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Article ; Online: Inhibition of MEK-ERK signaling reduces seizures in two mouse models of tuberous sclerosis complex.

Nguyen, Lena H / Leiser, Steven C / Song, Dekun / Brunner, Daniela / Roberds, Steven L / Wong, Michael / Bordey, Angelique

Epilepsy research

2022 Volume 181, Page(s) 106890

Abstract: Tuberous sclerosis complex (TSC) is a monogenic disorder characterized by hyperactivation of the mTOR signaling pathway and developmental brain malformations leading to intractable epilepsy. Although treatment with the recently approved mTOR inhibitor, ... ...

Abstract	Tuberous sclerosis complex (TSC) is a monogenic disorder characterized by hyperactivation of the mTOR signaling pathway and developmental brain malformations leading to intractable epilepsy. Although treatment with the recently approved mTOR inhibitor, everolimus, results in clinically relevant seizure suppression in up to 40% of TSC patients, seizures remain uncontrolled in a large number of cases, underscoring the need to identify novel treatment targets. The MEK-ERK signaling pathway has been found to be aberrantly activated in TSC and inhibition of MEK-ERK activity independently of mTOR rescued neuronal dendrite overgrowth in mice modeling TSC neuropathology. Here, we evaluated the efficacy of MEK-ERK inhibition on seizures in two mouse models of TSC. We found that treatment with the MEK inhibitor PD0325901 (mirdametinib) significantly reduced seizure activity in both TSC mouse models. These findings support inhibiting MEK-ERK activity as a potential alternative strategy to treat seizures in TSC.
MeSH term(s)	Animals ; Disease Models, Animal ; Humans ; Mice ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Seizures/drug therapy ; Signal Transduction ; Tuberous Sclerosis/complications ; Tuberous Sclerosis/drug therapy
Chemical Substances	Mitogen-Activated Protein Kinase Kinases (EC 2.7.12.2)
Language	English
Publishing date	2022-02-18
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	632939-1
ISSN	1872-6844 ; 0920-1211
ISSN (online)	1872-6844
ISSN	0920-1211
DOI	10.1016/j.eplepsyres.2022.106890
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Article: Overexpression of long non-coding RNA CRNDE facilitates epithelial-mesenchymal transition and correlates with poor prognosis in intrahepatic cholangiocarcinoma.

Xia, Xiu-Liang / Xue, Dong / Xiang, Ting-Hai / Xu, Huai-Yong / Song, De-Kun / Cheng, Pei-Guang / Wang, Jian-Qiang

Oncology letters

2018 Volume 15, Issue 4, Page(s) 4105–4112

Abstract: The clinical significance and essential role of long non-coding RNA colorectal neoplasia differentially expressed (lncRNA CRNDE) have been well illuminated in various cancers. However, the function of CRNDE in intrahepatic cholangiocarcinoma (IHCC) has ... ...

Abstract	The clinical significance and essential role of long non-coding RNA colorectal neoplasia differentially expressed (lncRNA CRNDE) have been well illuminated in various cancers. However, the function of CRNDE in intrahepatic cholangiocarcinoma (IHCC) has not been reported at present. The aim of the present study was to investigate the role of CRNDE in IHCC. Firstly, the relative expression of CRNDE was observed to be upregulated in IHCC cell lines and tissues. And high CRNDE expression was statistically associated with IHCC differentiation grade, lymph node metastasis, tumor-nodes-metastasis (TNM) stage and size. Survival analysis identified that high CRNDE expression is a predictor of worse overall survival (OS) and progression-free survival (PFS) in patients with IHCC. Moreover, high CRNDE expression was identified as an independent risk factor of IHCC poor OS and PFS. Further studies of
Language	English
Publishing date	2018-01-17
Publishing country	Greece
Document type	Journal Article
ZDB-ID	2573196-8
ISSN	1792-1082 ; 1792-1074
ISSN (online)	1792-1082
ISSN	1792-1074
DOI	10.3892/ol.2018.7815
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Article ; Online: Novel brain permeant mTORC1/2 inhibitors are as efficacious as rapamycin or everolimus in mouse models of acquired partial epilepsy and tuberous sclerosis complex.

