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Journal ArticleDOI

P2X7R antagonists in chronic stress-based depression models: a review.

TL;DR: In this article, a review summarizes the findings and analyses their methodology and proposes adherence to the Research Domain Criteria and the STRANGE framework to minimize experimental bias and increase data purview.
Abstract: Depression affects around 320 million people worldwide. Growing evidence proposes the immune system to be the core interface between psychosocial stress and the neurobiological and behavioural features of depression. Many studies have identified purinergic signalling via the P2X7 receptor (P2X7R) to be of great importance in depression genesis yet only a few have evaluated P2X7R antagonists in chronic stress-based depression models. This review summarizes their findings and analyses their methodology. The four available studies used three to nine weeks of unpredictable, chronic mild stress or unpredictable, chronic stress in male mice or rats. Stress paradigm composition varied moderately, with stimuli being primarily psychophysical rather than psychosocial. Behavioural testing was performed during or after the last week of stress application and resulted in depressive-like behaviours, immune changes (NLRP3 assembly, interleukin-1β level increase, microglia activation) and neuroplasticity impairment. During the second half of each stress paradigm, a P2X7R antagonist (Brilliant Blue G, A-438079, A-804598) was applied. Studies differed with regard to antagonist dosage and application timing. Nonetheless, all treatments attenuated the stress-induced neurobiological changes and depressive-like behaviours. The evidence at hand underpins the importance of P2X7R signalling in chronic stress and depression. However, improvements in study planning and reporting are necessary to minimize experimental bias and increase data purview. To achieve this, we propose adherence to the Research Domain Criteria and the STRANGE framework.

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Journal ArticleDOI
TL;DR: Microglia, brain resident immune cells, modulate development, activity, and plasticity of the central nervous system as discussed by the authors , and they emerge as strong contenders for novel neurotherapies, shifting away from merely attenuation of excessive microglial inflammatory and phagocytic activities.

24 citations

Journal ArticleDOI
TL;DR: The participation of P2X7Rs in the development of the depressive-like behaviors in all forms of acute (TST, FST, foot shock) and chronic stress (UCMS) in the rodent models used is confirmed and may have relevance for the etiology of MDD in humans.
Abstract: Extracellular adenosine 5′-triphosphate (ATP) in the brain is suggested to be an etiological factor of major depressive disorder (MDD). It has been assumed that stress-released ATP stimulates P2X7 receptors (Rs) at the microglia, thereby causing neuroinflammation; however, other central nervous system (CNS) cell types such as astrocytes also possess P2X7Rs. In order to elucidate the possible involvement of the MDD-relevant hippocampal astrocytes in the development of a depressive-like state, we used various behavioral tests (tail suspension test [TST], forced swim test [FST], restraint stress, inescapable foot shock, unpredictable chronic mild stress [UCMS]), as well as fluorescence immunohistochemistry, and patch-clamp electrophysiology in wild-type (WT) and genetically manipulated rodents. The TST and FST resulted in learned helplessness manifested as a prolongation of the immobility time, while inescapable foot shock caused lower sucrose consumption as a sign of anhedonia. We confirmed the participation of P2X7Rs in the development of the depressive-like behaviors in all forms of acute (TST, FST, foot shock) and chronic stress (UCMS) in the rodent models used. Further, pharmacological agonists and antagonists acted in a different manner in rats and mice due to their diverse potencies at the respective receptor orthologs. In hippocampal slices of mice and rats, only foot shock increased the current responses to locally applied dibenzoyl-ATP (Bz-ATP) in CA1 astrocytes; in contrast, TST and restraint depressed these responses. Following stressful stimuli, immunohistochemistry demonstrated an increased co-localization of P2X7Rs with a microglial marker, but no change in co-localization with an astroglial marker. Pharmacological damage to the microglia and astroglia has proven the significance of the microglia for mediating all types of depression-like behavioral reactions, while the astroglia participated only in reactions induced by strong stressors, such as foot shock. Because, in addition to acute stressors, their chronic counterparts induce a depressive-like state in rodents via P2X7R activation, we suggest that our data may have relevance for the etiology of MDD in humans.

11 citations

Journal ArticleDOI
TL;DR: In this paper , the authors discuss the release of purines from astrocytes, and the expression/function of purinergic receptors, and discuss possible therapeutic options based on knowledge recently acquired in this field.

8 citations

Journal ArticleDOI
TL;DR: In this article , the role of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome in the pathology of depression is discussed.
Abstract: Increasing evidence suggests that the failure of clinical antidepressants may be related with neuroinflammation. The NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome is an intracellular multiprotein complex, and has been considered as a key contributor to the development of neuroinflammation. Inhibition of NLRP3 inflammasome is an effective method for depression treatment. In this review, we summarized current researches highlighting the role of NLRP3 inflammasome in the pathology of depression. Firstly, we discussed NLRP3 inflammasome activation in patients with depression and animal models. Secondly, we outlined the possible mechanisms driving the activation of NLRP3 inflammasome. Thirdly, we discussed the pathogenetic role of NLRP3 inflammasome in depression. Finally, we overviewed the current and potential antidepressants targeting the NLRP3 inflammasome. Overall, the inhibition of NLRP3 inflammasome activation may be a potential therapeutic strategy for inflammation-related depression.

