Long-lasting antidepressant-like activity of the GPR39 zinc receptor agonist TC-G 1008

Starowicz, Gabriela; Jarosz, Magdalena; Frąckiewicz, Ewelina; Grzechnik, Natalia; Ostachowicz, Beata; Nowak, Gabriel; Młyniec, Katarzyna

doi:10.1016/j.jad.2018.11.003

Cited by 27 publications

(34 citation statements)

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“…GPR39 plays an important role in wound healing, depression, in ammatory bowel diseases, alcohol use disorder, insulin secretion and several cancers [23,46,[48][49][50][51][52]. However, the neuroprotective function of GPR39 has been partially con rmed.…”

Section: Discussionmentioning

confidence: 99%

Activation of GPR39 With TC-G 1008 Attenuates Neuroinflammation Via SIRT1/PGC-1α/Nrf2 Pathway Post Neonatal Hypoxic-ischemic Injury in Rats

Xie

Jiang

Doycheva

et al. 2021

Preprint

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Background: Hypoxic-ischemic encephalopathy (HIE) is a severe anoxic brain injury that leads to premature mortality or long-term disabilities in infants. Neuroinflammation is a vital contributor to the pathogenic cascade post HIE and a mediator to secondary neuronal death. As a plasma membrane G-protein coupled receptor, GPR39, exhibits anti-inflammatory activity in several diseases. This study aimed to explore the neuroprotective function of GPR39 through inhibition of inflammation post hypoxic-ischemic (HI) injury and to elaborate the contribution of sirtuin 1(SIRT1)/ peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α)/ nuclear factor, erythroid 2 like 2(Nrf2) in G protein-coupled receptor 39 (GPR39)-mediated protection.Methods: A total of 206 10-day old Sprague Dawley rat pups were subjected to HIE or sham surgery. TC-G 1008 was administered intranasally at 1h, 25h, 49h, and 73h post HIE induction. SIRT1 inhibitor EX527, GPR39 CRISPR, and PGC-1α CRISPR were administered to elucidate the underlying mechanisms. Brain infarct area, short-term and long-term neurobehavioral tests, Nissl staining, western blot, and immunofluorescence staining were performed post HIE.Results: The expression of GPR39 and pathway-related proteins, SIRT1、PGC-1α and Nrf2 were increased in a time-dependent manner, peaking at 24 h or 48h post HIE. Intranasal administration of TC-G 1008 reduced the percent infarcted area and improved short-term and long-term neurological deficits. Moreover, TC-G 1008 treatment significantly increased the expression of SIRT1, PGC-1α, Nrf2, IL-6, IL-1β, and TNF-α. GPR39 CRISPR EX527 and PGC-1α CRISPR abolished GPR39’s neuroprotective effects post HIE.Conclusions:TC-G 1008 attenuated neuroinflammation in part via the SIRT1/PGC-1α/Nrf2 pathway in a neonatal rat model of HIE. TC-G 1008 may be a novel therapeutic target for treatment post neonatal HIE injury.

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Section: Discussionmentioning

confidence: 99%

Activation of GPR39 With TC-G 1008 Attenuates Neuroinflammation Via SIRT1/PGC-1α/Nrf2 Pathway Post Neonatal Hypoxic-ischemic Injury in Rats

Xie

Jiang

Doycheva

et al. 2021

Preprint

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“…Both of these pathways lead to increased cAMP response element-binding protein (CREB) phosphorylation and cAMP response element (CRE)-dependent transcription and results in increased brain-derived neurotrophic factor (BDNF)/ Tropomyosin receptor kinase B (TrkB) in neurons. The latter pathway has been implicated in a variety of neuronal functions, including synaptic plasticity and remodeling, neuronal growth, circadian entrainment, improved memory, and protection against neuronal cell death and depression [ 26 , 45 , 59 , 60 , 61 ]. Outside the nervous system, the ligand-activated Gαq pathway is also linked to downstream extracellular signal-regulated kinase (ERK) 1/2 activation and phosphorylation of protein kinase B/Ak-strain transforming pathways (PKB/AKT) via MAP and phosphoinositide 3 (PI3) kinase to promote cell proliferation and survival in colon epithelial cells via CRE-dependent transcription [ 23 , 62 , 63 , 64 ].…”

