Publications by authors named "Trevor W Stone"

87 Publications

TLR expression profiles are a function of disease status in rheumatoid arthritis and experimental arthritis.

J Autoimmun 2021 Mar 22;118:102597. Epub 2021 Jan 22.

Kennedy Institute for Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Oxford, OX3 7FY, UK.

The role of the innate immune system has been established in the initiation and perpetuation of inflammatory disease, but less attention has been paid to its role in the resolution of inflammation and return to homeostasis. Toll-like receptor (TLR) expression profiles were analysed in tissues with differing disease status in rheumatoid arthritis (RA), ankylosing spondylitis (AS), and in experimental arthritis. TLR gene expression was measured in whole blood and monocytes, before and after TNF blockade. In RA and osteoarthritis synovia, the expression of TLRs was quantified by standard curve qPCR. In addition, four distinct stages of disease were defined and validated in collagen-induced arthritis (CIA), the gold standard animal model for RA - pre-onset, early disease, late disease and immunised mice that were resistant to the development of disease. TLR expression was measured in spleens, lymph nodes, blood cells, liver and the paws (inflamed and unaffected). In RA whole blood, the expression of TLR1, 4 and 6 was significantly reduced by TNF blockade but the differences in TLR expression profiles between responders and non-responders were less pronounced than the differences between RA and AS patients. In RA non-responders, monocytes had greater TLR2 expression prior to therapy compared to responders. The expression of TLR1, 2, 4 and 8 was higher in RA synovium compared to control OA synovium. Circulating cytokine levels in CIA resistant mice were similar to naïve mice, but anti-collagen antibodies were similar to arthritic mice. Distinct profiles of inflammatory gene expression were mapped in paws and organs with differing disease status. TLR expression in arthritic paws tended to be similar in early and late disease, with TLR1 and 2 moderately higher in late disease. TLR expression in unaffected paws varied according to gene and disease status but was generally lower in resistant paws. Disease status-specific profiles of TLR expression were observed in spleens, lymph nodes, blood cells and the liver. Notably, TLR2 expression rose then fell in the transition from naïve to pre-onset to early arthritis. TLR gene expression profiles are strongly associated with disease status. In particular, increased expression in the blood precedes clinical manifestation.
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http://dx.doi.org/10.1016/j.jaut.2021.102597DOI Listing
March 2021

Gut microbiota-derived vitamins - underrated powers of a multipotent ally in psychiatric health and disease.

Prog Neuropsychopharmacol Biol Psychiatry 2021 Apr 9;107:110240. Epub 2021 Jan 9.

Department of Psychiatry, Medical University of Warsaw, Poland.

Despite the well-established roles of B-vitamins and their deficiencies in health and disease, there is growing evidence indicating a key role of those nutrients in functions of the central nervous system and in psychopathology. Clinical data indicate the substantial role of B-vitamins in various psychiatric disorders, including major depression, bipolar disorder, schizophrenia, autism, and dementia, including Alzheimer's and Parkinson's diseases. As enzymatic cofactors, B-vitamins are involved in many physiological processes such as the metabolism of glucose, fatty acids and amino acids, metabolism of tryptophan in the kynurenine pathway, homocysteine metabolism, synthesis and metabolism of various neurotransmitters and neurohormones including serotonin, dopamine, adrenaline, acetylcholine, GABA, glutamate, D-serine, glycine, histamine and melatonin. Those vitamins are highly involved in brain energetic metabolism and respiration at the cellular level. They have a broad range of anti-inflammatory, immunomodulatory, antioxidant and neuroprotective properties. Furthermore, some of those vitamins are involved in the regulation of permeability of the intestinal and blood-brain barriers. Despite the fact that a substantial amount of the above vitamins is acquired from various dietary sources, deficiencies are not uncommon, and it is estimated that micronutrient deficiencies affect about two billion people worldwide. The majority of gut-resident microbes and the broad range of bacteria available in fermented food, express genetic machinery enabling the synthesis and metabolism of B-vitamins and, consequently, intestinal microbiota and fermented food rich in probiotic bacteria are essential sources of B-vitamins for humans. All in all, there is growing evidence that intestinal bacteria-derived vitamins play a significant role in physiology and that dysregulation of the "microbiota-vitamins frontier" is related to various disorders. In this review, we will discuss the role of vitamins in mental health and explore the perspectives and potential of how gut microbiota-derived vitamins could contribute to mental health and psychiatric treatment.
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http://dx.doi.org/10.1016/j.pnpbp.2020.110240DOI Listing
April 2021

Postural instability years after stroke.

J Stroke Cerebrovasc Dis 2020 Sep 23;29(9):105038. Epub 2020 Jun 23.

Department of Rehabilitation, Institute of Neurorehabilitation, Sopron, Hungary. Electronic address:

Background: Following a stroke, balance disturbances often persist despite full recovery of the paretic side.

Aims: The aims were to determine how long postural instability could be detected after stroke and the differences in post-stroke patients under and above 65 years of age.

Methods: Static and dynamic posturography (passing weights from hand to hand around the body) measurements were performed on 29 patients with stroke after 3 ± 2.4 years (≤65 years) and 4.7 ± 3.3 years. (> 65 years) compared with 38 controls.

Results: Only the pathway and the velocity assessed by dynamic posturography were significantly higher (p < 0.05) in the younger group of patients compared with the controls. The older group of patients had significantly elevated parameters measured by both static (p < 0.01) and dynamic posturography (p < 0.05).

Conclusions: we conclude, using a sensitive and reproducible method to assess both static and dynamic adjustments to maintain balance, that postural instability is significantly greater in post-stroke patients than control subjects. This difference is demonstrable up to 4 years after stroke, despite full recovery of the affected side.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.105038DOI Listing
September 2020

IDO and Kynurenine Metabolites in Peripheral and CNS Disorders.

Front Immunol 2020 5;11:388. Epub 2020 Mar 5.

The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom.

