Publications by authors named "Robert Schwarcz"

146 Publications

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

Eur J Neurosci 2021 Sep 17;54(6):5968-5981. Epub 2021 Aug 17.

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, USA.

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.
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http://dx.doi.org/10.1111/ejn.15416DOI Listing
September 2021

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

Antioxidants (Basel) 2021 Jan 20;10(2). Epub 2021 Jan 20.

Neurochemistry and Behavior Laboratory, National Institute of Neurology and Neurosurgery "Manuel Velasco Suárez", Mexico City 14269, Mexico.

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 . 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 . 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.
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http://dx.doi.org/10.3390/antiox10020147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909398PMC
January 2021

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

Front Neurosci 2020 8;14:927. Epub 2020 Sep 8.

Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, United States.

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 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.
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http://dx.doi.org/10.3389/fnins.2020.00927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509407PMC
September 2020

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

Psychopharmacology (Berl) 2020 Jul 25;237(7):1931-1941. Epub 2020 Mar 25.

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, 55 Wade Avenue, Baltimore, MD, 21228, USA.

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.
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http://dx.doi.org/10.1007/s00213-020-05507-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308198PMC
July 2020

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

Psychopharmacology (Berl) 2020 Jun 11;237(6):1723-1735. Epub 2020 Mar 11.

Department of Psychology, The Ohio State University, Columbus, OH, USA.

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.
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http://dx.doi.org/10.1007/s00213-020-05495-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313359PMC
June 2020

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

Prog Neuropsychopharmacol Biol Psychiatry 2020 06 4;100:109883. Epub 2020 Feb 4.

Department of Life Sciences and Biotechnologies, University of Ferrara, Ferrara, Italy; Laboratory for the Technology of Advanced Therapies (LTTA Centre), University of Ferrara, Ferrara, Italy.

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. 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.
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http://dx.doi.org/10.1016/j.pnpbp.2020.109883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260707PMC
June 2020

The Impact of Submental Deoxycholic Acid Injections on Neck Surgery

J Drugs Dermatol 2019 Dec;18(12):1281

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.
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December 2019

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

Commun Biol 2019 24;2:271. Epub 2019 Jul 24.

1Manchester Institute of Biotechnology and School of Chemistry, The University of Manchester, Manchester, M1 7DN UK.

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 () is neuroprotective in a HD model but is minimally brain penetrant in mice. The prodrug variant () crosses the blood-brain barrier, releases in the brain, thereby lowering levels of 3-hydroxykynurenine, a toxic KP metabolite linked to neurodegeneration. Prodrug 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.
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http://dx.doi.org/10.1038/s42003-019-0520-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656724PMC
May 2020

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

Ophthalmic Plast Reconstr Surg 2020 Jan/Feb;36(1):26-29

Department of Otolaryngology-Head and Neck Surgery, Icahn School of Medicine at Mount Sinai, New York, New York, U.S.A.

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.
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http://dx.doi.org/10.1097/IOP.0000000000001448DOI Listing
March 2021

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

Dev Neurosci 2019 22;41(1-2):102-111. Epub 2019 May 22.

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, USA.

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.
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http://dx.doi.org/10.1159/000499736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732239PMC
March 2020

The Aesthetic Oculoplastic Surgery Video Teleconference Consult.

Aesthet Surg J 2019 06;39(7):714-718

Department of Ophthalmology, Division of Oculoplastic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA.

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.
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http://dx.doi.org/10.1093/asj/sjz058DOI Listing
June 2019

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

Dermatol Surg 2019 07;45(7):954-958

Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York.

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.

Objective: Our study investigated the utility of preinjection aspiration as a safety checkpoint for HA fillers through comparison of physiochemical and rheological properties in an in vitro model.

Materials And Methods: Whole blood was drawn from vacutainers using syringes containing 10 commonly used HA fillers. Each HA filler was examined with the plunger pulled back at volumes of 0.2 and 0.5 cc. The time required to visualize a flash was recorded. Data were compared using physiochemical and rheological properties, pullback volumes, and needle gauges.

Results: Using a multivariable regression model, HA concentration, elastic modulus (G'), viscous modulus (G″), and complex modulus (G*) had significant relationships with time to flash, whereas needle gauge and pullback volume did not. However, when comparing pullback volume using an appropriate paired analysis, 0.5 cc pullback volume had a significantly decreased mean time to flash than 0.2 cc.

