Purinergic system in psychiatric diseases

Cheffer, Arquimedes; Castillo, A.; Corrêa-Velloso, Juliana; Gonçalves, Maria Carolina Bittencourt; Naaldijk, Yahaira; Nascimento, Isis C.; Burnstock, Geoffrey; Ulrich, Henning

doi:10.1038/mp.2017.188

Cited by 117 publications

(117 citation statements)

References 241 publications

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“…11). P2rx7s and downstream signaling pathways coupled to them are common signaling highways in the pathological nervous system; their involvement has been shown previously in animal models of psychiatric disorders (Cheffer et al, 2018), such as major depression, bipolar disorder (Basso et al, 2009;Csölle et al, 2013a, b), schizophrenia (Koványi et al, 2016), but not in ASD models. The experimental proof for endogenous P2rx7s participation in MIA-induced behavioral and morphological changes in the offspring are as follows: (1) In P2rx7 Ϫ/Ϫ mice, maternal poly(I:C) did not induce social deficit, sensorimotor impairment, repetitive behaviors; in addition, cerebellar Purkinje cell atrophy and synaptosome destruction were also absent or alleviated.…”

Section: Discussionmentioning

confidence: 95%

P2X7 receptors drive poly(I:C) induced autism-like behavior in mice

et al. 2019

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Maternal immune activation (MIA) is a principal environmental risk factor contributing to autism spectrum disorder (ASD), which compromises fetal brain development at critical periods of pregnancy and might be causally linked to ASD symptoms. We report that endogenous activation of the purinergic ion channel P2X7 (P2rx7) is necessary and sufficient to transduce MIA to autistic phenotype in male offspring. MIA induced by poly(I:C) injections to P2rx7 WT mouse dams elicited an autism-like phenotype in their offspring, and these alterations were not observed in P2rx7-deficient mice, or following maternal treatment with a specific P2rx7 antagonist, JNJ47965567. Genetic deletion and pharmacological inhibition of maternal P2rx7s also counteracted the induction of IL-6 in the maternal plasma and fetal brain, and disrupted brain development, whereas postnatal P2rx7 inhibition alleviated behavioral and morphological alterations in the offspring. Administration of ATP to P2rx7 WT dams also evoked autistic phenotype, but not in KO dams, implying that P2rx7 activation by ATP is sufficient to induce autism-like features in offspring. Our results point to maternal and offspring P2rx7s as potential therapeutic targets for the early prevention and treatment of ASD.

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Section: Discussionmentioning

confidence: 95%

P2X7 receptors drive poly(I:C) induced autism-like behavior in mice

et al. 2019

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“…The purinergic system in BD could prove a promising path concerning not only therapeutic options, but mostly by identifying diagnostic, prognostic, and therapeutic biomarkers; new “omics” such as proteomics and metabolomics could provide valuable insight into the purinergic dysfunction in BD.…”

Section: Discussionmentioning

confidence: 99%

“…It has been hypothesized that reduced adenosinergic activity, mostly at A1 receptors‐level (with a corresponding increase in UA levels), is associated with the complex dysfunction on neurotransmitters' pathways related to manic behavior . Increasing evidence suggests that impairment in the purinergic system plays a part in the pathophysiology of mood disorders, namely BD and major depressive disorder (MDD) . Allopurinol, a hypouricemic agent, has been shown to be effective in treating acute mania, when used together with a mood stabilizer .…”

Section: Introductionmentioning

confidence: 99%

Serum uric acid as a predictor of bipolarity in individuals with a major depressive episode

