ATP-activated P2X7 receptor in the pathophysiology of mood disorders and as an emerging target for the development of novel antidepressant therapeutics

Wei, Linyu; Mortadza, Sharifah Alawieyah Syed; Yan, Jing; Zhang, Libin; Wang, Lu; Yin, Yulong; Li, Chaokun; Chalon, Sylvie; Emond, Patrick; Belzung, Catherine; Li, Dongliang; Lu, Chengbiao; Roger, Sébastien; Jiang, Lin‐Hua

doi:10.1016/j.neubiorev.2018.02.005

Cited by 35 publications

(36 citation statements)

References 181 publications

(195 reference statements)

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“…It can be derived from the available literature as discussed in our review that P2X7Rs may be promising targets to treat MD and BD (Bhattacharya, 2018;Wei et al, 2018). However, the following three difficulties are major obstacles in developing new P2X7R antagonists for the treatment of mood disorders: (1) a number of P2X7R antagonists act in rodent receptor orthologs but not in human receptor orthologs when investigated under in vitro conditions (Bhattacharya and Biber, 2016); (2) the disease can be modeled by depressive-like states induced by applying acute or chronic inescapable stress to rodents; however, it is most likely that there is no perfect analogy with the human disease (Ribeiro et al, 2019); and (3) P2X7R antagonists have to pass the blood-brain barrier in order to exert effects in the CNS.…”

Section: P2x7r Antagonists As Possible Therapeutic Agents To Treat Momentioning

confidence: 99%

“…The majority of compounds disclosed in the last decade are human-specific P2X7R antagonists with no or weak rodent activity but suffer from lack of robust CNS permeability. However, numerous blood-brain barrier-permeable P2X7R antagonists have been developed by Abbott, Astra-Zeneca, GlaxoSmithKline, and especially Janssen more recently (Bhattacharya, 2018;Wei et al, 2018). The Janssen compounds JNJ-47965567 (Bhattacharya et al, 2013) and JNJ-42253432 (Lord et al, 2014) demonstrated activity in rodent and human P2X7Rs, had good rat pharmacokinetic profiles, and had excellent brain penetration, when dosed subcutaneously.…”

Section: P2x7r Antagonists As Possible Therapeutic Agents To Treat Momentioning

confidence: 99%

“…The mood disorder major depression (MD) is characterized by extreme sadness, depressed mood, and loss of interest that persist for at least 2 weeks and interferes with the individual's social functioning (Harvey et al, 2007;Deussing and Arzt, 2018;Wei et al, 2018;Ribeiro et al, 2019). During bipolar disorder (BD), the mood state cycles between high (mania) and low (depression) episodes.…”

Section: Introductionmentioning

confidence: 99%

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Pathological ATPergic Signaling in Major Depression and Bipolar Disorder

Illéš

Verkhratsky

Tang

2020

Front. Mol. Neurosci.

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The mood disorders, major depression (MD) and bipolar disorder (BD), have a high lifetime prevalence in the human population and accordingly generate huge costs for health care. Efficient, rapidly acting, and side-effect-free pharmaceuticals are hitherto not available, and therefore, the identification of new therapeutic targets is an imperative task for (pre)clinical research. Such a target may be the purinergic P2X7 receptor (P2X7R), which is localized in the central nervous system (CNS) at microglial and neuroglial cells mediating neuroinflammation. MD and BD are due to neuroinflammation caused in the first line by the release of the pro-inflammatory cytokine interleukin-1β (IL-1β) from the microglia. IL-1β in turn induces the secretion of corticotropin-releasing hormone (CRH) and in consequence the secretion of adrenocorticotropic hormone (ACTH) and cortisol, which together with a plethora of further cytokines/chemokines lead to mood disorders. A number of biochemical/molecular biological measurements including the use of P2X7R-or IL-1β-deficient mice confirmed this chain of events. More recent studies showed that a decrease in the astrocytic release of ATP in the prefrontal cortex and hippocampus is a major cause of mood disorders. It is an attractive hypothesis that compensatory increases in P2X7Rs in these areas of the brain are the immediate actuators of MD and BD. Hence, blood-brain barrier-permeable P2X7R antagonists may be promising therapeutic tools to improve depressive disorders in humans.

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Section: P2x7r Antagonists As Possible Therapeutic Agents To Treat Momentioning

confidence: 99%

Section: P2x7r Antagonists As Possible Therapeutic Agents To Treat Momentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pathological ATPergic Signaling in Major Depression and Bipolar Disorder

Illéš

Verkhratsky

Tang

2020

Front. Mol. Neurosci.