Theilmann, Wiebke / Gericke, Birthe / Schidlitzki, Alina / Muneeb Anjum, Syed Muhammad / Borsdorf, Saskia / Harries, Timon / Roberds, Steven L / Aguiar, Dean J / Brunner, Daniela / Leiser, Steven C / Song, Dekun / Fabbro, Doriano / Hillmann, Petra / Wymann, Matthias P / Löscher, Wolfgang

Neuropharmacology

2020 Volume 180, Page(s) 108297

Abstract: Mechanistic target of rapamycin (mTOR) regulates cell proliferation, growth and survival, and is activated in cancer and neurological disorders, including epilepsy. The rapamycin derivative ("rapalog") everolimus, which allosterically inhibits the mTOR ... ...

Abstract	Mechanistic target of rapamycin (mTOR) regulates cell proliferation, growth and survival, and is activated in cancer and neurological disorders, including epilepsy. The rapamycin derivative ("rapalog") everolimus, which allosterically inhibits the mTOR pathway, is approved for the treatment of partial epilepsy with spontaneous recurrent seizures (SRS) in individuals with tuberous sclerosis complex (TSC). In contrast to the efficacy in TSC, the efficacy of rapalogs on SRS in other types of epilepsy is equivocal. Furthermore, rapalogs only poorly penetrate into the brain and are associated with peripheral adverse effects, which may compromise their therapeutic efficacy. Here we compare the antiseizure efficacy of two novel, brain-permeable ATP-competitive and selective mTORC1/2 inhibitors, PQR620 and PQR626, and the selective dual pan-PI3K/mTORC1/2 inhibitor PQR530 in two mouse models of chronic epilepsy with SRS, the intrahippocampal kainate (IHK) mouse model of acquired temporal lobe epilepsy and Tsc1
MeSH term(s)	Animals ; Disease Models, Animal ; Epilepsies, Partial/drug therapy ; Epilepsies, Partial/physiopathology ; Everolimus/pharmacology ; Everolimus/therapeutic use ; Immunosuppressive Agents/pharmacology ; Immunosuppressive Agents/therapeutic use ; Male ; Mechanistic Target of Rapamycin Complex 1/antagonists & inhibitors ; Mechanistic Target of Rapamycin Complex 2/antagonists & inhibitors ; Mice ; Mice, Knockout ; Sirolimus/therapeutic use ; Treatment Outcome ; Tuberous Sclerosis/drug therapy ; Tuberous Sclerosis/physiopathology
Chemical Substances	Immunosuppressive Agents ; Everolimus (9HW64Q8G6G) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Mechanistic Target of Rapamycin Complex 2 (EC 2.7.11.1) ; Sirolimus (W36ZG6FT64)
Language	English
Publishing date	2020-09-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218272-5
ISSN	1873-7064 ; 0028-3908
ISSN (online)	1873-7064
ISSN	0028-3908
DOI	10.1016/j.neuropharm.2020.108297
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Article ; Online: Histamine may contribute to vortioxetine's procognitive effects; possibly through an orexigenic mechanism.

Smagin, Gennady N / Song, Dekun / Budac, David P / Waller, Jessica A / Li, Yan / Pehrson, Alan L / Sánchez, Connie

Progress in neuro-psychopharmacology & biological psychiatry

2016 Volume 68, Page(s) 25–30

Abstract: Vortioxetine is a novel multimodal antidepressant that acts as a serotonin (5-HT)3, 5-HT7, and 5-HT1D receptor antagonist; 5-HT1B receptor partial agonist; 5-HT1A receptor agonist; and 5-HT transporter inhibitor in vitro. In preclinical and clinical ... ...

