Cognitive manic symptoms associated with the <i>P2RX7</i> gene in bipolar disorder

Backlund, Lena; Nikamo, Pernilla; Hukic, Dzana Sudic; Ek, Inger Römer; Träskman‐Bendz, Lil; Landén, Mikael; Edman, Gunnar; Schalling, Martin; Frisén, Louise; Ösby, Urban

doi:10.1111/j.1399-5618.2011.00952.x

Cited by 42 publications

(29 citation statements)

References 57 publications

(70 reference statements)

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“…The latter finding was suggested to take place as a compensatory neuroprotective mechanism (Liu et al, 2014), which is supported by our finding that lithium increases FGF-2 gene expression in LCLs. Finally, our results also show that lithium increases the expression of P2RX4 and P2RX7, both of which belong to the family of purinergic receptors previously linked to BD pathophysiology (Backlund et al, 2011; Halmai et al, 2013; Mantere et al, 2012). …”

Section: Discussionsupporting

confidence: 76%

Distinct lithium-induced gene expression effects in lymphoblastoid cell lines from patients with bipolar disorder

Fries

Colpo

Monroy-Jaramillo

et al. 2017

European Neuropsychopharmacology

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Lithium is the most commonly prescribed medication for the treatment of bipolar disorder (BD), yet the mechanisms underlying its beneficial effects are still unclear. We aimed to compare the effects of lithium treatment in lymphoblastoid cell lines (LCLs) from BD patients and controls. LCLs were generated from sixty-two BD patients (based on DSM-IV) and seventeen healthy controls matched for age, sex, and ethnicity. Patients were recruited from outpatient clinics from February 2012 to October 2014. LCLs were treated with 1 mM lithium for 7 days followed by microarray gene expression assay and validation by real-time quantitative PCR. Baseline differences between groups, as well as differences between vehicle- and lithium-treated cells within each group were analyzed. The biological significance of differentially expressed genes was examined by pathway enrichment analysis. No significant differences in baseline gene expression (adjusted p-value < 0.05) were detected between groups. Lithium treatment of LCLs from controls did not lead to any significant differences. However, lithium altered the expression of 236 genes in LCLs from patients; those genes were enriched for signaling pathways related to apoptosis. Among those genes, the alterations in the expression of PIK3CG, SERP1 and UPP1 were validated by real-time PCR. A significant correlation was also found between circadian functioning and CEBPG and FGF2 expression levels. In summary, our results suggest that lithium treatment induces expression changes in genes associated with the apoptosis pathway in BD LCLs. The more pronounced effects of lithium in patients compared to controls suggest a disease-specific effect of this drug.

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Section: Discussionsupporting

confidence: 76%

Distinct lithium-induced gene expression effects in lymphoblastoid cell lines from patients with bipolar disorder

Fries

Colpo

Monroy-Jaramillo

et al. 2017

European Neuropsychopharmacology

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“…Interestingly, the study by Mantere and colleagues (2012) demonstrated that the P2X7 receptor subunit Gln460Arg polymorphism was specifically associated with neuroticism in the context of mood disorders. The Thr348Ala allele has been correlated with symptoms of mania including cognitive impairment, distractibility, and talkativeness (Backlund et al, 2011). Nevertheless, other studies found no correlation between P2X7 SNPs and mood disorders (Table 2).…”

Section: Human Studiesmentioning

confidence: 99%

“…All but three studies (two in BD and one in MDD) found no association with mood disorders (either BD or MDD) (Barden et al, 2006; Lucae et al, 2006; McQuillin et al, 2009). Five studies found an association with symptom profile (Hejjas et al, 2009; Backlund et al, 2011; Soronen et al, 2011; Mantere et al, 2012; Halmai et al, 2013). Notably, only two studies found no association with symptom profile, and in both cases this was in subjects with depression (Lavebratt et al, 2010; Halmai et al, 2013).…”

Section: Human Studiesmentioning

confidence: 99%

“…Overall, the findings suggest a likely association between the Gln460Arg P2X7 gene polymorphism and state (symptom severity or profile), but not trait (diagnosis). Similarly, though it has not been frequently studied, the 348Ala SNP has been associated with BD and anxiety disorders (panic and agoraphobia), though only the anxiety disorders study was of a case-control design (Erhardt et al, 2007; Backlund et al, 2011). …”

Section: Human Studiesmentioning

confidence: 99%

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Purinergic system dysfunction in mood disorders: a key target for developing improved therapeutics