The importance of the kynurenine pathway in normal immune system function has led to an appreciation of its possible contribution to autoimmune disorders such as rheumatoid arthritis. Indoleamine-2,3-dioxygenase (IDO) activity exerts a protective function, limiting the severity of experimental arthritis, whereas deletion or inhibition exacerbates the symptoms. Other chronic disorder with an inflammatory component, such as atherosclerosis, are also suppressed by IDO activity. It is suggested that this overall anti-inflammatory activity is mediated by a change in the relative production or activity of Th17 and regulatory T cell populations. Kynurenines may play an anti-inflammatory role also in CNS disorders such as Huntington's disease, Alzheimer's disease and multiple sclerosis, in which signs of inflammation and neurodegeneration are involved. The possibility is discussed that in Huntington's disease kynurenines interact with other anti-inflammatory molecules such as Human Lymphocyte Antigen-G which may be relevant in other disorders. Kynurenine involvement may account for the protection afforded to animals with cerebral malaria and trypanosomiasis when they are treated with an inhibitor of kynurenine-3-monoxygenase (KMO). There is some evidence that changes in IL-10 may contribute to this protection and the relationship between kynurenines and IL-10 in arthritis and other inflammatory conditions should be explored. In addition, metabolites of kynurenine downstream of KMO, such as anthranilic acid and 3-hydroxy-anthranilic acid can influence inflammation, and the ratio of these compounds is a valuable biomarker of inflammatory status although the underlying molecular mechanisms of the changes require clarification. Hence it is essential that more effort be expended to identify their sites of action as potential targets for drug development. Finally, we discuss increasing awareness of the epigenetic regulation of IDO, for example by DNA methylation, a phenomenon which may explain differences between individuals in their susceptibility to arthritis and other inflammatory disorders.
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http://dx.doi.org/10.3389/fimmu.2020.00388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066259PMC
March 2020

Dependence and Guidance Receptors-DCC and Neogenin-In Partial EMT and the Actions of Serine Proteases.

Authors:
Trevor W Stone

Front Oncol 2020 4;10:94. Epub 2020 Feb 4.

NDORMS, University of Oxford, Oxford, United Kingdom.

The Epithelial-Mesenchymal Transition (EMT) is an important concept in understanding the processes of oncogenesis, especially with respect to the relationship between cell proliferation and metastatic properties such as spontaneous cell motility, chemotaxic migration and tissue invasion. EMT is now recognized as a more complex phenomenon than an all-or-nothing event, in which different components of the EMT may have distinct roles in the physio-pathological regulation of cell function and which may in turn depend on differential interactions with cell constituents and metabolic products. This mini-review summarizes recent work on the induction of cancer properties in parallel with the presence of EMT activities in the presence of serine proteases, with the focus on those tumor suppressors known as "dependence" receptors such as neogenin and Deleted in Colorectal Cancer (DCC). It is concluded that various forms of partial EMT should be given more detailed investigation and consideration as the results could have valuable implications for the development of disease-specific and patient-specific therapies.
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http://dx.doi.org/10.3389/fonc.2020.00094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010924PMC
February 2020

IDO activation, inflammation and musculoskeletal disease.

Exp Gerontol 2020 03 26;131:110820. Epub 2019 Dec 26.

The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford OX3 7FY, UK. Electronic address:

The IDO/kynurenine pathway is now established as a major regulator of immune system function. The initial enzyme, indoleamine 2,3-dioxygenase (IDO1) is induced by IFNγ, while tryptophan-2,3-dioxygenase (TDO) is induced by corticosteroids. The pathway is therefore positioned to mediate the effects of systemic inflammation or stress-induced steroids on tissue function and its expression increases with age. Disorders of the musculoskeletal system are a common feature of ageing and many of these conditions are characterized by an inflammatory state. In inflammatory arthritis and related disorders, kynurenine protects against the development of disease, while inhibition or deletion of IDO1 increases its severity. The long-term regulation of autoimmune disorders may be influenced by the epigenetic modulation of kynurenine pathway genes, with recent data suggesting that methylation of IDO may be involved. Osteoporosis is also associated with abnormalities of the kynurenine pathway, reflected in an inversion of the ratio between blood levels of the metabolites anthranilic acid and 3-hydroxy-anthranilic acid. This review discusses evidence to date on the role of the IDO/kynurenine pathway and the highly prevalent age-related disorders of osteoporosis and rheumatoid arthritis and identifies key areas that require further research.
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http://dx.doi.org/10.1016/j.exger.2019.110820DOI Listing
March 2020

Does kynurenic acid act on nicotinic receptors? An assessment of the evidence.

Authors:
Trevor W Stone

J Neurochem 2020 03 24;152(6):627-649. Epub 2019 Nov 24.

Institute for Neuroscience and Psychology, University of Glasgow, Glasgow, G12 8QQ, UK.

As a major metabolite of kynurenine in the oxidative metabolism of tryptophan, kynurenic acid is of considerable biological and clinical importance as an endogenous antagonist of glutamate in the central nervous system. It is most active as an antagonist at receptors sensitive to N-methyl-D-aspartate (NMDA) which regulate neuronal excitability and plasticity, brain development and behaviour. It is also thought to play a causative role in hypo-glutamatergic conditions such as schizophrenia, and a protective role in several neurodegenerative disorders, notably Huntington's disease. An additional hypothesis, that kynurenic acid could block nicotinic receptors for acetylcholine in the central nervous system has been proposed as an alternative mechanism of action of kynurenate. However, the evidence for this alternative mechanism is highly controversial, partly because at least eight earlier studies concluded that kynurenic acid blocked NMDA receptors but not nicotinic receptors and five subsequent, independent studies designed to repeat the results have failed to do so. Many studies considered to support the alternative 'nicotinic' hypothesis have been based on the use of analogs of kynurenate such as 7-chloro-kynurenic acid, or putatively nicotinic modulators such as galantamine, but a detailed analysis of the pharmacology of these compounds suggests that the results have often been misinterpreted, especially since the pharmacology of galantamine itself has been disputed. This review examines the evidence in detail, with the conclusion that there is no confirmed, reliable evidence for an antagonist activity of kynurenic acid at nicotinic receptors. Therefore, since there is overwhelming evidence for kynurenate acting at ionotropic glutamate receptors, especially NMDAR glutamate and glycine sites, with some activity at GPR35 sites and Aryl Hydrocarbon Receptors, results with kynurenic acid should be interpreted only in terms of these confirmed sites of action.
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http://dx.doi.org/10.1111/jnc.14907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078985PMC
March 2020

Serine protease modulation of Dependence Receptors and EMT protein expression.

Cancer Biol Ther 2019 7;20(3):349-367. Epub 2018 Nov 7.

a College of Medical, Veterinary and Life Sciences , University of Glasgow , Glasgow , UK.