Abstract	Vortioxetine is a novel multimodal antidepressant that acts as a serotonin (5-HT)3, 5-HT7, and 5-HT1D receptor antagonist; 5-HT1B receptor partial agonist; 5-HT1A receptor agonist; and 5-HT transporter inhibitor in vitro. In preclinical and clinical studies vortioxetine demonstrates positive effects on cognitive dysfunction. Vortioxetine's effect on cognitive function likely involves the modulation of several neurotransmitter systems. Acute and chronic administration of vortioxetine resulted in changes in histamine concentrations in microdialysates collected from the rat prefrontal cortex and ventral hippocampus. Based on these results and a literature review of the current understanding of the interaction between the histaminergic and serotonergic systems and the role of histamine on cognitive function, we hypothesize that vortioxetine through an activation of the orexinergic system stimulates the tuberomammilary nucleus and enhances histaminergic neurotransmission, which contributes to vortioxetine's positive effects on cognitive function.
MeSH term(s)	Animals ; Cognition/drug effects ; Cognitive Dysfunction/drug therapy ; Histamine/metabolism ; Hypothalamic Area, Lateral/drug effects ; Orexins/drug effects ; Piperazines/pharmacology ; Serotonin Agents/pharmacology ; Sulfides/pharmacology ; Synaptic Transmission/drug effects
Chemical Substances	Orexins ; Piperazines ; Serotonin Agents ; Sulfides ; vortioxetine (3O2K1S3WQV) ; Histamine (820484N8I3)
Language	English
Publishing date	2016-07-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	781181-0
ISSN	1878-4216 ; 0278-5846
ISSN (online)	1878-4216
ISSN	0278-5846
DOI	10.1016/j.pnpbp.2016.03.001
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Article ; Online: Synthesis and Characterization of the Novel Rodent-Active and CNS-Penetrant P2X7 Receptor Antagonist Lu AF27139.

Hopper, Allen T / Juhl, Martin / Hornberg, Jorrit / Badolo, Lassina / Kilburn, John Paul / Thougaard, Annemette / Smagin, Gennady / Song, Dekun / Calice, Londye / Menon, Veena / Dale, Elena / Zhang, Hong / Cajina, Manuel / Nattini, Megan E / Gandhi, Adarsh / Grenon, Michel / Jones, Ken / Khayrullina, Tanzilya / Chandrasena, Gamini /

Thomsen, Christian / Zorn, Stevin H / Brodbeck, Robb / Poda, Suresh Babu / Staal, Roland / Möller, Thomas

Journal of medicinal chemistry

2021 Volume 64, Issue 8, Page(s) 4891–4902

Abstract: There remains an insufficient number of P2X7 receptor antagonists with adequate rodent potency, CNS permeability, and pharmacokinetic properties from which to evaluate CNS disease hypotheses preclinically. Herein, we describe the molecular pharmacology, ... ...

Abstract	There remains an insufficient number of P2X7 receptor antagonists with adequate rodent potency, CNS permeability, and pharmacokinetic properties from which to evaluate CNS disease hypotheses preclinically. Herein, we describe the molecular pharmacology, safety, pharmacokinetics, and functional CNS target engagement of Lu AF27139, a novel rodent-active and CNS-penetrant P2X7 receptor antagonist. Lu AF27139 is highly selective and potent against rat, mouse, and human forms of the receptors. The rat pharmacokinetic profile is favorable with high oral bioavailability, modest clearance (0.79 L/(h kg)), and good CNS permeability.
MeSH term(s)	Adenosine Triphosphate/analogs & derivatives ; Adenosine Triphosphate/pharmacology ; Animals ; Cell Line ; Central Nervous System/drug effects ; Central Nervous System/metabolism ; Dogs ; Female ; Half-Life ; Humans ; Interleukin-1beta/metabolism ; Lipopolysaccharides/pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Microglia/cytology ; Microglia/drug effects ; Microglia/metabolism ; Microsomes, Liver/metabolism ; Monocytes/cytology ; Monocytes/drug effects ; Monocytes/metabolism ; Purinergic P2X Receptor Antagonists/chemical synthesis ; Purinergic P2X Receptor Antagonists/metabolism ; Purinergic P2X Receptor Antagonists/pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Purinergic P2X7/chemistry ; Receptors, Purinergic P2X7/metabolism
Chemical Substances	Interleukin-1beta ; Lipopolysaccharides ; Purinergic P2X Receptor Antagonists ; Receptors, Purinergic P2X7 ; 3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate (4P5DXU1F8Q) ; Adenosine Triphosphate (8L70Q75FXE)
Language	English
Publishing date	2021-04-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.0c02249
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Article ; Online: MMI-166, a selective matrix metalloproteinase inhibitor, promotes apoptosis in human pancreatic cancer.