Conclusion: Preinjection aspiration may have utility as a safety checkpoint for HA fillers. Practitioners may have to adjust pullback volume and waiting time to visualize the flash based on physiochemical and rheological properties.
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http://dx.doi.org/10.1097/DSS.0000000000001767DOI Listing
July 2019

Maternal genotype determines kynurenic acid levels in the fetal brain: Implications for the pathophysiology of schizophrenia.

J Psychopharmacol 2018 11 24;32(11):1223-1232. Epub 2018 Oct 24.

3 Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, USA.

Background: Several studies suggest a pathophysiologically relevant association between increased brain levels of the neuroinhibitory tryptophan metabolite kynurenic acid and cognitive dysfunctions in people with schizophrenia. Elevated kynurenic acid in schizophrenia may be secondary to a genetic alteration of kynurenine 3-monooxygenase, a pivotal enzyme in the kynurenine pathway of tryptophan degradation. In rats, prenatal exposure to kynurenine, the direct bioprecursor of kynurenic acid, induces cognitive impairments reminiscent of schizophrenia in adulthood, suggesting a developmental dimension to the link between kynurenic acid and schizophrenia.

Aim: The purpose of this study was to explore the possible impact of the maternal genotype on kynurenine pathway metabolism.

Methods: We exposed pregnant wild-type ( Kmo ) and heterozygous ( Kmo) mice to kynurenine (10 mg/day) during the last week of gestation and determined the levels of kynurenic acid and two other neuroactive kynurenine pathway metabolites, 3-hydroxykynurenine and quinolinic acid, in fetal brain and placenta on embryonic day 17/18.

Results: Maternal kynurenine treatment raised kynurenic acid levels significantly more in the brain of heterozygous offspring of Kmo than in the brain of Kmo offspring. Conversely, 3-hydroxykynurenine and quinolinic acid levels in the fetal brain tended to be lower in heterozygous animals derived from kynurenine-treated Kmo mice than in corresponding Kmo offspring. Genotype-related effects on the placenta were qualitatively similar but less pronounced. Kynurenine treatment also caused a preferential elevation in cerebral kynurenic acid levels in Kmo compared to Kmo dams.

Conclusions: The disproportionate kynurenic acid increase in the brain of Kmo animals indicates that the maternal Kmo genotype may play a key role in the pathophysiology of schizophrenia.
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http://dx.doi.org/10.1177/0269881118805492DOI Listing
November 2018

Inhibition of kynurenine aminotransferase II attenuates hippocampus-dependent memory deficit in adult rats treated prenatally with kynurenine.

Hippocampus 2019 02 4;29(2):73-77. Epub 2018 Dec 4.

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland.

A combination of genetic and environmental factors contributes to schizophrenia (SZ), a catastrophic psychiatric disorder with a hypothesized neurodevelopmental origin. Increases in the brain levels of the tryptophan metabolite kynurenic acid (KYNA), an endogenous antagonist of α7 nicotinic acetylcholine and NMDA receptors, have been implicated specifically in the cognitive deficits seen in persons with SZ. Here we evaluated this role of KYNA by adding the KYNA precursor kynurenine (100 mg/day) to chow fed to pregnant rat dams from embryonic day (ED) 15 to ED 22 (control: ECon; kynurenine treated: EKyn). Upon termination of the treatment, all rats received normal rodent chow until the animals were evaluated in adulthood (postnatal days 56-85). EKyn treatment resulted in increased extracellular KYNA and reduced extracellular glutamate in the hippocampus, measured by in vivo microdialysis, and caused impairments in hippocampus-dependent learning in adult rats. Acute administration of BFF816, a systemically active inhibitor of kynurenine aminotransferase II (KAT II), the major KYNA-synthesizing enzyme in the brain, normalized neurochemistry and prevented contextual memory deficits in adult EKyn animals. Collectively, these results demonstrate that acute inhibition of KYNA neosynthesis can overcome cognitive impairments that arise as a consequence of elevated brain KYNA in early brain development.
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http://dx.doi.org/10.1002/hipo.23040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367926PMC
February 2019

Maternal immune activation in rats blunts brain cytokine and kynurenine pathway responses to a second immune challenge in early adulthood.

Prog Neuropsychopharmacol Biol Psychiatry 2019 03 27;89:286-294. Epub 2018 Sep 27.