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“…4 P2X7 receptor is hypothesized to be critical in mediating brain inflammation and CNS neuron-glia signaling leading to neurodegenerative and psychiatric diseases. [5][6][7] JNJ-54175446 has been tested in single ascending dose (SAD; NCT02475148) 8 and multiple ascending dose (MAD; NCT02515955) studies in healthy subjects and is well-tolerated up to 600 mg single dose and 450 mg once daily following oral administration. The median time to achieve maximal concentration (T max ) ranged from 2-4 hours under fasted conditions, and the elimination halflife was ~ 35 hours.…”

Section: Translational Pk/pd Aided Human Pet Dose Selectionmentioning

confidence: 99%

“…In both the CNS and periphery, P2X7 receptor activation is associated with inflammasome activation leading to the production of the pro‐inflammatory cytokines, such as interleukin (IL)‐1β . P2X7 receptor is hypothesized to be critical in mediating brain inflammation and CNS neuron‐glia signaling leading to neurodegenerative and psychiatric diseases …”

mentioning

confidence: 99%

Translational Model‐Informed Dose Selection for a Human Positron Emission Tomography Imaging Study of JNJ‐54175446, a P2X7 Receptor Antagonist

Miao

Ravenstijn

et al. 2019

Clinical Translational Sci

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Positron emission tomography (PET) provides useful information in target engagement or receptor occupancy in the brain for central nervous system (CNS) drug development, however, dose selection for human PET studies is challenging and largely empirical. Here, we describe a translational pharmacokinetic/pharmacodynamic (PK/PD) modeling work to inform dose selection for a human PET study of JNJ‐54175446, a CNS‐penetrating P2X7 receptor antagonist. Models were developed using data on monkey brain occupancy and plasma drug exposures from a monkey PET study and early human clinical studies that provided data on drug exposures and human ex vivo‐stimulated peripheral interleukin (IL)‐1β release. The observed plasma PK of JNJ‐54175446 in human was adequately described by a one‐compartment model with parallel zero‐order and first‐order absorption and first‐order elimination. An exposure‐occupancy model was extrapolated from monkey to human assuming a similar unbound potency (all other model parameters remained unchanged). This model was then used to simulate human brain occupancy to guide human PET study dose selection, together with the human population PK model. The corroboration of model predicted occupancy by the observed occupancy data from the human PET study supports the use of a monkey as a predictive model for human PET target engagement. Potency estimate for brain occupancy was generally comparable to that for the suppression of the provoked peripheral IL‐1β release ex vivo, indicating that blood IL‐1β release may be used as a surrogate of central occupancy for JNJ‐54175446. Translational PK/PD modeling approach could be used for selecting optimal doses for human PET and other clinical studies.

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Leveraging the ATP‐P2X7 receptor signalling axis to alleviate traumatic CNS damage and related complications

Yin

Wei

Caseley

et al. 2023

Medicinal Research Reviews

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The P2X7 receptor is an exceptional member of the P2X purinergic receptor family, with its activation requiring high concentrations of extracellular adenosine 5ʹ‐triphosphate (ATP) that are often associated with tissue damage and inflammation. In the central nervous system (CNS), it is highly expressed in glial cells, particularly in microglia. In this review, we discuss the role and mechanisms of the P2X7 receptor in mediating neuroinflammation and other pathogenic events in a variety of traumatic CNS damage conditions, which lead to loss of neurological and cognitive functions. We raise the perspective on the steady progress in developing CNS‐penetrant P2X7 receptor‐specific antagonists that leverage the ATP‐P2X7 receptor signaling axis as a potential therapeutic strategy to alleviate traumatic CNS damage and related complications.

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ATP-activated P2X7 receptor in the pathophysiology of mood disorders and as an emerging target for the development of novel antidepressant therapeutics

Cited by 35 publications

References 181 publications

Pathological ATPergic Signaling in Major Depression and Bipolar Disorder

Pathological ATPergic Signaling in Major Depression and Bipolar Disorder

Translational Model‐Informed Dose Selection for a Human Positron Emission Tomography Imaging Study of JNJ‐54175446, a P2X7 Receptor Antagonist

Leveraging the ATP‐P2X7 receptor signalling axis to alleviate traumatic CNS damage and related complications

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