Expression of the tumour suppressor Deleted in Colorectal Cancer (DCC) and the related protein neogenin is reduced by the mammalian serine protease chymotrypsin or the bacterial serine protease subtilisin, with increased cell migration. The present work examines whether these actions are associated with changes in the expression of cadherins, β-catenin and vimentin, established markers of the Epithelial-Mesenchymal Transition (EMT) which has been linked with cell migration and tumour metastasis. The results confirm the depletion of DCC and neogenin and show that chymotrypsin and subtilisin also reduce expression of β-catenin in acutely prepared tissue sections but not in human mammary adenocarcinoma MCF-7 or MDA-MB-231 cells cultured in normal media, or primary normal human breast cells. A loss of β-catenin was also seen in low serum media but transfecting cells with a dcc-containing plasmid induced resistance. E-cadherin was not consistently affected but vimentin was induced by low serum-containing media and was increased by serine proteases in MCF-7 and MDA-MB-231 cells in parallel with increased wound closure. Vimentin might contribute to the promotion of cell migration. The results suggest that changes in EMT proteins depend on the cells or tissues concerned and do not parallel the expression of DCC and neogenin. The increased cell migration induced by serine proteases is not consistently associated with the expression of the EMT proteins implying either that the increased migration may be independent of EMT or supporting the view that EMT is not itself consistently related to migration. (241).
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http://dx.doi.org/10.1080/15384047.2018.1529109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370372PMC
May 2020

Long term follow-up study of non-invasive brain stimulation (NBS) (rTMS and tDCS) in Parkinson's disease (PD). Strong age-dependency in the effect of NBS.

Brain Res Bull 2018 09 26;142:78-87. Epub 2018 Jun 26.

Semmelweis University, Digital Health Department, Budapest, Hungary.

Background: Transcranial magnetic stimulation (rTMS) may influence the progression of PD compared with levodopa. The long term mind modification effect of repeated rTMS and tDCS is not known, nor are the predictors for the effect of NBS.

Objective/hypothesis: We hypothesized that the regularly repeated rTMS would decrease the development of PD. Later, the treatment protocol was completed with transcranial direct current stimulation (tDCS), supposing that there is an add-on effect. NBS may differently influence motor and mental aspects of the disease.

Methods: Thirty patients with PD were followed for 3.5 years in an open study. They were stimulated with 1 Hz rTMS every half year for 1.5 years. After that the tDCS was add to the stimulation over both sides of the cerebellum for the next 2 years. UPDRS, Trail Making Test and dual tests were used. The linear regression lines of score systems and percentage of yearly increment were counted, analyzed by ANOVA.

Results: The yearly progression rate for UPDRS total was 2% for 3.5 years, 0.6% ≤65 years, 3.6% >65 years. The increment was around zero during the rTMS + tDCS stimulations in patients ≤65 years. The slope of the equation showed the same tendency. The individual sensitivity to the NBS was high. tTMS and tDCS >65 yrs improved pathological executive function (p < 0.0001).

Conclusion: The motor ability in PD was maintained at the same level in patients ≤65 years with NBS for the 3.5 years in contrast to patients >65 years. The cognitive function of patients >65 yrs was favorable influenced by rTMS and tDCS. Age is the main predictor of the effect of NBS. rTMS and tDCS can slow the progression of PD without any side effects but in an age-dependent way.
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http://dx.doi.org/10.1016/j.brainresbull.2018.06.014DOI Listing
September 2018

Obesity and Cancer: Existing and New Hypotheses for a Causal Connection.

EBioMedicine 2018 Apr 27;30:14-28. Epub 2018 Feb 27.

Ashtead Hospital, The Warren, Ashtead, Surrey KT21 2SB, UK.

Existing explanations of obesity-associated cancer emphasise direct mutagenic effects of dietary components or hormonal imbalance. Some of these hypotheses are reviewed briefly, but recent evidence suggests a major role for chronic inflammation in cancer risk, possibly involving dietary content. These ideas include the inflammation-induced activation of the kynurenine pathway and its role in feeding and metabolism by activation of the aryl hydrocarbon receptor (AHR) and by modulating synaptic transmission in the brain. Evidence for a role of the kynurenine pathway in carcinogenesis then provides a potentially major link between obesity and cancer. A second new hypothesis is based on evidence that serine proteases can deplete cells of the tumour suppressors Deleted in Colorectal Cancer (DCC) and neogenin. These enzymes include mammalian chymotryptic proteases released by pro-inflammatory neutrophils and macrophages. Blood levels of chymotrypsin itself increase in parallel with food intake. The mechanistically similar bacterial enzyme subtilisin is widespread in the environment, animal probiotics, meat processing and cleaning products. Simple public health schemes in these areas, with selective serine protease inhibitors and AHR antagonists and could prevent a range of intestinal and other cancers.
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http://dx.doi.org/10.1016/j.ebiom.2018.02.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5952217PMC
April 2018

Microbial carcinogenic toxins and dietary anti-cancer protectants.

Cell Mol Life Sci 2017 07 25;74(14):2627-2643. Epub 2017 Feb 25.

Department of General Internal Medicine, Ashtead Hospital, Ashtead, Surrey, KT21 2SB, UK.

Several toxins are known which account for the ability of some bacteria to initiate or promote carcinogenesis. These ideas are summarised and evidence is discussed for more specific mechanisms involving chymotrypsin and the bacterial chymotryptic enzyme subtilisin. Subtilisin and Bacillus subtilis are present in the gut and environment and both are used commercially in agriculture, livestock rearing and meat processing. The enzymes deplete cells of tumour suppressors such as deleted in colorectal cancer (DCC) and neogenin, so their potential presence in the food chain might represent an important link between diet and cancer. Over-eating increases secretion of chymotrypsin which is absorbed from the gut and could contribute to several forms of cancer linked to obesity. Inhibition of these serine proteases by Bowman-Birk inhibitors in fruit and vegetables could account for some of the protective effects of a plant-rich diet. These interactions represent previously unknown non-genetic mechanisms for the modification of tumour suppressor proteins and provide a plausible explanation contributing to both the pro-oncogenic effects of meat products and the protective activity of a plant-rich diet. The data suggest that changes to farming husbandry and food processing methods to remove these sources of extrinsic proteases might significantly reduce the incidence of several cancers.
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http://dx.doi.org/10.1007/s00018-017-2487-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487888PMC
July 2017

Kynurenine Pathway Activation in Human African Trypanosomiasis.