Laboratory of Behavioral Neuroimmunology, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA. Electronic address:

Maternal immune activation (MIA) with the viral mimic poly I:C provides an established rodent model for studying schizophrenia (SZ) and other human neurodevelopmental disorders. Postnatal infections are additional risk factors in SZ and may cumulatively contribute to the emergence of pathophysiology. Underlying mechanisms may involve metabolites of the kynurenine pathway (KP) of tryptophan degradation, which is readily induced by inflammatory stimuli. Here we compared the expression of selected cytokines and KP enzymes, and the levels of selected KP metabolites, in the brain of MIA offspring following a second, acute immune challenge with lipopolysaccharides (LPS) on postnatal day (PND) 35 (adolescence) or PND 60 (early adulthood). Assessed in adolescence, MIA did not alter the expression of pro-inflammatory cytokines (except TNF-α) or KP metabolite levels compared to controls, but substantially reduced the expression of the anti-inflammatory cytokines IL-4 and IL-10 and influenced the expression of two of the four KP enzymes examined (IDO1 and TDO2). LPS treatment caused distinct changes in the expression of pro- and anti-inflammatory cytokines, as well as KP enzymes in MIA offspring, but had no effect on KP metabolites compared to control rats. Several of these effects were blunted in MIA offspring receiving LPS on PND 60. Notably, LPS caused a significant reduction in brain kynurenine levels in these animals. Of relevance for SZ-related hypotheses, these results indicate that MIA leads to an increasingly defective, rather than an overactive, immune regulation of cerebral KP metabolism during the postnatal period.
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http://dx.doi.org/10.1016/j.pnpbp.2018.09.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249106PMC
March 2019

Astrocytic Mechanisms Involving Kynurenic Acid Control Δ-Tetrahydrocannabinol-Induced Increases in Glutamate Release in Brain Reward-Processing Areas.

Mol Neurobiol 2019 May 27;56(5):3563-3575. Epub 2018 Aug 27.

Behavioral Neuroscience Research Branch, Intramural Research Program, Department of Health and Human Services, National Institute on Drug Abuse, National Institutes of Health, 251 Bayview Blvd., Baltimore, MD, 21224, USA.

The reinforcing effects of Δ-tetrahydrocannabinol (THC) in rats and monkeys, and the reinforcement-related dopamine-releasing effects of THC in rats, can be attenuated by increasing endogenous levels of kynurenic acid (KYNA) through systemic administration of the kynurenine 3-monooxygenase inhibitor, Ro 61-8048. KYNA is a negative allosteric modulator of α7 nicotinic acetylcholine receptors (α7nAChRs) and is synthesized and released by astroglia, which express functional α7nAChRs and cannabinoid CB1 receptors (CB1Rs). Here, we tested whether these presumed KYNA autoreceptors (α7nAChRs) and CB1Rs regulate glutamate release. We used in vivo microdialysis and electrophysiology in rats, RNAscope in situ hybridization in brain slices, and primary culture of rat cortical astrocytes. Acute systemic administration of THC increased extracellular levels of glutamate in the nucleus accumbens shell (NAcS), ventral tegmental area (VTA), and medial prefrontal cortex (mPFC). THC also reduced extracellular levels of KYNA in the NAcS. These THC effects were prevented by administration of Ro 61-8048 or the CB1R antagonist, rimonabant. THC increased the firing activity of glutamatergic pyramidal neurons projecting from the mPFC to the NAcS or to the VTA in vivo. These effects were averted by pretreatment with Ro 61-8048. In vitro, THC elicited glutamate release from cortical astrocytes (on which we demonstrated co-localization of the CB1Rs and α7nAChR mRNAs), and this effect was prevented by KYNA and rimonabant. These results suggest a key role of astrocytes in interactions between the endocannabinoid system, kynurenine pathway, and glutamatergic neurotransmission, with ramifications for the pathophysiology and treatment of psychiatric and neurodegenerative diseases.
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http://dx.doi.org/10.1007/s12035-018-1319-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393222PMC
May 2019

Exercise Your Kynurenines to Fight Depression.

Trends Neurosci 2018 08;41(8):491-493

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21228, USA. Electronic address:

Kynurenines, the major degradative products of the essential amino acid tryptophan, may play critical roles in the pathophysiology of depressive disorders. In 2014, Agudelo and colleagues reported that exercise indirectly modulates the metabolism of kynurenines in skeletal muscle, which in turn influences the brain and enhances resilience to depression.
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http://dx.doi.org/10.1016/j.tins.2018.05.010DOI Listing
August 2018

Importance of kynurenine 3-monooxygenase for spontaneous firing and pharmacological responses of midbrain dopamine neurons: Relevance for schizophrenia.

