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Antidepressant use has resulted in a variety of negative consequences, including permanent brain damage and erectile dysfunction. So, the purpose lies in developing something more productive with minimal side effects and consequently improved efficacy. A growing body of evidences indicated a remarkable purinergic signalling system, which helped in dealing with this complication. This has been found to be a powerful formula in dealing with psychiatric disorders. P1 (adenosine), P2X, and P2Y (ATP) are the receptors, involved in the pathology as well as exhibiting the therapeutic action by triggering the purinergic pathway. It was found that A2A and P2X7 receptors specifically were involved and recognized as possible targets for treating depression. Further, the development of biomarkers for the diagnosis of depression has also been attributed to accelerate the process. One such biomarker includes serum uric acid. Many clinical studies reveal the importance of antagonizing P2X7 and A2A receptors, for promising research in understanding the molecular premises of depression. However, further investigations are still needed to be done to open several unfolded mysteries for a better and safe upshot. The selective antagonists for A2A and P2X7 receptors may have antidepressant effects showing positive results, in agreement with non-clinical testing. In this review, efforts are being devoted to the targeted receptors in bringing out antidepressant effects with a possible link involving depression and defined purinergic signalling. Additionally, the overview of various receptors, including their functions and distribution, is being explored in a representative way along with the biomarkers involved., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Alchornea laxiflora (Benth.) Pax & K. Hoffm. (A. laxiflora) has been indicated in traditional medicine to treat depression. However, scientific rationalization is still lacking. Hence, this study aimed to investigate the antidepressant potential of A. laxiflora using network pharmacology and molecular docking analysis. Materials and methods: The active compounds and potential targets of A. laxiflora and depression-related targets were retrieved from public databases, such as PubMed, PubChem, DisGeNET, GeneCards, OMIM, SwissTargetprediction, BindingDB, STRING, and DAVID. Essential bioactive compounds, potential targets, and signaling pathways were predicted using in silico analysis, including BA-TAR, PPI, BA-TAR-PATH network construction, and GO and KEGG pathway enrichment analysis. Later on, with molecular docking analysis, the interaction of essential bioactive compounds of A. laxiflora and predicted core targets of depression were verified. Results: The network pharmacology approach identified 15 active compounds, a total of 219 compound-related targets, and 14,574 depression-related targets with 200 intersecting targets between them. SRC, EGFR, PIK3R1, AKT1, and MAPK1 were the core targets, whereas 3-acetyloleanolic acid and 3-acetylursolic acid were the most active compounds of A. laxiflora with antidepressant potential. GO functional enrichment analysis revealed 129 GO terms, including 82 biological processes, 14 cellular components, and 34 molecular function terms. KEGG pathway enrichment analysis yielded significantly enriched 108 signaling pathways. Out of them, PI3K-Akt and MAPK signaling pathways might have a key role in treating depression. Molecular docking analysis results exhibited that core targets of depression, such as SRC, EGFR, PIK3R1, AKT1, and MAPK1, bind stably with the analyzed bioactive compounds of A. laxiflora. Conclusion: The present study elucidates the bioactive compounds, potential targets, and pertinent mechanism of action of A. laxiflora in treating depression. A. laxiflora might exert an antidepressant effect by regulating PI3K-Akt and MAPK signaling pathways. However, further investigations are required to validate. [ABSTRACT FROM AUTHOR]

Depression is the most prevalent and devastating neuropsychiatric disorder. There are several conventional antidepressants used for the treatment of depression. But due to their undesired adverse effects, patient compliance is very poor. Thus, developing novel medications for the treatment of depression is a critical strategic priority for meeting therapeutic demands. Current research is looking for alternatives to traditional antidepressants to reduce undesired side effects and increase efficacy. Phytoconstituents provide a wide research range in antidepressant treatments. In the present article, we have conducted a comprehensive assessment of neurological evidence, which supports the usefulness of phytoconstituents in the treatment of the depressive disorder. Secondary plant metabolites including alkaloids, polyphenols, glycosides, saponins, and terpenoids were found to exhibit antidepressant action. Most of the phytoconstituents were found to mediate their antidepressant effect through the upregulation of brain-derived neurotrophic factor (BDNF), serotonin, noradrenaline, and dopamine. Some were also found to exert antidepressant effects by inhibiting the monoamine oxidase (MAO) activity and hypothalamic-pituitary-adrenal (HPA) axis overactivity. [Display omitted] • Phytoconstituents are secondary plant metabolites and exhibit intense biological activities. • Phytoconstituents ameliorated depression-like symptoms in both preclinical and clinical studies. • Phytoconstituents showed the upregulation of BDNF, hippocampal neurogenesis, and monoamine levels. • Phytoconstituents exhibited the inhibition of MAO activity, neuroinflammation, oxidative stress, and HPA axis hyperactivity. • Phytoconstituents are the emerging therapeutic alternative for the treatment of depression. [ABSTRACT FROM AUTHOR]

Depression is a chronic and prevalent neuropsychiatric disorder; clinical symptoms include excessive sad mood, anhedonia, increased anxiety, disturbed sleep, and cognitive deficits. The exact etiopathogenesis of depression is not well understood. Studies have suggested that tumor necrosis factor-alpha (TNF-α) and interleukins (ILs) perform vital roles in the pathogenesis and treatment of depression. Increasing evidence suggests the upregulation of TNF-α and ILs expression in patients with depression. Therefore, biologics like TNF inhibitors (etanercept, infliximab, adalimumab) and IL inhibitors (ustekinumab) have become key compounds in the treatment of depression. Interestingly, treatment with an antidepressant has been found to decrease the TNF-α level and improve depression-like behaviors in several preclinical and clinical studies. In the current article, we have reviewed the recent findings linking TNF-α and the pathogenesis of depression proving TNF-α inhibitors as potential new therapeutic agents. Animal models and clinical studies further support that TNF-α inhibitors are effective in ameliorating depression-like behaviors. Moreover, studies showed that peripheral injection of TNF-α exhibits depressive symptoms. These symptoms have been improved by treatment with TNF-α inhibitors. Hence suggesting TNF-α inhibitors as potential new antidepressants for the management of depressive disorder. TNF-α- Tumor necrosis factor-alpha, TNFR- TNF-α receptor, IL-6- Interleukin-6, IL-R- IL receptor, TAK-1-Transforming growth factor beta-activated kinase 1, MAPK- Mitogen-activated protein kinase, NF-κB- Necrosis factor kappa B, SERT- Serotonin transporter, IDO-Indoleamine-2,3-dioxygenase. [Display omitted] • TNF-α plays an important role in the pathogenesis of depression. • TNFR1 or TNFR2 knockout exhibits antidepressant behaviors in animal models. • TNF-α activates the SERT and IDO • TNF-α induces the overactivation of the HPAaxis • TNF-α inhibitors ameliorate depressive-like behavior [ABSTRACT FROM AUTHOR]