Ortiz

Ulrich

Zarate

et al. 2015

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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Uric acid and purines (such as adenosine) regulate mood, sleep, activity, appetite, cognition, memory, convulsive threshold, social interaction, drive, and impulsivity. A link between purinergic dysfunction and mood disorders was first proposed a century ago. Interestingly, a recent nationwide population-based study showed elevated risk of gout in subjects with bipolar disorder (BD), and a recent meta-analysis and systematic review of placebo-controlled trials of adjuvant purinergic modulators confirmed their benefits in bipolar mania. Uric acid may modulate energy and activity levels, with higher levels associated with higher energy and BD spectrum. Several recent genetic studies suggest that the purinergic system particularly the modulation of P1 and P2 receptor subtypes—plays a role in mood disorders, lending credence to this model. Nucleotide concentrations can be measured using brain spectroscopy, and ligands for in vivo positron emission tomography (PET) imaging of adenosine (P1) receptors have been developed, thus allowing potential target engagement studies. This review discusses the key role of the purinergic system in the pathophysiology of mood disorders. Focusing on this promising therapeutic target may lead to the development of therapies with antidepressant, mood stabilization, and cognitive effects.

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“…There is growing evidence that strengthens the role of P2X7 in mood disorders. Several human genetic studies have associated the highly polymorphic P2RX7 gene with both bipolar disorder and depression (McQuillin et al, 2009;Backlund et al, 2011;Soronen et al, 2011) and some of these mutations have been linked to modulation of P2X7 channel function in vitro (Roger et al, 2010;Stokes et al, 2010). The progress in the field has been somewhat hampered by the absence of a suitable brain-penetrant P2X7-selective antagonist, because most of the P2X7 compounds described in the literature are either human-specific (low affinity for rodent P2X7), or suffer from poor brain penetration or are nonselective and may exert polypharmacology in vivo.…”

Section: Introductionmentioning

confidence: 99%

Pharmacology of a Novel Central Nervous System–Penetrant P2X7 Antagonist JNJ-42253432

Lord

Aluisio

Shoblock

et al. 2014

J Pharmacol Exp Ther

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In the central nervous system, the ATP-gated Purinergic receptor P2X ligand-gated ion channel 7 (P2X7) is expressed in glial cells and modulates neurophysiology via release of gliotransmitters, including the proinflammatory cytokine interleukin (IL)-1b. In this study, we characterized JNJ-42253432 [2-methyl-N-([1-(4-phenylpiperazin-1-yl)cyclohexyl]methyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide] as a centrally permeable (brain-to-plasma ratio of 1), high-affinity P2X7 antagonist with desirable pharmacokinetic and pharmacodynamic properties for in vivo testing in rodents. JNJ-42253432 is a high-affinity antagonist for the rat (pK i 9.1 6 0.07) and human (pK i 7.9 6 0.08) P2X7 channel. The compound blocked the ATPinduced current and Bz-ATP [29(39)-O-(4-benzoylbenzoyl)adenosine-59-triphosphate tri(triethylammonium)]-induced release of IL-1b in a concentration-dependent manner. When dosed in rats, JNJ-42253432 occupied the brain P2X7 channel with an ED 50 of 0.3 mg/kg, corresponding to a mean plasma concentration of 42 ng/ml. The compound blocked the release of IL-1b induced by Bz-ATP in freely moving rat brain. At higher doses/exposure, JNJ-42253432 also increased serotonin levels in the rat brain, which is due to antagonism of the serotonin transporter (SERT) resulting in an ED 50 of 10 mg/kg for SERT occupancy. JNJ-42253432 reduced electroencephalography spectral power in the a-1 band in a dose-dependent manner; the compound also attenuated amphetamine-induced hyperactivity. JNJ-42253432 significantly increased both overall social interaction and social preference, an effect that was independent of stress induced by foot-shock. Surprisingly, there was no effect of the compound on either neuropathic pain or inflammatory pain behaviors. In summary, in this study, we characterize JNJ-42253432 as a novel brain-penetrant P2X7 antagonist with high affinity and selectivity for the P2X7 channel.

show abstract

Cognitive manic symptoms associated with the P2RX7 gene in bipolar disorder

Abstract: There is an association between specific symptoms of bipolar disorder and the P2RX7 gene. This finding may open up new approaches to elucidating the neurobiology behind bipolar symptoms.

Cited by 42 publications

References 57 publications

Distinct lithium-induced gene expression effects in lymphoblastoid cell lines from patients with bipolar disorder

Distinct lithium-induced gene expression effects in lymphoblastoid cell lines from patients with bipolar disorder

Purinergic system dysfunction in mood disorders: a key target for developing improved therapeutics

Pharmacology of a Novel Central Nervous System–Penetrant P2X7 Antagonist JNJ-42253432

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