Gao, Chong-Chong / Gong, Ben-Gang / Wu, Jun-Ben / Cheng, Pi-Guang / Xu, Huai-Yong / Song, De-Kun / Li, Fei

Medical oncology (Northwood, London, England)

2015 Volume 32, Issue 1, Page(s) 418

Abstract: MMI-166 is a third-generation selective matrix metalloproteinase (MMP) inhibitor that prevents tumor invasion and metastasis by downregulating the activity of MMP-2 and MMP-9. However, MMI-166's effect in pancreatic cancer cells has not been widely ... ...

Abstract	MMI-166 is a third-generation selective matrix metalloproteinase (MMP) inhibitor that prevents tumor invasion and metastasis by downregulating the activity of MMP-2 and MMP-9. However, MMI-166's effect in pancreatic cancer cells has not been widely studied. Initially, we treated SW1990, human pancreatic cancer cells, with 0, 50 or 100 μg/ml of MMI-166 for 24 h. Apoptosis in the cells was then observed by inverted fluorescence microscope and flow cytometry; the apoptosis rate was dependent on MMI-166 concentration. We then injected nude mice with SW1990 cells. Volume of the resulting xenograft tumors in nude mice treated with MMI-166 was far less than that of the control group, whereas their apoptotic index was much greater. Expression of MMP-2, MMP-9, c-myc and survivin were markedly lower in tumors from the treated mice than in the control group. In cell experiments, MMP-2 and MMP-9 activities were downregulated by MMI-166 compared with controls, as were both mRNA and protein levels of MMP-2, MMP-9 and c-myc, although survivin expression did not differ. These results show that MMI-166 can induce apoptosis of pancreatic cancer cells in vitro and in vivo. The mechanism may be related to downregulation of c-myc by MMI-166.
MeSH term(s)	Animals ; Apoptosis/drug effects ; Biomarkers, Tumor/metabolism ; Down-Regulation ; Humans ; Male ; Matrix Metalloproteinase 2/metabolism ; Matrix Metalloproteinase 9/metabolism ; Matrix Metalloproteinase Inhibitors/pharmacology ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Pancreatic Neoplasms/metabolism ; Pancreatic Neoplasms/pathology ; Proto-Oncogene Proteins c-myc/metabolism ; Sulfonamides/pharmacology
Chemical Substances	Biomarkers, Tumor ; MYC protein, human ; Matrix Metalloproteinase Inhibitors ; N-alpha-(4-(2-phenyl-2H- tetrazole-5-yl) phenyl sulfonyl)-D-tryptophan ; Proto-Oncogene Proteins c-myc ; Sulfonamides ; MMP2 protein, human (EC 3.4.24.24) ; Matrix Metalloproteinase 2 (EC 3.4.24.24) ; MMP9 protein, human (EC 3.4.24.35) ; Matrix Metalloproteinase 9 (EC 3.4.24.35)
Language	English
Publishing date	2015-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1201189-7
ISSN	1559-131X ; 0736-0118 ; 1357-0560
ISSN (online)	1559-131X
ISSN	0736-0118 ; 1357-0560
DOI	10.1007/s12032-014-0418-5
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Article ; Online: Vortioxetine, but not escitalopram or duloxetine, reverses memory impairment induced by central 5-HT depletion in rats: evidence for direct 5-HT receptor modulation.

Jensen, Jesper Bornø / du Jardin, Kristian Gaarn / Song, Dekun / Budac, David / Smagin, Gennady / Sanchez, Connie / Pehrson, Alan Lars

European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology

2014 Volume 24, Issue 1, Page(s) 148–159

Abstract: Depressed patients suffer from cognitive dysfunction, including memory deficits. Acute serotonin (5-HT) depletion impairs memory and mood in vulnerable patients. The investigational multimodal acting antidepressant vortioxetine is a 5-HT3, 5-HT7 and 5- ... ...