J Infect Dis 2017 03;215(5):806-812

Department of Neurology, College of Medical, Veterinary, and Life Sciences, University of Glasgow, UK.

Background: The kynurenine pathway of tryptophan oxidation is associated with central nervous system (CNS) inflammatory pathways. Inhibition of this pathway ameliorates CNS inflammation in rodent models of the late (meningoencephalitic) stage of human African trypanosomiasis (HAT). In this study, we evaluate whether the kynurenine pathway is activated in clinical HAT and associated with CNS inflammatory responses.

Methods: We measured cerebrospinal fluid (CSF) tryptophan and kynurenine metabolite concentrations in patients infected with Trypanosoma brucei rhodesiense, using liquid chromatography-mass spectrometry.

Results: Kynurenine concentration in CSF was increased in both the early and late stages of disease, with a progressive increase in tryptophan oxidation associated with stage progression. Kynurenine pathway activation was associated with increases in neuroinflammatory markers, but there was no clear relationship to neurological symptoms.

Conclusions: CNS kynurenine pathway activation occurs during HAT, including cases prior to the current diagnostic cutoff for late-stage infection, providing evidence for early CNS involvement in HAT. Metabolite data demonstrate that the kynurenine-3-monooxygenase and kynurenine aminotransferase branches of the kynurenine pathway are active. The association between tryptophan oxidation and CNS inflammatory responses as measured by CSF interleukin 6 (IL-6) concentration supports a role of kynurenine metabolites in the inflammatory pathogenesis of late-stage HAT.
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http://dx.doi.org/10.1093/infdis/jiw623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388295PMC
March 2017

Quinolinic acid induces neuritogenesis in SH-SY5Y neuroblastoma cells independently of NMDA receptor activation.

Eur J Neurosci 2017 03 26;45(5):700-711. Epub 2017 Jan 26.

Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, West Medical Building, Glasgow, G12 8QQ, UK.

Glutamate and nicotinamide adenine dinucleotide (NAD ) have been implicated in neuronal development and several types of cancer. The kynurenine pathway of tryptophan metabolism includes quinolinic acid (QA) which is both a selective agonist at N-methyl-D-aspartate (NMDA) receptors and also a precursor for the formation of NAD . The effect of QA on cell survival and differentiation has therefore been examined on SH-SY5Y human neuroblastoma cells. Retinoic acid (RA, 10 μm) induced differentiation of SH-SY5Y cells into a neuronal phenotype showing neurite growth. QA (50-150 nm) also caused a concentration-dependent increase in the neurite/soma ratio, indicating differentiation. Both RA and QA increased expression of the neuronal marker β3-tubulin in whole-cell homogenates and in the neuritic fraction assessed using a neurite outgrowth assay. Expression of the neuronal proliferation marker doublecortin revealed that, unlike RA, QA did not decrease the number of mitotic cells. QA-induced neuritogenesis coincided with an increase in the generation of reactive oxygen species. Neuritogenesis was prevented by diphenylene-iodonium (an inhibitor of NADPH oxidase) and superoxide dismutase, supporting the involvement of reactive oxygen species. NMDA itself did not promote neuritogenesis and the NMDA antagonist dizocilpine (MK-801) did not prevent quinolinate-induced neuritogenesis, indicating that the effects of QA were independent of NMDA receptors. Nicotinamide caused a significant increase in the neurite/soma ratio and the expression of β3-tubulin in the neuritic fraction. Taken together, these results suggest that QA induces neuritogenesis by promoting oxidizing conditions and affecting the availability of NAD , independently of NMDA receptors.
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http://dx.doi.org/10.1111/ejn.13499DOI Listing
March 2017

The Gut-Brain Axis, BDNF, NMDA and CNS Disorders.

Neurochem Res 2016 Nov 23;41(11):2819-2835. Epub 2016 Aug 23.

Institute of Neurosciences and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, West Medical Building, Glasgow, G12 8QQ, UK.

Gastro-intestinal (GI) microbiota and the 'gut-brain axis' are proving to be increasingly relevant to early brain development and the emergence of psychiatric disorders. This review focuses on the influence of the GI tract on Brain-Derived Neurotrophic Factor (BDNF) and its relationship with receptors for N-methyl-D-aspartate (NMDAR), as these are believed to be involved in synaptic plasticity and cognitive function. NMDAR may be associated with the development of schizophrenia and a range of other psychopathologies including neurodegenerative disorders, depression and dementias. An analysis of the routes and mechanisms by which the GI microbiota contribute to the pathophysiology of BDNF-induced NMDAR dysfunction could yield new insights relevant to developing novel therapeutics for schizophrenia and related disorders. In the absence of GI microbes, central BDNF levels are reduced and this inhibits the maintenance of NMDAR production. A reduction of NMDAR input onto GABA inhibitory interneurons causes disinhibition of glutamatergic output which disrupts the central signal-to-noise ratio and leads to aberrant synaptic behaviour and cognitive deficits. Gut microbiota can modulate BDNF function in the CNS, via changes in neurotransmitter function by affecting modulatory mechanisms such as the kynurenine pathway, or by changes in the availability and actions of short chain fatty acids (SCFAs) in the brain. Interrupting these cycles by inducing changes in the gut microbiota using probiotics, prebiotics or antimicrobial drugs has been found promising as a preventative or therapeutic measure to counteract behavioural deficits and these may be useful to supplement the actions of drugs in the treatment of CNS disorders.
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http://dx.doi.org/10.1007/s11064-016-2039-1DOI Listing
November 2016

Selective depletion of tumour suppressors Deleted in Colorectal Cancer (DCC) and neogenin by environmental and endogenous serine proteases: linking diet and cancer.

BMC Cancer 2016 10 6;16(1):772. Epub 2016 Oct 6.

College of Medical, Veterinary and Life Sciences, West Medical Building, University of Glasgow, Glasgow, G12 8QQ, UK.

Background: The related tumour suppressor proteins Deleted in Colorectal Cancer (DCC) and neogenin are absent or weakly expressed in many cancers, whereas their insertion into cells suppresses oncogenic behaviour. Serine proteases influence the initiation and progression of cancers although the mechanisms are unknown.