Section: Deorphaned Endogenous Ligands Implicate Gpr39 In Moderating Neuro-excitability and Vascular Tone Through Gαq And/or Gαs Pathwaysmentioning

confidence: 99%

“…GPR39 expression by Western blot in the frontal cortex of mice was upregulated after a 14-day treatment with selective monoaminergic inhibitor antidepressants, but not with a broader acting tricyclic antidepressant [ 38 , 103 , 107 , 108 ]. GPR39 deficiency may abolish these monoaminergic-based antidepressant effects since GPR39 KO mice do respond to treatment with the selective serotonin reuptake inhibitor (SSRI), escitalopram, in a forced-swim depression assay [ 61 , 102 ]. These findings indicate that GPR39-dependent anti-depressive effects may be pathway or cell-type specific, with three main modes of action currently under investigation: modulation of zinc levels, neurotransmitter signaling, and neuroinflammation.…”

Section: Targeting Gpr39 As a Therapy For Neurological And Neuropsychiatric Disordersmentioning

confidence: 99%

Role of GPR39 in Neurovascular Homeostasis and Disease

Barnes

Alkayed

2021

IJMS

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GPR39, a member of the ghrelin family of G protein-coupled receptors, is zinc-responsive and contributes to the regulation of diverse neurovascular and neurologic functions. Accumulating evidence suggests a role as a homeostatic regulator of neuronal excitability, vascular tone, and the immune response. We review GPR39 structure, function, and signaling, including constitutive activity and biased signaling, and summarize its expression pattern in the central nervous system. We further discuss its recognized role in neurovascular, neurological, and neuropsychiatric disorders.

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“…Interestingly, ZnR/GPR39 is downregulated in MDD and upregulated by antidepressant treatment (Młyniec et al, 2015). Furthermore, in mice the zinc receptor agonist TC-G 1008 reduces the immobility time in the forced swim test (Starowicz et al, 2019). Activation of ZnR/GPR39 triggers a variety of biochemical pathways associated with cell proliferation, anti-apoptotic properties and neuroplasticity (Hershfinkel, 2018).…”

Section: The Immunomodulating Mineral Zincmentioning

confidence: 99%

The Way to a Human’s Brain Goes Through Their Stomach: Dietary Factors in Major Depressive Disorder

Aly

Engmann

2020

Front. Neurosci.

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Globally, more than 250 million people are affected by depression (major depressive disorder; MDD), a serious and debilitating mental disorder. Currently available treatment options can have substantial side effects and take weeks to be fully effective. Therefore, it is important to find safe alternatives, which act more rapidly and in a larger number of patients. While much research on MDD focuses on chronic stress as a main risk factor, we here make a point of exploring dietary factors as a somewhat overlooked, yet highly promising approach towards novel antidepressant pathways. Deficiencies in various groups of nutrients often occur in patients with mental disorders. These include vitamins, especially members of the B-complex (B6, B9, B12). Moreover, an imbalance of fatty acids, such as omega-3 and omega-6, or an insufficient supply with minerals, including magnesium and zinc, are related to MDD. While some of them are relevant for the synthesis of monoamines, others play a crucial role in inflammation, neuroprotection and the synthesis of growth factors. Evidence suggests that when deficiencies return to normal, changes in mood and behavior can be, at least in some cases, achieved. Furthermore, supplementation with dietary factors (so called “nutraceuticals”) may improve MDD symptoms even in the absence of a deficiency. Non-vital dietary factors may affect MDD symptoms as well. For instance, the most commonly consumed psychostimulant caffeine may improve behavioral and molecular markers of MDD. The molecular structure of most dietary factors is well known. Hence, dietary factors may provide important molecular tools to study and potentially help treat MDD symptoms. Within this review, we will discuss the role of dietary factors in MDD risk and symptomology, and critically discuss how they might serve as auxiliary treatments or preventative options for MDD.

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Long-lasting antidepressant-like activity of the GPR39 zinc receptor agonist TC-G 1008

Cited by 27 publications

References 88 publications

Activation of GPR39 With TC-G 1008 Attenuates Neuroinflammation Via SIRT1/PGC-1α/Nrf2 Pathway Post Neonatal Hypoxic-ischemic Injury in Rats

Activation of GPR39 With TC-G 1008 Attenuates Neuroinflammation Via SIRT1/PGC-1α/Nrf2 Pathway Post Neonatal Hypoxic-ischemic Injury in Rats

Role of GPR39 in Neurovascular Homeostasis and Disease

The Way to a Human’s Brain Goes Through Their Stomach: Dietary Factors in Major Depressive Disorder

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