7 citations

Journal ArticleDOI
TL;DR: In this paper , the relationship between inflammation and the development of osteoporosis and the role of the P2X7 receptor in regulating the dynamic regulation of bone reconstruction were covered, and the relevance of polymorphisms in skeletal physiology was analyzed.
Abstract: Increasing evidence suggests that both the occurrence and progression of osteoporosis are associated with inflammation, especially in primary osteoporosis. The maintenance of skeletal homeostasis is dependent on the complex regulation of bone metabolism. Numerous evidence suggested that purinoceptor networks are essential for bone homeostasis. In this review, the relationship between inflammation and the development of osteoporosis and the role of P2X7 receptor (P2X7R) in regulating the dynamic regulation of bone reconstruction were covered. We also discussed how P2X7R regulates the balance between resorption and bone formation by osteoblasts and reviewed the relevance of P2X7R polymorphisms in skeletal physiology. Finally, we analyzed potential targets of P2X7R for osteoporosis.

4 citations

References
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Journal ArticleDOI
TL;DR: The Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) provides a comprehensive assessment of prevalence, incidence, and years lived with disability (YLDs) for 328 causes in 195 countries and territories from 1990 to 2016.

10,401 citations

Journal ArticleDOI
TL;DR: All-cause age-standardised YLD rates decreased by 3·9% from 1990 to 2017; however, the all-age YLD rate increased by 7·2% while the total sum of global YLDs increased from 562 million (421–723) to 853 million (642–1100).

7,419 citations

Journal ArticleDOI
TL;DR: A meta-analysis of studies measuring cytokine concentration in patients with major depression reports significantly higher concentrations of the proinflammatory cytokines TNF-alpha and IL-6 in depressed subjects compared with control subjects, strengthening evidence that depression is accompanied by activation of the IRS.

3,800 citations

Journal ArticleDOI
TL;DR: The presence of diabetes doubles the odds of comorbid depression, and the prevalence of depression was significantly higher in diabetic women than in diabetic men, and in uncontrolled studies than in controlled studies.
Abstract: OBJECTIVE —To estimate the odds and prevalence of clinically relevant depression in adults with type 1 or type 2 diabetes. Depression is associated with hyperglycemia and an increased risk for diabetic complications; relief of depression is associated with improved glycemic control. A more accurate estimate of depression prevalence than what is currently available is needed to gauge the potential impact of depression management in diabetes. RESEARCH DESIGN AND METHODS —MEDLINE and PsycINFO databases and published references were used to identify studies that reported the prevalence of depression in diabetes. Prevalence was calculated as an aggregate mean weighted by the combined number of subjects in the included studies. We used χ 2 statistics and odds ratios (ORs) to assess the rate and likelihood of depression as a function of type of diabetes, sex, subject source, depression assessment method, and study design. RESULTS —A total of 42 eligible studies were identified; 20 (48%) included a nondiabetic comparison group. In the controlled studies, the odds of depression in the diabetic group were twice that of the nondiabetic comparison group (OR = 2.0, 95% CI 1.8–2.2) and did not differ by sex, type of diabetes, subject source, or assessment method. The prevalence of comorbid depression was significantly higher in diabetic women (28%) than in diabetic men (18%), in uncontrolled (30%) than in controlled studies (21%), in clinical (32%) than in community (20%) samples, and when assessed by self-report questionnaires (31%) than by standardized diagnostic interviews (11%). CONCLUSIONS —The presence of diabetes doubles the odds of comorbid depression. Prevalence estimates are affected by several clinical and methodological variables that do not affect the stability of the ORs.

3,758 citations

Journal ArticleDOI
Hans Selye1
01 Jul 1936-Nature
TL;DR: If the organism is severely damaged by acute non-specific nocuous agents such as exposure to cold, surgical injury, production of spinal shock, excessive muscular exercise, or intoxications with sublethal doses of diverse drugs, a typical syndrome appears, the symptoms of which are independent of the nature of the damaging agent or the pharmacological type of the drug employed.
Abstract: EXPERIMENTS on rats show that if the organism is severely damaged by acute non-specific nocuous agents such as exposure to cold, surgical injury, production of spinal shock (transcision of the cord), excessive muscular exercise, or intoxications with sublethal doses of diverse drugs (adrenaline, atropine, morphine, formaldehyde, etc.), a typical syndrome appears, the symptoms of which are independent of the nature of the damaging agent or the pharmacological type of the drug employed, and represent rather a response to damage as such.

3,667 citations