings using tissue slices from KAT II knockout mice confirmed these conclusions. Together, these results clarify the dynamics of KP metabolism during pregnancy and provide the basis for the conceptualization of interventions aimed at manipulating cerebral KP function in the prenatal period.

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. METHODS: A 1-year retrospective chart review (May 2016 to May 2017) of patients who underwent aesthetic oculoplastic Skype consults from 2 authors' practices was performed. The authors analyzed patient demographics, referral source, chief complaint, location of residence, length of consult, and conversion to face-to-face consultation and intervention. RESULTS: Seventy-nine patients (60 women and 19 men) underwent Skype evaluations. Mean age was 49 years. Sixty-four consults (81%) lasted 15 minutes or less. Referral sources included the internet (67%), another physician (19%), self-referral (7.5%), referred by former patients (4%), and social media sites (2.5%). Consultations were obtained for revision (49%), or first-time (30%) eyelid/eyebrow surgery, cosmetic ptosis surgery (6%), laser skin procedures (5%), cosmetic orbital decompression (5%), and lower eyelid fat prolapse (5%). Twenty patients (25%) followed-up with in-person consultation. Sixteen of these patients (80%) had surgical (56%) or nonsurgical (44%) interventions. CONCLUSIONS: Skype consults are an efficient, in-office modality to increase patient flow through the office, expand patient base, and generate income. In this report, 25% of Skype contacts followed-up with formal in-person consultations, of which 80% had surgical or nonsurgical interventions.