Abstract	Depressed patients suffer from cognitive dysfunction, including memory deficits. Acute serotonin (5-HT) depletion impairs memory and mood in vulnerable patients. The investigational multimodal acting antidepressant vortioxetine is a 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and 5-HT transporter (SERT) inhibitor that enhances memory in normal rats in novel object recognition (NOR) and conditioned fear (Mørk et al., 2013). We hypothesized that vortioxetine's 5-HT receptor mechanisms are involved in its memory effects, and therefore investigated these effects in 5-HT depleted rats. Four injections of the irreversible tryptophan hydroxylase inhibitor 4-chloro-dl-phenylalanine methyl ester hydrochloride (PCPA, 86mg/kg, s.c.) induced 5-HT depletion, as measured in hippocampal homogenate and microdialysate. The effects of acute challenge with vortioxetine or the 5-HT releaser fenfluramine on extracellular 5-HT were measured in PCPA-treated and control rats. PCPA's effects on NOR and spontaneous alternation (SA) performance were assessed along with the effects of acute treatment with 5-hydroxy-l-tryptophan (5-HTP), vortioxetine, the selective 5-HT reuptake inhibitor escitalopram, or the 5-HT norepinephrine reuptake inhibitor duloxetine. SERT occupancies were estimated by ex vivo autoradiography. PCPA depleted central 5-HT by >90% in tissue and microdialysate, and impaired NOR and SA performance. Restoring central 5-HT with 5-HTP reversed these deficits. At similar SERT occupancies (>90%) vortioxetine, but not escitalopram or duloxetine, restored memory performance. Acute fenfluramine significantly increased extracellular 5-HT in control and PCPA-treated rats, while vortioxetine did so only in control rats. Thus, vortioxetine restores 5-HT depletion impaired memory performance in rats through one or more of its receptor activities.
MeSH term(s)	5-Hydroxytryptophan/administration & dosage ; Animals ; Carbidopa/administration & dosage ; Citalopram/therapeutic use ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Duloxetine Hydrochloride ; Exploratory Behavior/drug effects ; Female ; Hippocampus/drug effects ; Hippocampus/metabolism ; Maze Learning/drug effects ; Memory Disorders/chemically induced ; Memory Disorders/drug therapy ; Memory Disorders/metabolism ; Memory Disorders/pathology ; Phenylalanine/analogs & derivatives ; Phenylalanine/pharmacology ; Piperazines/therapeutic use ; Protein Binding/drug effects ; Rats ; Rats, Long-Evans ; Recognition (Psychology)/drug effects ; Serotonin/deficiency ; Serotonin Uptake Inhibitors/therapeutic use ; Sulfides/therapeutic use ; Thiophenes/therapeutic use
Chemical Substances	Piperazines ; Serotonin Uptake Inhibitors ; Sulfides ; Thiophenes ; Citalopram (0DHU5B8D6V) ; phenylalanine methyl ester (2577-90-4) ; Serotonin (333DO1RDJY) ; vortioxetine (3O2K1S3WQV) ; Phenylalanine (47E5O17Y3R) ; Duloxetine Hydrochloride (9044SC542W) ; 5-Hydroxytryptophan (C1LJO185Q9) ; Carbidopa (MNX7R8C5VO)
Language	English
Publishing date	2014-01
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1082947-7
ISSN	1873-7862 ; 0924-977X
ISSN (online)	1873-7862
ISSN	0924-977X
DOI	10.1016/j.euroneuro.2013.10.011
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Article ; Online: Task- and Treatment Length-Dependent Effects of Vortioxetine on Scopolamine-Induced Cognitive Dysfunction and Hippocampal Extracellular Acetylcholine in Rats.

Pehrson, Alan L / Hillhouse, Todd M / Haddjeri, Nasser / Rovera, Renaud / Porter, Joseph H / Mørk, Arne / Smagin, Gennady / Song, Dekun / Budac, David / Cajina, Manuel / Sanchez, Connie

The Journal of pharmacology and experimental therapeutics

2016 Volume 358, Issue 3, Page(s) 472–482

Abstract: Major depressive disorder (MDD) is a common psychiatric disorder that often features impairments in cognitive function, and these cognitive symptoms can be important determinants of functional ability. Vortioxetine is a multimodal antidepressant that may ...