et al. 2018

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| INTRODUC TI ONBipolar Disorder (BD) is one of the top 20 leading causes of disability worldwide. 1 It affects more than 1% of the population, with an estimated lifetime prevalence of 0.6% for type I BD, 0.4% for type II BD, and 1.4% for subthreshold manifestations of BD. 2 Despite the availability of effective treatments, the delay between the onset of BD and its diagnosis and management is often very long, with a pooled interval of almost 6 years. 3 Early diagnosis is difficult in clinical practice because the onset of BD is often characterized by a Objectives: There are no well-established biomarkers to predict the risk of conversion to bipolar disorder (BD) in patients with depression. Given the putative role of purinergic neurotransmission dysfunction in BD, the purpose of our study was to evaluate if higher serum uric acid (UA) levels could predict BD conversion in depressed inpatients. Methods:We reviewed retrospectively the records of subjects hospitalized between June 2007 and June 2010 with a diagnosis of major depressive disorder (MDD) who had undergone routine UA levels testing at admission. At an approximate 10-year follow-up we identified subjects with a subsequent diagnosis of BD. We compared UA levels between the BD-converter and non-BD converter groups, performed Receiver operating characteristic curve analysis to evaluate the prognostic accuracy of serum UA levels and calculated the clinical utility index (CUI) as a risk biomarker for conversion to BD. Results:The study included 250 subjects (55 "BD-converters" and 195 "No BD-converters"). "BD-converters" had significantly higher plasma UA levels compared to "No BD-converters" in their index hospitalization irrespective of gender (males:403.84 ± 91.76 vs 270.81 ± 53.58 µmol/L; U = 94.5, P < 0.001 and females 302.19 ± 52.64 vs 202.69 ± 48.93 µmol/L; t = 10.75, P < 0.001). Serum UA levels showed a very good to excellent accuracy for predicting conversion to BD in inpatients with MDD (area under the curve [AUC]: 0.90; 95% CI: 0.86, 0.94) and had a good to excellent CUI− and a moderate to good CUI+ grading for discriminating BDconverter cases from non-BD converters. Conclusions:Our study suggests that depressed patients with higher levels of serum UA are at greater risk of a subsequent manic or hypomanic episode. The purinergic system could prove a promising path for the search of biomarkers in BD. K E Y W O R D Sbipolar disorder, major depressive disorder, uric acid

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“…A large number of human CNS disease studies have implicated adenosine 2A receptors (A 2A ), including schizophrenia [192], Pick's disease [193], MCI [194], bipolar disorder [195], and HD [196], and additionally in pre-clinical models of AD [197], addiction [198], aging [199], attention deficit hyperactivity disorder [200], epilepsy [201], hyperoxia [202], multiple sclerosis (MS) [203], PD [204], restless leg syndrome [205], and tauopathy [206], amongst others. For in-depth reviews, refer to Waarde et al [207] and Cheffer et al [208].…”

Section: Adenosine a 2amentioning

confidence: 99%

Advances in CNS PET: the state-of-the-art for new imaging targets for pathophysiology and drug development

McCluskey

Plisson

Rabiner

et al. 2019

Eur J Nucl Med Mol Imaging

102

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Purpose A limit on developing new treatments for a number of central nervous system (CNS) disorders has been the inadequate understanding of the in vivo pathophysiology underlying neurological and psychiatric disorders and the lack of in vivo tools to determine brain penetrance, target engagement, and relevant molecular activity of novel drugs. Molecular neuroimaging provides the tools to address this. This article aims to provide a state-of-the-art review of new PET tracers for CNS targets, focusing on developments in the last 5 years for targets recently available for inhuman imaging. Methods We provide an overview of the criteria used to evaluate PET tracers. We then used the National Institute of Mental Health Research Priorities list to identify the key CNS targets. We conducted a PubMed search (search period 1st of January 2013 to 31st of December 2018), which yielded 40 new PET tracers across 16 CNS targets which met our selectivity criteria. For each tracer, we summarised the evidence of its properties and potential for use in studies of CNS pathophysiology and drug evaluation, including its target selectivity and affinity, inter and intra-subject variability, and pharmacokinetic parameters. We also consider its potential limitations and missing characterisation data, but not specific applications in drug development. Where multiple tracers were present for a target, we provide a comparison of their properties. Results and conclusions Our review shows that multiple new tracers have been developed for proteinopathy targets, particularly tau, as well as the purinoceptor P2X7, phosphodiesterase enzyme PDE10A, and synaptic vesicle glycoprotein 2A (SV2A), amongst others. Some of the most promising of these include 18 F-MK-6240 for tau imaging, 11 C-UCB-J for imaging SV2A, 11 C-CURB and 11 C-MK-3168 for characterisation of fatty acid amide hydrolase, 18 F-FIMX for metabotropic glutamate receptor 1, and 18 F-MNI-444 for imaging adenosine 2A. Our review also identifies recurrent issues within the field. Many of the tracers discussed lack in vivo blocking data, reducing confidence in selectivity. Additionally, late-stage identification of substantial off-target sites for multiple tracers highlights incomplete preclinical characterisation prior to translation, as well as human disease state studies carried out without confirmation of test-retest reproducibility.

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Purinergic system in psychiatric diseases

Cited by 117 publications

References 241 publications

P2X7 receptors drive poly(I:C) induced autism-like behavior in mice

P2X7 receptors drive poly(I:C) induced autism-like behavior in mice

Serum uric acid as a predictor of bipolarity in individuals with a major depressive episode

Advances in CNS PET: the state-of-the-art for new imaging targets for pathophysiology and drug development

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