Methods: The effects of environmental (bacterial subtilisin) and endogenous mammalian (chymotrypsin) serine proteases were examined on protein expression in fresh, normal tissue and human neuroblastoma and mammary adenocarcinoma lines. Cell proliferation and migration assays (chemoattraction and wound closure) were used to examine cell function. Cells lacking DCC were transfected with an ectopic dcc plasmid.

Results: Subtilisin and chymotrypsin selectively depleted DCC and neogenin from cells at nanomolar concentrations without affecting related proteins. Cells showed reduced adherence and increased migration, but after washing they re-attached within 24 h, with recovery of protein expression. These effects are induced by chymotryptic activity as they are prevented by chymostatin and the soybean Bowman-Birk inhibitor typical of many plant protease inhibitors.

Conclusions: Bacillus subtilis, which secretes subtilisin is widely present in soil, the environment and the intestinal contents, while subtilisin itself is used in meat processing, animal feed probiotics and many household cleaning agents. With chymotrypsin present in chyme, blood and tissues, these proteases may contribute to cancer development by depleting DCC and neogenin. Blocking their activity by Bowman-Birk inhibitors may explain the protective effects of a plant diet. Our findings identify a potential non-genetic contribution to cancer cell behaviour which may explain both the association of processed meats and other factors with cancer incidence and the protection afforded by plant-rich diets, with significant implications for cancer prevention.
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http://dx.doi.org/10.1186/s12885-016-2795-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5054602PMC
October 2016

Kynurenine pathway metabolism following prenatal KMO inhibition and in Mecp2 mice, using liquid chromatography-tandem mass spectrometry.

Neurochem Int 2016 11 10;100:110-119. Epub 2016 Sep 10.

Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK. Electronic address:

To quantify the full range of tryptophan metabolites along the kynurenine pathway, a liquid chromatography - tandem mass spectrometry method was developed and used to analyse brain extracts of rodents treated with the kynurenine-3-mono-oxygenase (KMO) inhibitor Ro61-8048 during pregnancy. There were significant increases in the levels of kynurenine, kynurenic acid, anthranilic acid and 3-hydroxy-kynurenine (3-HK) in the maternal brain after 5 h but not 24 h, while the embryos exhibited high levels of kynurenine, kynurenic acid and anthranilic acid after 5 h which were maintained at 24 h post-treatment. At 24 h there was also a strong trend to an increase in quinolinic acid levels (P = 0.055). No significant changes were observed in any of the other kynurenine metabolites. The results confirm the marked increase in the accumulation of some neuroactive kynurenines when KMO is inhibited, and re-emphasise the potential importance of changes in anthranilic acid. The prolonged duration of metabolite accumulation in the embryo brains indicates a trapping of compounds within the embryonic CNS independently of maternal levels. When brains were examined from young mice heterozygous for the meCP2 gene - a potential model for Rett syndrome - no differences were noted from control mice, suggesting that the proposed roles for kynurenines in autism spectrum disorder are not relevant to Rett syndrome, supporting its recognition as a distinct, independent, condition.
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http://dx.doi.org/10.1016/j.neuint.2016.09.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5115650PMC
November 2016

Dependence receptor involvement in subtilisin-induced long-term depression and in long-term potentiation.

Neuroscience 2016 Nov 31;336:49-62. Epub 2016 Aug 31.

Institute of Neurosciences and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.

The serine protease subtilisin induces a form of long-term depression (LTD) which is accompanied by a reduced expression of the axo-dendritic guidance molecule Unco-ordinated-5C (Unc-5C). One objective of the present work was to determine whether a loss of Unc-5C function contributed to subtilisin-induced LTD by using Unc-5C antibodies in combination with the pore-forming agents Triton X-100 (0.005%) or streptolysin O in rat hippocampal slices. In addition we have assessed the effect of subtilisin on the related dependence receptor Deleted in Colorectal Cancer (DCC) and used antibodies to this protein for functional studies. Field excitatory postsynaptic potentials (fEPSPs) were analyzed in rat hippocampal slices and protein extracts were used for Western blotting. Subtilisin produced a greater loss of DCC than of Unc-5C, but the antibodies had no effect on resting excitability or fEPSPs and did not modify subtilisin-induced LTD. However, antibodies to DCC but not Unc-5C did reduce the amplitude of theta-burst long-term potentiation (LTP). In addition, two inhibitors of endocytosis - dynasore and tat-gluR2(3Y) - were tested and, although the former compound had no effect on neurophysiological responses, tat-gluR2(3Y) did reduce the amplitude of subtilisin-induced LTD without affecting the expression of DCC or Unc-5C but with some loss of PostSynaptic Density Protein-95. The results support the view that the dependence receptor DCC may be involved in LTP and suggest that the endocytotic removal of a membrane protein or proteins may contribute to subtilisin-induced LTD, although it appears that neither Unc-5C nor DCC are involved in this process.
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http://dx.doi.org/10.1016/j.neuroscience.2016.08.043DOI Listing
November 2016

The kynurenine pathway: Towards metabolic equilibrium.

Neuropharmacology 2017 01 24;112(Pt B):235-236. Epub 2016 Aug 24.

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

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http://dx.doi.org/10.1016/j.neuropharm.2016.08.029DOI Listing
January 2017

The kynurenine pathway and the brain: Challenges, controversies and promises.

Neuropharmacology 2017 Jan 7;112(Pt B):237-247. Epub 2016 Aug 7.

Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.

Research on the neurobiology of the kynurenine pathway has suffered years of relative obscurity because tryptophan degradation, and its involvement in both physiology and major brain diseases, was viewed almost exclusively through the lens of the well-established metabolite serotonin. With increasing recognition that kynurenine and its metabolites can affect and even control a variety of classic neurotransmitter systems directly and indirectly, interest is expanding rapidly. Moreover, kynurenine pathway metabolism itself is modulated in conditions such as infection and stress, which are known to induce major changes in well-being and behaviour, so that kynurenines may be instrumental in the etiology of psychiatric and neurological disorders. It is therefore likely that the near future will not only witness the discovery of additional physiological and pathological roles for brain kynurenines, but also ever-increasing interest in drug development based on these roles. In particular, targeting the kynurenine pathway with new specific agents may make it possible to prevent disease by appropriate pharmacological or genetic manipulations. The following overview focuses on areas of kynurenine research which are either controversial, of major potential therapeutic interest, or just beginning to receive the degree of attention which will clarify their relevance to neurobiology and medicine. It also highlights technical issues so that investigators entering the field, and new research initiatives, are not misdirected by inappropriate experimental approaches or incorrect interpretations at this time of skyrocketing interest in the subject matter. This article is part of the Special Issue entitled 'The Kynurenine Pathway in Health and Disease'.
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http://dx.doi.org/10.1016/j.neuropharm.2016.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5803785PMC
January 2017

Tryptophan and kynurenines: continuing to court controversy.