Neuropharmacology 2018 08 5;138:130-139. Epub 2018 Jun 5.

Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden; Department of Physiology and Pharmacology, Karolinska Institute, Biomedicum 5C, 171 77, Stockholm, Sweden. Electronic address:

Kynurenine 3-monooxygenase (KMO) is an essential enzyme of the kynurenine pathway, converting kynurenine into 3-hydroxykynurenine. Inhibition of KMO increases kynurenine, resulting in elevated levels of kynurenic acid (KYNA), an endogenous N-methyl-d-aspartate and α*7-nicotinic receptor antagonist. The concentration of KYNA is elevated in the brain of patients with schizophrenia, possibly as a result of a reduced KMO activity. In the present study, using in vivo single cell recording techniques, we investigated the electrophysiological characteristics of ventral tegmental area dopamine (VTA DA) neurons and their response to antipsychotic drugs in a KMO knock-out (K/O) mouse model. KMO K/O mice exhibited a marked increase in spontaneous VTA DA neuron activity as compared to wild-type (WT) mice. Furthermore, VTA DA neurons showed clear-cut, yet qualitatively opposite, responses to the antipsychotic drugs haloperidol and clozapine in the two genotypes. The anti-inflammatory drug parecoxib successfully lowered the firing activity of VTA DA neurons in KMO K/O, but not in WT mice. Minocycline, an antibiotic and anti-inflammatory drug, produced no effect in this regard. Taken together, the present data further support the usefulness of KMO K/O mice for studying distinct aspects of the pathophysiology and pharmacological treatment of psychiatric disorders such as schizophrenia.
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http://dx.doi.org/10.1016/j.neuropharm.2018.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794148PMC
August 2018

Assessing and Modulating Kynurenine Pathway Dynamics in Huntington's Disease: Focus on Kynurenine 3-Monooxygenase.

Methods Mol Biol 2018 ;1780:397-413

Department of Genetics and Genome Biology, University of Leicester, Leicester, UK.

The link between disturbances in kynurenine pathway (KP) metabolism and Huntington's disease (HD) pathogenesis has been explored for a number of years. Several novel genetic and pharmacological tools have recently been developed to modulate key regulatory steps in the KP such as the reaction catalyzed by the enzyme kynurenine 3-monooxygenase (KMO). This insight has offered new options for exploring the mechanistic link between this metabolic pathway and HD, and provided novel opportunities for the development of candidate drug-like compounds. Here, we present an overview of the field, focusing on some novel approaches for interrogating the pathway experimentally.
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http://dx.doi.org/10.1007/978-1-4939-7825-0_18DOI Listing
February 2019

Salivary kynurenic acid response to psychological stress: inverse relationship to cortical glutamate in schizophrenia.

Neuropsychopharmacology 2018 07 18;43(8):1706-1711. Epub 2018 Apr 18.

Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, USA.

Frontal glutamatergic synapses are thought to be critical for adaptive, long-term stress responses. Prefrontal cortices, including the anterior cingulate cortex (ACC) contribute to stress perception and regulation, and are involved in top-down regulation of peripheral glucocorticoid and inflammatory responses to stress. Levels of kynurenic acid (KYNA) in saliva increase in response to psychological stress, and this stress-induced effect may be abnormal in people with schizophrenia. Here we test the hypothesis that ACC glutamatergic functioning may contribute to the stress-induced salivary KYNA response in schizophrenia. In 56 patients with schizophrenia and 58 healthy controls, our results confirm that levels of KYNA in saliva increase following psychological stress. The magnitude of the effect correlated negatively with proton magnetic resonance spectroscopy (MRS) glutamate + glutamine (r = -.31, p = .017) and glutamate (r = -0.27, p = .047) levels in the ACC in patients but not in the controls (all p ≥ .45). Although, a causal relationship cannot be ascertained in this cross-sectional study, these findings suggest a potentially meaningful link between central glutamate levels and kynurenine pathway response to stress in individuals with schizophrenia.
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http://dx.doi.org/10.1038/s41386-018-0072-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006286PMC
July 2018

Influence of plasma cytokines on kynurenine and kynurenic acid in schizophrenia.

Neuropsychopharmacology 2018 07 27;43(8):1675-1680. Epub 2018 Feb 27.

Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, USA.

Abnormalities in the kynurenine pathway (KP) of tryptophan degradation, leading to the dysfunction of neuroactive KP metabolites in the brain, have been implicated in the pathophysiology of schizophrenia (SZ). One plausible mechanism involves dysregulation of various pro-inflammatory cytokines associated with the disease, which affect indoleamine-2,3-dioxygenase (IDO), a key enzyme for tryptophan to kynurenine conversion. In order to test this hypothesis directly, we measured plasma levels of the major KP metabolites kynurenine and kynurenic acid (KYNA), as well as four major cytokines, in a sample of 106 SZ patients and 104 control participants. In contrast to the replicable findings of elevation of KYNA in the central nervous system in SZ, plasma levels of KYNA were significantly lower in SZ compared to controls (p = .004). Kynurenine levels were significantly correlated with levels of interferon-γ (p < .001), which is involved in the regulation of IDO, in both patients and controls. However, although patients had higher levels of interleukin-6 (IL-6) compared to controls (p = .012), IL-6 levels were not correlated with kynurenine or KYNA, and did not explain group differences in KYNA. Based on the lack of evidence that pro-inflammatory cytokines were significantly related to the KP abnormality in SZ despite an adequate sample size, further studies must consider alternative hypotheses to identify the origins of the KP abnormalities in SZ.
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http://dx.doi.org/10.1038/s41386-018-0038-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006321PMC
July 2018

Prenatal kynurenine treatment in rats causes schizophrenia-like broad monitoring deficits in adulthood.

Psychopharmacology (Berl) 2018 03 11;235(3):651-661. Epub 2017 Nov 11.

Maryland Psychiatric Research Center, University of Maryland School of Medicine, P.O. Box 21247, Baltimore, MD, 21228, USA.

Rationale: Elevated brain kynurenic acid (KYNA) levels are implicated in the pathology and neurodevelopmental pathogenesis of schizophrenia. In rats, embryonic treatment with kynurenine (EKyn) causes elevated brain KYNA levels in adulthood and cognitive deficits reminiscent of schizophrenia.

Objectives: Growing evidence suggests that people with schizophrenia have a narrowed attentional focus, and we aimed at establishing whether these abnormalities may be related to KYNA dysregulation.

Methods: To test whether EKyn rats display broad monitoring deficits, kynurenine was added to the chow of pregnant Wistar dams on embryonic days 15-22. As adults, 20 EKyn and 20 control rats were trained to stable performance on the five-choice serial reaction time task, requiring the localization of 1-s light stimuli presented randomly across five apertures horizontally arranged along a curved wall, equating the locomotor demands of reaching each hole.

Results: EKyn rats displayed elevated omission errors and reduced anticipatory responses relative to control rats, indicative of a lower response rate, and showed reduced locomotor activity. The ability to spread attention broadly was measured by parsing performance by stimulus location. Both groups displayed poorer stimulus detection with greater target location eccentricity, but this effect was significantly more pronounced in the EKyn group. Specifically, the groups differed in the spatial distribution of correct but not incorrect responses. This pattern cannot be explained by differences in response rate and is indicative of a narrowed attentional focus.

Conclusions: The findings suggest a potential etiology of broad monitoring deficits in schizophrenia, which may constitute a core cognitive deficit.
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http://dx.doi.org/10.1007/s00213-017-4780-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823752PMC
March 2018

Quantitative Analysis of Kynurenine Aminotransferase II in the Adult Rat Brain Reveals High Expression in Proliferative Zones and Corpus Callosum.

Neuroscience 2018 01 8;369:1-14. Epub 2017 Nov 8.

Laboratory of Behavioral Neuroimmunology, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA. Electronic address:

Kynurenic acid, a metabolite of the kynurenine pathway of tryptophan degradation, acts as an endogenous antagonist of alpha7 nicotinic and NMDA receptors and is implicated in a number of neurophysiological and neuropathological processes including cognition and neurodegenerative events. Therefore, kynurenine aminotransferase II (KAT II/AADAT), the enzyme responsible for the formation of the majority of neuroactive kynurenic acid in the brain, has prompted significant interest. Using immunohistochemistry, this enzyme was localized primarily in astrocytes throughout the adult rat brain, but detailed neuroanatomical studies are lacking. Here, we employed quantitative in situ hybridization to analyze the relative expression of KAT II mRNA in the brain of rats under normal conditions and 6 h after the administration of lipopolysaccharides (LPSs). Specific hybridization signals for KAT II were detected, with the highest expression in the subventricular zone (SVZ), the rostral migratory stream and the floor of the third ventricle followed by the corpus callosum and the hippocampus. This pattern of mRNA expression was paralleled by differential protein expression, determined by serial dilutions of antibodies (up to 1:1 million), and was confirmed to be primarily astrocytic in nature. The mRNA signal in the SVZ and the hippocampus was substantially increased by the LPS treatment without detectable changes elsewhere. These results demonstrate that KAT II is expressed in the rat brain in a region-specific manner and that gene expression is sensitive to inflammatory processes. This suggests an unrecognized role for kynurenic acid in the brain's germinal zones.
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http://dx.doi.org/10.1016/j.neuroscience.2017.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5766363PMC
January 2018

Prenatal Dynamics of Kynurenine Pathway Metabolism in Mice: Focus on Kynurenic Acid.

Dev Neurosci 2017 28;39(6):519-528. Epub 2017 Oct 28.

Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

The kynurenine pathway (KP), the major catabolic route of tryptophan in mammals, contains several neuroactive metabolites, including kynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK). KP metabolism, and especially the fate of KYNA, during pregnancy is poorly understood, yet it may play a significant role in the development of psychiatric disorders later in life. The present study was designed to investigate the prenatal features of KP metabolism in vivo, with special focus on KYNA. To this end, pregnant CD-1 mice were treated systemically with kynurenine (100 mg/kg), KYNA (10 mg/kg), or saline on embryonic day 18. As expected, administration of either kynurenine or KYNA increased KYNA levels in the maternal plasma and placenta. Maternal kynurenine treatment also raised kynurenine levels in the fetal plasma and brain, demonstrating the ability of this pivotal KP metabolite to cross the placenta and increase the levels of both KYNA and 3-HK in the fetal brain. In contrast, maternal administration of KYNA caused only a small, nonsignificant elevation in KYNA levels in fetal plasma and brain. Complementary experiments using an ex vivo placental perfusion procedure confirmed the significant transplacental transfer of kynurenine and demonstrated that only a very small fraction of maternal kynurenine is converted to KYNA in the placenta and released into the fetal compartment under physiological conditions. Jointly, these results help to clarify the contributions of the maternal circulation and the placenta to fetal KYNA in the late prenatal period.
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http://dx.doi.org/10.1159/000481168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338215PMC
September 2018

Preferential Disruption of Prefrontal GABAergic Function by Nanomolar Concentrations of the α7nACh Negative Modulator Kynurenic Acid.

J Neurosci 2017 08 20;37(33):7921-7929. Epub 2017 Jul 20.

Department of Cellular and Molecular Pharmacology, The Chicago Medical School at Rosalind Franklin University, North Chicago, Illinois 60064,

Increased concentrations of kynurenic acid (KYNA) in the prefrontal cortex (PFC) are thought to contribute to the development of cognitive deficits observed in schizophrenia. Although this view is consistent with preclinical studies showing a negative impact of prefrontal KYNA elevation on executive function, the mechanism underlying such a disruption remains unclear. Here, we measured changes in local field potential (LFP) responses to ventral hippocampal stimulation and conducted whole-cell patch-clamp recordings in brain slices to reveal how nanomolar concentrations of KYNA alter synaptic transmission in the PFC of male adult rats. Our data show that prefrontal infusions of KYNA attenuated the inhibitory component of PFC LFP responses, a disruption that resulted from local blockade of α7-nicotinic acetylcholine receptors (α7nAChR). At the cellular level, we found that the inhibitory action exerted by KYNA in the PFC occurred primarily at local GABAergic synapses through an α7nAChR-dependent presynaptic mechanism. As a result, the excitatory-inhibitory ratio of synaptic transmission becomes imbalanced in a manner that correlates highly with the level of GABAergic suppression by KYNA. Finally, prefrontal infusion of a GABAR positive allosteric modulator was sufficient to overcome the disrupting effect of KYNA and normalized the pattern of LFP inhibition in the PFC. Thus, the preferential inhibitory effect of KYNA on prefrontal GABAergic transmission could contribute to the onset of cognitive deficits observed in schizophrenia because proper GABAergic control of PFC output is one key mechanism for supporting such cortical functions. Brain kynurenic acid (KYNA) is an astrocyte-derived metabolite and its abnormal elevation in the prefrontal cortex (PFC) is thought to impair cognitive functions in individuals with schizophrenia. However, the mechanism underlying the disrupting effect of KYNA remains unclear. Here we found that KYNA biases the excitatory-inhibitory balance of prefrontal synaptic activity toward a state of disinhibition. Such disruption emerges as a result of a preferential suppression of local GABAergic transmission by KYNA via presynaptic inhibition of α7-nicotinic acetylcholine receptor signaling. Therefore, the degree of GABAergic dysregulation in the PFC could be a clinically relevant contributing factor for the onset of cognitive deficits resulting from abnormal increases of cortical KYNA.
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http://dx.doi.org/10.1523/JNEUROSCI.0932-17.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559765PMC
August 2017

