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Article: P2X7 Forges Ahead in Neonatal Hypoxia.

Dingledine, Ray

2023 Volume 23, Issue 4, Page(s) 251–253

Language	English
Publishing date	2023-05-05
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	2270080-8
ISSN	1535-7597
ISSN	1535-7597
DOI	10.1177/15357597231172324
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Article ; Online: Why Is It so Hard to Do Good Science?

Dingledine, Ray

eNeuro

2018 Volume 5, Issue 5

Abstract: Good science" means answering important questions convincingly, a challenging endeavor under the best of circumstances. Our inability to replicate many biomedical studies has been the subject of numerous commentaries both in the scientific and lay press. ...

Abstract	"Good science" means answering important questions convincingly, a challenging endeavor under the best of circumstances. Our inability to replicate many biomedical studies has been the subject of numerous commentaries both in the scientific and lay press. In response, statistics has re-emerged as a necessary tool to improve the objectivity of study conclusions. However, psychological aspects of decision making introduce preconceived preferences into scientific judgment that cannot be eliminated by any statistical method. The psychology of decision making, expounded by Kahneman, Tversky, and Thaler, is well known in the field of economics, but the underlying concepts of cognitive psychology are also relevant to scientific judgments. I repeated experiments carried out on undergraduates by Kahneman and colleagues four to five decades ago, but with scientists, and obtained essentially the same results. The experiments were in the form of written reactions to scenarios, and participants were scientists at all career stages. The findings reinforce the roles that two inherent intuitions play in scientific decision making: our drive to create a coherent narrative from new data regardless of its quality or relevance and our inclination to seek patterns in data whether they exist or not. Moreover, we do not always consider how likely a result is regardless of its
MeSH term(s)	Bayes Theorem ; Cognition/physiology ; Decision Making/physiology ; Humans ; Judgment/physiology ; Learning/physiology ; Research ; Research Design ; Science
Language	English
Publishing date	2018-09-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2800598-3
ISSN	2373-2822 ; 2373-2822
ISSN (online)	2373-2822
ISSN	2373-2822
DOI	10.1523/ENEURO.0188-18.2018
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Article ; Online: Pharmacological inhibition of the inflammatory receptor CCR2 relieves the early deleterious consequences of status epilepticus.

Alemán-Ruiz, Carlos / Wang, Wenyi / Dingledine, Ray / Varvel, Nicholas H

Scientific reports

2023 Volume 13, Issue 1, Page(s) 5651

Abstract: Generalized status epilepticus (SE) triggers a robust neuroinflammatory response involving reactive astrocytosis, activation of brain-resident microglia, and brain infiltration of CCR2+ monocytes. Multiple lines of evidence indicate that quenching SE- ... ...

Abstract	Generalized status epilepticus (SE) triggers a robust neuroinflammatory response involving reactive astrocytosis, activation of brain-resident microglia, and brain infiltration of CCR2+ monocytes. Multiple lines of evidence indicate that quenching SE-induced neuroinflammation can alleviate the adverse consequences of SE, including neuronal damage and cognitive impairments. Our recent findings show that blocking monocyte brain entry after SE, via global Ccr2 KO, rescues several SE-induced adverse effects including blood-brain barrier (BBB) erosion, microgliosis and neuronal damage while enhancing weight regain. The goals of the present study were to determine if CCR2 antagonism with a small molecule after SE replicates the effects of the CCR2 knockout. Male Ccr2
MeSH term(s)	Mice ; Male ; Animals ; Gliosis/drug therapy ; Status Epilepticus/chemically induced ; Status Epilepticus/drug therapy ; Monocytes/physiology ; Macrophages ; Seizures ; Inflammation ; Receptors, Chemokine ; Receptors, CCR2/genetics ; Mice, Inbred C57BL
Chemical Substances	Receptors, Chemokine ; Receptors, CCR2 ; Ccr2 protein, mouse
Language	English
Publishing date	2023-04-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-32752-9
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Article ; Online: Pharmacological inhibition of the inflammatory receptor CCR2 relieves the early deleterious consequences of status epilepticus

Carlos Alemán-Ruiz / Wenyi Wang / Ray Dingledine / Nicholas H. Varvel

Scientific Reports, Vol 13, Iss 1, Pp 1-

2023 Volume 14

Abstract: Abstract Generalized status epilepticus (SE) triggers a robust neuroinflammatory response involving reactive astrocytosis, activation of brain-resident microglia, and brain infiltration of CCR2+ monocytes. Multiple lines of evidence indicate that ... ...

Abstract	Abstract Generalized status epilepticus (SE) triggers a robust neuroinflammatory response involving reactive astrocytosis, activation of brain-resident microglia, and brain infiltration of CCR2+ monocytes. Multiple lines of evidence indicate that quenching SE-induced neuroinflammation can alleviate the adverse consequences of SE, including neuronal damage and cognitive impairments. Our recent findings show that blocking monocyte brain entry after SE, via global Ccr2 KO, rescues several SE-induced adverse effects including blood–brain barrier (BBB) erosion, microgliosis and neuronal damage while enhancing weight regain. The goals of the present study were to determine if CCR2 antagonism with a small molecule after SE replicates the effects of the CCR2 knockout. Male Ccr2 +/rfp heterozygous mice were subject to intraperitoneal injection of kainic acid, scored for seizure severity, weight recovery, and nest building capability. Surviving mice were randomized into CCR2 antagonist and vehicle groups. The CCR2 antagonist, or vehicle, was administered 24- and 48-h post-SE via oral gavage, and mice were sacrificed three days post-SE. Mice subject to the CCR2 antagonist displayed faster weight recovery between one- and three-days post-SE and modestly enhanced ability to build a nest on the third day after SE when compared to vehicle-treated controls. CCR2 antagonism limited monocyte recruitment to the hippocampus and reduced numbers of Iba1+ macrophages. The mRNA levels of inflammatory mediators were depressed by 47%, and glial markers were reduced by 30% in mice treated with the CCR2 antagonist compared to controls. Astrocytosis was reduced in four brain regions. Neuroprotection was observed in the hippocampus, and erosion of the BBB was lessened in mice subject to the antagonist. Our findings provide proof-of-concept that brief CCR2 antagonism beginning one day after SE can alleviate multiple adverse SE-induced effects, including functional impairment, and identify circulating CCR2+ monocytes as a viable therapeutic ...
Keywords	Medicine ; R ; Science ; Q
Subject code	630
Language	English
Publishing date	2023-04-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Phase 1 Clinical Results for NP10679, a pH-sensitive GluN2B-selective N-methyl-d-aspartate Receptor Inhibitor.