Authors:
Trevor W Stone

Clin Sci (Lond) 2016 08;130(15):1335-7

Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, West Medical Building, University of Glasgow, Glasgow G12 8QQ, U.K.

The role of the amino acid tryptophan in the generation of 5-hydroxy-tryptamine (5-HT) has been expanded over the past 30 years with recognition that its oxidation by indoleamine-2,3-dioxygenase (IDO) results in the formation of kynurenine and metabolites which regulate neuronal excitability, psychiatric status, immune cell activity and balance, and probably implantation and the development of embryos. While the amount of work on this kynurenine pathway continues to accelerate, it is important that disagreements about results, differences of interpretation or problems with technical issues are presented openly and discussed thoroughly so that new research is not mis-led in ways that could have been foreseen. In this issue of Clinical Science, Badawy et al. discuss in depth two opposing views of how changes in tryptophan availability or utilisation bring about their effects on cell function. The original concept that local depletion of tryptophan is responsible seems to be less attractive than the view that kynurenine and its metabolites have direct, potent actions on cells. This conclusion not only clarifies our understanding of the importance of tryptophan metabolism to kynurenine but also raises the possibility that the actions of those metabolites could be novel targets for the development of agonists and antagonists with a range of medical implications.
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http://dx.doi.org/10.1042/CS20160294DOI Listing
August 2016

Protection by the flavonoids quercetin and luteolin against peroxide- or menadione-induced oxidative stress in MC3T3-E1 osteoblast cells.

Nat Prod Res 2015 26;29(12):1127-32. Epub 2014 Nov 26.

a College of Medical, Veterinary & Life Sciences, Institute of Neuroscience and Psychology, University of Glasgow , Glasgow G12 8QQ , UK.

Potential protective effects of the flavonoids quercetin and luteolin have been examined against the oxidative stress of MC3T3-E1 osteoblast-like cells. Although hydrogen peroxide and menadione reduced cell viability, the toxicity was prevented by desferrioxamine or catalase but not superoxide dismutase, suggesting the involvement of hydrogen peroxide in both cases. Quercetin and luteolin reduced the oxidative damage, especially that caused by hydrogen peroxide. When cultures were pre-incubated with quercetin or luteolin, protection was reduced or lost. Protection was also reduced when a 24 h pre-incubation with the flavonoids was followed by exposure to menadione alone. Pretreating cultures with luteolin impaired protection by quercetin, whereas quercetin pretreatment did not affect protection by luteolin. It is concluded that quercetin and luteolin suppress oxidative damage to MC3T3-E1 cells, especially caused by peroxide. The reduction in protection by pretreatment implies a down-regulation of part of the toxic transduction pathway.
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http://dx.doi.org/10.1080/14786419.2014.980252DOI Listing
March 2016

Modified neocortical and cerebellar protein expression and morphology in adult rats following prenatal inhibition of the kynurenine pathway.

Brain Res 2014 Aug 21;1576:1-17. Epub 2014 Jun 21.

Institute of Neuroscience and Psychology, West Medical Building, University of Glasgow, Glasgow G12 8QQ, UK. Electronic address:

Inhibition of the kynurenine pathway of tryptophan metabolism during gestation can lead to changes in synaptic transmission, neuronal morphology and plasticity in the rat hippocampus. This suggests a role for the kynurenine pathway in early brain development, probably caused by kynurenine modulation of N-methyl-d-aspartate (NMDA) glutamate receptors which are activated by the tryptophan metabolite quinolinic acid and blocked by kynurenic acid. We have now examined samples of neocortex and cerebellum of adult animals to assess the effects of a prenatally administered kynurenine-3-monoxygenase inhibitor (Ro61-8048) on protein and mRNA expression, dendritic structure and immuno-histochemistry. No changes were seen in mRNA expression using quantitative real-time polymerase chain reaction. Changes were detected in the expression of several proteins including the GluN2A subunit, unco-ordinated-5H3 (unc5H3), doublecortin, cyclo-oxygenase, sonic hedgehog and Disrupted in schizophrenia-1 (DISC1), although no differences in immunoreactive cell numbers were observed. In the midbrain, dependence receptor expression was also changed. The numbers and lengths of individual dendritic regions were not changed but there were significant increases in the overall complexity values of apical and basal dendritic trees. The data support the hypothesis that constitutive kynurenine metabolism plays a critical role in early, embryonic brain development, although fewer effects are produced in the neocortex and cerebellum than in the hippocampus and the nature of the changes seen are qualitatively different. The significant changes in DISC1 and unc5H3 may be relevant to cerebellar dysfunction and schizophrenia respectively, in which these proteins have been previously implicated.
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http://dx.doi.org/10.1016/j.brainres.2014.06.016DOI Listing
August 2014

Prenatal inhibition of the kynurenine pathway leads to structural changes in the hippocampus of adult rat offspring.

Eur J Neurosci 2014 May 19;39(10):1558-71. Epub 2014 Mar 19.

Institute of Neuroscience and Psychology, West Medical Building, University of Glasgow, Glasgow, G12 8QQ, UK.