Characterization of the Effects of L-4-Chlorokynurenine on Nociception in Rodents.

J Pain 2017 10 18;18(10):1184-1196. Epub 2017 Apr 18.

VistaGen Therapeutics, Inc, South San Francisco, California.

Upon systemic administration in rats, the prodrug L-4-chlorokynurenine (4-Cl-KYN; AV-101; VistaGen Therapeutics, Inc, South San Francisco, CA) is rapidly absorbed, actively transported across the blood-brain barrier, and converted in astrocytes to 7-chlorokynurenic acid (7-Cl-KYNA), a potent and specific antagonist of the glycine B coagonist site of the N-methyl-D-aspartate (NMDA) receptor. We examined the effects of 4-Cl-KYN in several rat models of hyperalgesia and allodynia and determined the concentrations of 4-Cl-KYN and newly produced 7-Cl-KYNA in serum, brain, and spinal cord. Adult male rats were given 4-Cl-KYN (56, 167, 500 mg/kg), the NMDA receptor antagonist MK-801 (.1, .3, 1.0 mg/kg), or gabapentin (33, 100, 300 mg/kg) intraperitoneally, and were then examined on rotarod, intraplantar formalin-evoked flinching, thermal escape in the normal and carrageenan-inflamed paw, and allodynia after sciatic nerve ligation. Our conclusions show that after systemic delivery, the highest 2 doses (167 and 500 mg/kg) of 4-Cl-KYN yielded brain concentrations of 7-Cl-KYNA exceeding its half maximal inhibitory concentration (IC) at the glycine B site and resulted in dose-dependent antihyperalgesia in the 4 models of facilitated processing associated with tissue inflammation and nerve injury. On the basis of the relative dose requirements for analgesic actions and side effect profiles from these experiments, 4-Cl-KYN is predicted to have antihyperalgesic efficacy and a therapeutic ratio equal to gabapentin and superior to MK-801.

Perspective: These studies show that systemic administration of the prodrug 4-Cl-KYN produces high central nervous system levels of 7-Cl-KYNA, a potent and highly selective antagonist of the NMDA receptor. Compared with other drugs tested, 4-Cl-KYN has robust antinociceptive effects with a better side effect profile, highlighting its potential for treating hyperpathic pain states.
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http://dx.doi.org/10.1016/j.jpain.2017.03.014DOI Listing
October 2017

Restraint Stress during Pregnancy Rapidly Raises Kynurenic Acid Levels in Mouse Placenta and Fetal Brain.

Dev Neurosci 2016 18;38(6):458-468. Epub 2017 Feb 18.

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.

Stressful events during pregnancy adversely affect brain development and may increase the risk of psychiatric disorders later in life. Early changes in the kynurenine (KYN) pathway (KP) of tryptophan (TRP) degradation, which contains several neuroactive metabolites, including kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), and quinolinic acid (QUIN), may constitute a molecular link between prenatal stress and delayed pathological consequences. To begin testing this hypothesis experimentally, we examined the effects of a 2-h restraint stress on KP metabolism in pregnant FVB/N mice on gestational day 17. TRP, KYN, KYNA, 3-HK, and QUIN levels were measured in maternal and fetal plasma and brain, as well as in the placenta, immediately after stress termination and 2 h later. In the same animals, we determined the activity of TRP 2,3-dioxygenase (TDO) in the maternal liver and in the placenta. Compared to unstressed controls, mostly transient changes in KP metabolism were observed in all of the tissues examined. Specifically, stress caused significant elevations of KYNA levels in the maternal plasma, placenta, and fetal brain, and also resulted in increased levels of TRP and KYN in the placenta, fetal plasma, and fetal brain. In contrast, 3-HK and QUIN levels remained unchanged from control values in all tissues at any time point. In the maternal liver, TDO activity was increased 2 h after stress cessation. Taken together, these findings indicate that an acute stress during the late gestational period preferentially affects the KYNA branch of KP metabolism in the fetal brain. Possible long-term consequences for postnatal brain development and pathology remain to be examined.
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http://dx.doi.org/10.1159/000455228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5462839PMC
January 2018

Adaptive and Behavioral Changes in Kynurenine 3-Monooxygenase Knockout Mice: Relevance to Psychotic Disorders.