Abstract	Major depressive disorder (MDD) is a common psychiatric disorder that often features impairments in cognitive function, and these cognitive symptoms can be important determinants of functional ability. Vortioxetine is a multimodal antidepressant that may improve some aspects of cognitive function in patients with MDD, including attention, processing speed, executive function, and memory. However, the cause of these effects is unclear, and there are several competing theories on the underlying mechanism, notably including regionally-selective downstream enhancement of glutamate neurotransmission and increased acetylcholine (ACh) neurotransmission. The current work sought to evaluate the ACh hypothesis by examining vortioxetine's ability to reverse scopolamine-induced impairments in rodent tests of memory and attention. Additionally, vortioxetine's effects on hippocampal extracellular ACh levels were examined alongside studies of vortioxetine's pharmacokinetic profile. We found that acute vortioxetine reversed scopolamine-induced impairments in social and object recognition memory, but did not alter scopolamine-induced impairments in attention. Acute vortioxetine also induced a modest and short-lived increase in hippocampal ACh levels. However, this short-term effect is at variance with vortioxetine's moderately long brain half life (5.1 hours). Interestingly, subchronic vortioxetine treatment failed to reverse scopolamine-induced social recognition memory deficits and had no effects on basal hippocampal ACh levels. These data suggest that vortioxetine has some effects on memory that could be mediated through cholinergic neurotransmission, however these effects are modest and only seen under acute dosing conditions. These limitations may argue against cholinergic mechanisms being the primary mediator of vortioxetine's cognitive effects, which are observed under chronic dosing conditions in patients with MDD.
MeSH term(s)	Acetylcholine/metabolism ; Animals ; Cognitive Dysfunction/chemically induced ; Cognitive Dysfunction/drug therapy ; Cognitive Dysfunction/metabolism ; Cognitive Dysfunction/physiopathology ; Extracellular Space/drug effects ; Extracellular Space/metabolism ; Hippocampus/drug effects ; Hippocampus/pathology ; Hippocampus/physiopathology ; Male ; Piperazines/pharmacology ; Piperazines/therapeutic use ; Rats ; Rats, Wistar ; Recognition (Psychology)/drug effects ; Scopolamine Hydrobromide/pharmacology ; Social Behavior ; Sulfides/pharmacology ; Sulfides/therapeutic use ; Synaptic Transmission/drug effects
Chemical Substances	Piperazines ; Sulfides ; vortioxetine (3O2K1S3WQV) ; Scopolamine Hydrobromide (451IFR0GXB) ; Acetylcholine (N9YNS0M02X)
Language	English
Publishing date	2016-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	3106-9
ISSN	1521-0103 ; 0022-3565
ISSN (online)	1521-0103
ISSN	0022-3565
DOI	10.1124/jpet.116.233924
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Article ; Online: Psychological Stress Activates the Inflammasome via Release of Adenosine Triphosphate and Stimulation of the Purinergic Type 2X7 Receptor.

Iwata, Masaaki / Ota, Kristie T / Li, Xiao-Yuan / Sakaue, Fumika / Li, Nanxin / Dutheil, Sophie / Banasr, Mounira / Duric, Vanja / Yamanashi, Takehiko / Kaneko, Koichi / Rasmussen, Kurt / Glasebrook, Andrew / Koester, Anja / Song, Dekun / Jones, Kenneth A / Zorn, Stevin / Smagin, Gennady / Duman, Ronald S

Biological psychiatry

2016 Volume 80, Issue 1, Page(s) 12–22

Abstract: Background: The mechanisms underlying stress-induced inflammation that contribute to major depressive disorder are unknown. We examine the role of the adenosine triphosphate (ATP)/purinergic type 2X7 receptor (P2X7R) pathway and the NLRP3 (nucleotide- ... ...