Glutamate receptors for N-methyl-d-aspartate (NMDA) are involved in early brain development. The kynurenine pathway of tryptophan metabolism includes the NMDA receptor agonist quinolinic acid and the antagonist kynurenic acid. We now report that prenatal inhibition of the pathway in rats with 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulphonamide (Ro61-8048) produces marked changes in hippocampal neuron morphology, spine density and the immunocytochemical localisation of developmental proteins in the offspring at postnatal day 60. Golgi-Cox silver staining revealed decreased overall numbers and lengths of CA1 basal dendrites and secondary basal dendrites, together with fewer basal dendritic spines and less overall dendritic complexity in the basal arbour. Fewer dendrites and less complexity were also noted in the dentate gyrus granule cells. More neurons containing the nuclear marker NeuN and the developmental protein sonic hedgehog were detected in the CA1 region and dentate gyrus. Staining for doublecortin revealed fewer newly generated granule cells bearing extended dendritic processes. The number of neuron terminals staining for vesicular glutamate transporter (VGLUT)-1 and VGLUT-2 was increased by Ro61-8048, with no change in expression of vesicular GABA transporter or its co-localisation with vesicle-associated membrane protein-1. These data support the view that constitutive kynurenine metabolism normally plays a role in early embryonic brain development, and that interfering with it has profound consequences for neuronal structure and morphology, lasting into adulthood.
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http://dx.doi.org/10.1111/ejn.12535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4368408PMC
May 2014

Prenatal activation of maternal TLR3 receptors by viral-mimetic poly(I:C) modifies GluN2B expression in embryos and sonic hedgehog in offspring in the absence of kynurenine pathway activation.

Immunopharmacol Immunotoxicol 2013 Oct 28;35(5):581-93. Epub 2013 Aug 28.

Institute for Neuroscience and Psychology, University of Glasgow, West Medical Building , Glasgow , United Kingdom and.

Activation of the immune system during pregnancy is believed to lead to psychiatric and neurological disorders in the offspring, but the molecular changes responsible are unknown. Polyinosinic:polycytidylic acid (poly(I:C)) is a viral-mimetic double-stranded RNA complex which activates Toll-Like-Receptor-3 and can activate the metabolism of tryptophan through the oxidative kynurenine pathway to compounds that modulate activity of glutamate receptors. The aim was to determine whether prenatal administration of poly(I:C) affects the expression of neurodevelopmental proteins in the offspring and whether such effects were mediated via the kynurenine pathway. Pregnant rats were treated with poly(I:C) during late gestation and the offspring were allowed to develop to postnatal day 21 (P21). Immunoblotting of the brains at P21 showed decreased expression of sonic hedgehog, a key protein in dopaminergic neuronal maturation. Expression of α-synuclein was decreased, while tyrosine hydroxylase was increased. Disrupted in Schizophrenia-1 (DISC-1) and 5-HT2C receptor levels were unaffected, as were the dependence receptors Unc5H1, Unc5H3 and Deleted in Colorectal Cancer (DCC), the inflammation-related transcription factor NFkB and the inducible oxidative enzyme cyclo-oxygenase-2 (COX-2). An examination of embryo brains 5 h after maternal poly(I:C) showed increased expression of GluN2B, with reduced doublecortin and DCC but no change in NFkB. Despite altered protein expression, there were no changes in the kynurenine pathway. The results show that maternal exposure to poly(I:C) alters the expression of proteins in the embryos and offspring which may affect the development of dopaminergic function. The oxidation of tryptophan along the kynurenine pathway is not involved in these effects.
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http://dx.doi.org/10.3109/08923973.2013.828745DOI Listing
October 2013

The kynurenine pathway as a therapeutic target in cognitive and neurodegenerative disorders.

Br J Pharmacol 2013 Jul;169(6):1211-27

Institute of Neuroscience & Psychology, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, UK.

Understanding the neurochemical basis for cognitive function is one of the major goals of neuroscience, with a potential impact on the diagnosis, prevention and treatment of a range of psychiatric and neurological disorders. In this review, the focus will be on a biochemical pathway that remains under-recognized in its implications for brain function, even though it can be responsible for moderating the activity of two neurotransmitters fundamentally involved in cognition - glutamate and acetylcholine. Since this pathway - the kynurenine pathway of tryptophan metabolism - is induced by immunological activation and stress, it also stands in a unique position to mediate the effects of environmental factors on cognition and behaviour. Targeting the pathway for new drug development could, therefore, be of value not only for the treatment of existing psychiatric conditions, but also for preventing the development of cognitive disorders in response to environmental pressures.
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http://dx.doi.org/10.1111/bph.12230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3831703PMC
July 2013

Prenatal inhibition of the tryptophan-kynurenine pathway alters synaptic plasticity and protein expression in the rat hippocampus.

Brain Res 2013 Apr 24;1504:1-15. Epub 2013 Jan 24.

Institute for Neuroscience and Psychology, University of Glasgow, West Medical Building, Glasgow G12 8QQ, UK.

Glutamate receptors sensitive to N-methyl-d-aspartate (NMDA) are important in early brain development, influencing cell proliferation and migration, neuritogenesis, axon guidance and synapse formation. The kynurenine pathway of tryptophan metabolism includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at these receptors. Rats were treated in late gestation with 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]-benzene-sulphonamide (Ro61-8048), an inhibitor of kynurenine-3-monoxygenase which diverts kynurenine metabolism to kynurenic acid. Within 5h of drug administration, there was a significant decrease in GluN2A expression and increased GluN2B in the embryo brains, with changes in sonic hedgehog at 24h. When injected dams were allowed to litter normally, the brains of offspring were removed at postnatal day 21 (P21). Recordings of hippocampal field excitatory synaptic potentials (fEPSPs) showed that prenatal exposure to Ro61-8048 increased neuronal excitability and paired-pulse facilitation. Long-term potentiation was also increased, with no change in long-term depression. At this time, levels of GluN2A, GluN2B and postsynaptic density protein PSD-95 were all increased. Among several neurodevelopmental proteins, the expression of sonic hedgehog was increased, but DISC1 and dependence receptors were unaffected, while raised levels of doublecortin and Proliferating Cell Nuclear Antigen (PCNA) suggested increased neurogenesis. The results reveal that inhibiting the kynurenine pathway in utero leads to molecular and functional synaptic changes in the embryos and offspring, indicating that the pathway is active during gestation and plays a significant role in the normal early development of the embryonic and neonatal nervous system.
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http://dx.doi.org/10.1016/j.brainres.2013.01.031DOI Listing
April 2013

An expanding range of targets for kynurenine metabolites of tryptophan.

Trends Pharmacol Sci 2013 Feb 1;34(2):136-43. Epub 2012 Nov 1.

Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.