Biol Psychiatry 2017 Nov 16;82(10):756-765. Epub 2016 Dec 16.

Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland. Electronic address:

Background: Kynurenine 3-monooxygenase converts kynurenine to 3-hydroxykynurenine, and its inhibition shunts the kynurenine pathway-which is implicated as dysfunctional in various psychiatric disorders-toward enhanced synthesis of kynurenic acid, an antagonist of both α7 nicotinic acetylcholine and N-methyl-D-aspartate receptors. Possibly as a result of reduced kynurenine 3-monooxygenase activity, elevated central nervous system levels of kynurenic acid have been found in patients with psychotic disorders, including schizophrenia.

Methods: In the present study, we investigated adaptive-and possibly regulatory-changes in mice with a targeted deletion of Kmo (Kmo) and characterized the kynurenine 3-monooxygenase-deficient mice using six behavioral assays relevant for the study of schizophrenia.

Results: Genome-wide differential gene expression analyses in the cerebral cortex and cerebellum of these mice identified a network of schizophrenia- and psychosis-related genes, with more pronounced alterations in cerebellar tissue. Kynurenic acid levels were also increased in these brain regions in Kmo mice, with significantly higher levels in the cerebellum than in the cerebrum. Kmo mice exhibited impairments in contextual memory and spent less time than did controls interacting with an unfamiliar mouse in a social interaction paradigm. The mutant animals displayed increased anxiety-like behavior in the elevated plus maze and in a light/dark box. After a D-amphetamine challenge (5 mg/kg, intraperitoneal), Kmo mice showed potentiated horizontal activity in the open field paradigm.

Conclusions: Taken together, these results demonstrate that the elimination of Kmo in mice is associated with multiple gene and functional alterations that appear to duplicate aspects of the psychopathology of several neuropsychiatric disorders.
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http://dx.doi.org/10.1016/j.biopsych.2016.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812460PMC
November 2017

Attenuating Nicotine Reinforcement and Relapse by Enhancing Endogenous Brain Levels of Kynurenic Acid in Rats and Squirrel Monkeys.

Neuropsychopharmacology 2017 Jul 31;42(8):1619-1629. Epub 2017 Jan 31.

Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, USA.

The currently available antismoking medications have limited efficacy and often fail to prevent relapse. Thus, there is a pressing need for newer, more effective treatment strategies. Recently, we demonstrated that enhancing endogenous levels of kynurenic acid (KYNA, a neuroinhibitory product of tryptophan metabolism) counteracts the rewarding effects of cannabinoids by acting as a negative allosteric modulator of α7 nicotinic receptors (α7nAChRs). As the effects of KYNA on cannabinoid reward involve nicotinic receptors, in the present study we used rat and squirrel monkey models of reward and relapse to examine the possibility that enhancing KYNA can counteract the effects of nicotine. To assess specificity, we also examined models of cocaine reward and relapse in monkeys. KYNA levels were enhanced by administering the kynurenine 3-monooxygenase (KMO) inhibitor, Ro 61-8048. Treatment with Ro 61-8048 decreased nicotine self-administration in rats and monkeys, but did not affect cocaine self-administration. In rats, Ro 61-8048 reduced the ability of nicotine to induce dopamine release in the nucleus accumbens shell, a brain area believed to underlie nicotine reward. Perhaps most importantly, Ro 61-8048 prevented relapse-like behavior when abstinent rats or monkeys were reexposed to nicotine and/or cues that had previously been associated with nicotine. Ro 61-8048 was also effective in monkey models of cocaine relapse. All of these effects of Ro 61-8048 in monkeys, but not in rats, were reversed by pretreatment with a positive allosteric modulator of α7nAChRs. These findings suggest that KMO inhibition may be a promising new approach for the treatment of nicotine addiction.
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http://dx.doi.org/10.1038/npp.2017.21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518900PMC
July 2017
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