Abstract	Background: The mechanisms underlying stress-induced inflammation that contribute to major depressive disorder are unknown. We examine the role of the adenosine triphosphate (ATP)/purinergic type 2X7 receptor (P2X7R) pathway and the NLRP3 (nucleotide-binding, leucine-rich repeat, pyrin domain containing 3) inflammasome in interleukin (IL)-1β and depressive behavioral responses to stress. Methods: The influence of acute restraint stress on extracellular ATP, glutamate, IL-1β, and tumor necrosis factor alpha in hippocampus was determined by microdialysis, and the influence of acute restraint stress on the NLRP3 inflammasome was determined by western blot analysis. The influence of P2X7R antagonist administration on IL-1β and tumor necrosis factor alpha and on anxiety and depressive behaviors was determined in the chronic unpredictable stress rodent model. The role of the NLRP3 inflammasome was determined by analysis of Nlrp3 null mice. Results: Acute restraint stress rapidly increased extracellular ATP, an endogenous agonist of P2X7R; the inflammatory cytokine IL-1β; and the active form of the NLRP3 inflammasome in the hippocampus. Administration of a P2X7R antagonist completely blocked the release of IL-1β and tumor necrosis factor alpha, another stress-induced cytokine, and activated NLRP3. Moreover, P2X7R antagonist administration reversed the anhedonic and anxiety behaviors caused by chronic unpredictable stress exposure, and deletion of the Nlrp3 gene rendered mice resistant to development of depressive behaviors caused by chronic unpredictable stress. Conclusions: These findings demonstrate that psychological "stress" is sensed by the innate immune system in the brain via the ATP/P2X7R-NLRP3 inflammasome cascade, and they identify novel therapeutic targets for the treatment of stress-related mood disorders and comorbid illnesses.
MeSH term(s)	Adenosine Triphosphate/metabolism ; Anhedonia/physiology ; Animals ; Anxiety/etiology ; Anxiety/immunology ; Anxiety/metabolism ; Behavior, Animal/physiology ; Depression/etiology ; Depression/immunology ; Depression/metabolism ; Disease Models, Animal ; Inflammasomes/metabolism ; Interleukin-1beta/metabolism ; Male ; Mice ; Mice, Knockout ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Purinergic P2Y Receptor Agonists/metabolism ; Purinergic P2Y Receptor Antagonists/metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, Purinergic P2Y2/metabolism ; Stress, Psychological/complications ; Stress, Psychological/immunology ; Stress, Psychological/metabolism ; Tumor Necrosis Factor-alpha/metabolism
Chemical Substances	Inflammasomes ; Interleukin-1beta ; NLR Family, Pyrin Domain-Containing 3 Protein ; Purinergic P2Y Receptor Agonists ; Purinergic P2Y Receptor Antagonists ; Receptors, Purinergic P2Y2 ; Tumor Necrosis Factor-alpha ; Adenosine Triphosphate (8L70Q75FXE)
Language	English
Publishing date	2016-07-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	209434-4
ISSN	1873-2402 ; 0006-3223
ISSN (online)	1873-2402
ISSN	0006-3223
DOI	10.1016/j.biopsych.2015.11.026
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Article: Qualification of LSP1-2111 as a Brain Penetrant Group III Metabotropic Glutamate Receptor Orthosteric Agonist.

Cajina, Manuel / Nattini, Megan / Song, Dekun / Smagin, Gennady / Jørgensen, Erling B / Chandrasena, Gamini / Bundgaard, Christoffer / Toft, Dorthe Bach / Huang, Xinyan / Acher, Francine / Doller, Dario

ACS medicinal chemistry letters

2013 Volume 5, Issue 2, Page(s) 119–123

Abstract: LSP1-2111 is a group III metabotropic glutamate receptor agonist with preference toward the mGlu4 receptor subtype. This compound has been extensively used as a tool to explore the pharmacology of mGlu4 receptor activation in preclinical animal ... ...

Abstract	LSP1-2111 is a group III metabotropic glutamate receptor agonist with preference toward the mGlu4 receptor subtype. This compound has been extensively used as a tool to explore the pharmacology of mGlu4 receptor activation in preclinical animal behavioral models. However, the blood-brain barrier penetration of this amino acid derivative has never been studied. We report studies on the central nervous system (CNS) disposition of LSP1-2111 using quantitative microdialysis in rat. Significant unbound concentrations of the drug relative to its in vitro binding affinity and functional potency were established in extracellular fluid (ECF). These findings support the use of LSP1-2111 to study the CNS pharmacology of mGlu4 receptor activation through orthosteric agonist mechanisms.
Language	English
Publishing date	2013-12-12
Publishing country	United States
Document type	Journal Article
ISSN	1948-5875
ISSN	1948-5875
DOI	10.1021/ml400338f
Database	MEDical Literature Analysis and Retrieval System OnLINE

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