The kynurenine pathway of tryptophan metabolism accounts for most of the tryptophan that is not committed to protein synthesis and includes compounds active in the nervous and immune systems. Kynurenine acts on the aryl hydrocarbon receptor, affecting the metabolism of xenobiotics and promoting carcinogenesis. Quinolinic acid is an agonist at N-methyl-D-aspartate receptors (NMDARs), but is also pro-oxidant, has immunomodulatory actions, and promotes the formation of hyperphosphorylated tau proteins. Kynurenic acid blocks NMDARs and α7-homomeric nicotinic cholinoceptors and is also an agonist at the orphan G-protein-coupled receptor GPR35. 3-Hydroxykynurenine and 3-hydroxyanthranilic acid have pronounced redox activity and regulate T cell function. Cinnabarinic acid can activate metabotropic glutamate receptors. This review highlights the increasing range of molecular targets for components of the kynurenine pathway in both the nervous and immune systems in relation to their relevance to disease and drug development.
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http://dx.doi.org/10.1016/j.tips.2012.09.006DOI Listing
February 2013

Effects of ethylenediamine in rodent models of seizure, motor coordination and anxiety.

Brain Res 2012 Sep 20;1473:155-60. Epub 2012 Jul 20.

Faculty of Medical Sciences, University of the West Indies, St Augustine, Trinidad and Tobago.

Ethylenediamine (EDA) activates GABA(A) receptors via both direct and indirect mechanisms. EDA has been shown to reduce seizures caused by systemic injection of proconvulsants in an animal model of generalized tonic-clonic seizures. However, there does not appear to have been any report on the effects of EDA in other seizure models. Hence, we used male Sprague-Dawley rats to test the effects of EDA on topically applied bicuculline (a model of simple partial seizures) and on maximal electroshock (MES, a model of generalized tonic-clonic seizures). We also examined the effects of EDA on motor coordination using a rotarod treadmill, and its potential anxiolytic properties using an elevated plus maze (EPM). EDA at concentrations of 50 μM and above reduced the frequency of epileptiform spikes on an electrocorticogram in a concentration-dependent manner. EDA at 100 and 1000 mg/kg i.p. increased the threshold for inducing limb extension on the MES. EDA did not affect the time spent by rats on the rotarod at 10 or 100mg/kg, but significantly reduced the time spent at doses of 1000 mg/kg. In the EPM, EDA at 10 or 100mg/kg significantly increased the frequency of entries and time spent in the open arms. We conclude that EDA has antiepileptic and anxiolytic activity at doses that do not affect motor coordination.
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http://dx.doi.org/10.1016/j.brainres.2012.07.019DOI Listing
September 2012

A novel dihydro-pyrazolo(3,4d)(1,2,4)triazolo(1,5a)pyrimidin-4-one (AJ23) is an antagonist at adenosine A(1) receptors and enhances consolidation of step-down avoidance.

Behav Brain Res 2012 Oct 28;234(2):184-91. Epub 2012 Jun 28.

Institute of Pharmacy and Biological Sciences, University of Strathclyde, Glasgow, G4 0NR, UK.

Adenosine A(1) receptor antagonists are of potential value in the treatment of cognitive dysfunction. We have developed compound AJ23 (7-methyl-1-phenyl-1,8-dihydro-pyrazolo-(3,4d)(1,2,4)-triazolo(1,5a)-pyrimidin-4-one) as a novel, non-xanthine based antagonist at A(1) receptors. It has micromolar affinity at human A(1) receptors with a 45-fold selectivity for A(1) over A(2A) receptors and little affinity for many other receptors and transporters tested in a screening panel. AJ23 blocks A(1) receptors in the rat hippocampus, increasing the baseline size of excitatory post-synaptic potentials and blocking the inhibitory effects of adenosine. When administered directly into the rodent hippocampus this compound improves consolidation in a step-down avoidance learning task. The results suggest that AJ23 or derivatives may represent possible leads for further chemical development towards a chemically novel group of antagonists at A(1) receptors with potential value as cognitive enhancers.
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http://dx.doi.org/10.1016/j.bbr.2012.06.023DOI Listing
October 2012

Prenatal activation of Toll-like receptors-3 by administration of the viral mimetic poly(I:C) changes synaptic proteins, N-methyl-D-aspartate receptors and neurogenesis markers in offspring.

Mol Brain 2012 Jun 9;5:22. Epub 2012 Jun 9.

Institute for Neuroscience and Psychology, University of Glasgow, West Medical Building, Glasgow, G12 8QQ, UK.

Background: There is mounting evidence for a neurodevelopmental basis for disorders such as autism and schizophrenia, in which prenatal or early postnatal events may influence brain development and predispose the young to develop these and related disorders. We have now investigated the effect of a prenatal immune challenge on brain development in the offspring. Pregnant rats were treated with the double-stranded RNA polyinosinic:polycytidylic acid (poly(I:C); 10 mg/kg) which mimics immune activation occurring after activation of Toll-like receptors-3 (TLR3) by viral infection. Injections were made in late gestation (embryonic days E14, E16 and E18), after which parturition proceeded naturally and the young were allowed to develop up to the time of weaning at postnatal day 21 (P21). The brains of these animals were then removed to assess the expression of 13 different neurodevelopmental molecules by immunoblotting.

Results: Measurement of cytokine levels in the maternal blood 5 hours after an injection of poly(I:C) showed significantly increased levels of monocyte chemoattractant protein-1 (MCP-1), confirming immune activation. In the P21 offspring, significant changes were detected in the expression of GluN1 subunits of NMDA receptors, with no difference in GluN2A or GluN2B subunits or the postsynaptic density protein PSD-95 and no change in the levels of the related small GTPases RhoA or RhoB, or the NMDA receptor modulator EphA4. Among presynaptic molecules, a significant increase in Vesicle Associated Membrane Protein-1 (VAMP-1; synaptobrevin) was seen, with no change in synaptophysin or synaptotagmin. Proliferating Cell Nuclear Antigen (PCNA), as well as the neurogenesis marker doublecortin were unchanged, although Sox-2 levels were increased, suggesting possible changes in the rate of new cell differentiation.

Conclusions: The results reveal the induction by prenatal poly(I:C) of selective molecular changes in the brains of P21 offspring, affecting primarily molecules associated with neuronal development and synaptic transmission. These changes may contribute to the behavioural abnormalities that have been reported in adult animals after exposure to poly(I:C) and which resemble symptoms seen in schizophrenia and related disorders.
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http://dx.doi.org/10.1186/1756-6606-5-22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3496691PMC
June 2012