Zaczek, Robert / Traynelis, Stephen F / Dingledine, Ray / Koszalka, George W / Laskowitz, Daniel T

Clinical pharmacology in drug development

2023 Volume 12, Issue 7, Page(s) 706–717

Abstract: NP10679 is a context-dependent and subunit-selective negative allosteric modulator of N-methyl-d-aspartate (NMDA) receptors. It is a more potent inhibitor of GluN2B-containing NMDA receptors at the acidic levels of extracellular pH (eg, 6.9) found in the ...

Abstract	NP10679 is a context-dependent and subunit-selective negative allosteric modulator of N-methyl-d-aspartate (NMDA) receptors. It is a more potent inhibitor of GluN2B-containing NMDA receptors at the acidic levels of extracellular pH (eg, 6.9) found in the penumbral regions associated with cerebral ischemia than at physiological pH. This property allows NP10679 to act selectively in ischemic tissue while minimizing the nonselective blockade of NMDA receptors in healthy brain, thereby reducing on-target adverse effects. We report the results of a first-in-human pharmacokinetic and safety phase 1 clinical trial in healthy volunteers receiving single or multiple doses of NP10679 (NCT04007263). We found that NP10679 was well-tolerated and with a half-life of 20 hours, which is amenable to once per day dosing. The only notable side effect in this clinical trial was modest somnolence at higher doses, atypical in that the subject could easily be aroused. The overall results suggest that NP10679 is a candidate for further development for use in acute brain injury, such as ischemic stroke or aneurysmal subarachnoid hemorrhage, as well as for use in neuropsychiatric indications.
MeSH term(s)	Humans ; Receptors, N-Methyl-D-Aspartate ; Hydrogen-Ion Concentration
Chemical Substances	Receptors, N-Methyl-D-Aspartate
Language	English
Publishing date	2023-01-15
Publishing country	United States
Document type	Clinical Trial, Phase I ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2649010-9
ISSN	2160-7648 ; 2160-763X
ISSN (online)	2160-7648
ISSN	2160-763X
DOI	10.1002/cpdd.1217
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Article ; Online: An Agonist Dependent Allosteric Antagonist of Prostaglandin EP2 Receptors.

Jiang, Chunxiang / Amaradhi, Radhika / Ganesh, Thota / Dingledine, Ray

ACS chemical neuroscience

2020 Volume 11, Issue 10, Page(s) 1436–1446

Abstract: All reported prostaglandin EP2 receptor antagonists have a purely orthosteric, competitive mode of action. Herein, we report the characterization of ... ...

Abstract	All reported prostaglandin EP2 receptor antagonists have a purely orthosteric, competitive mode of action. Herein, we report the characterization of compound
MeSH term(s)	Animals ; Humans ; Interleukin-6 ; Mice ; Prostaglandins ; Receptors, Prostaglandin E, EP2 Subtype ; Tumor Necrosis Factor-alpha
Chemical Substances	Interleukin-6 ; Prostaglandins ; Receptors, Prostaglandin E, EP2 Subtype ; Tumor Necrosis Factor-alpha
Language	English
Publishing date	2020-05-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1948-7193
ISSN (online)	1948-7193
DOI	10.1021/acschemneuro.0c00078
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Article ; Online: Inhibition of the prostaglandin EP2 receptor prevents long-term cognitive impairment in a model of systemic inflammation.

Jiang, Chunxiang / Caskurlu, Aysegul / Ganesh, Thota / Dingledine, Ray

Brain, behavior, & immunity - health

2020 Volume 8, Page(s) 100132

Abstract: Long-term cognitive and affective impairments are common problems in the survivors of sepsis, which weakens their vocational and daily life ability. Neuroinflammation has been reported to exert a key role in the development of cognitive deficit in ... ...

Abstract	Long-term cognitive and affective impairments are common problems in the survivors of sepsis, which weakens their vocational and daily life ability. Neuroinflammation has been reported to exert a key role in the development of cognitive deficit in different disorders including epilepsy, Alzheimer's disease (AD) and stroke. Mice treated with lipopolysaccharide (LPS), an endotoxin produced by gram-negative bacteria, show a robust but short-lived neuroinflammation and develop long-term memory and affective problems. In this study, we test the hypothesis that pharmacological blockade of the EP2 receptor for prostaglandin E2 reduces neuroinflammation and prevents long-term affective and memory deficits in a mouse model of LPS-induced, sepsis-associated encephalopathy (SAE). Our results show that an EP2 antagonist, TG6-10-1, promotes the recovery of body weight, mitigates neuroinflammation as judged by inflammatory cytokines and microgliosis, prevents the loss of synaptic proteins, and ameliorates depression-like behavior in the sucrose preference test as well as memory loss in the novel object recognition test. Our results point to a new avenue to ameliorate neuroinflammation and long-term affective and cognition problems of sepsis survivors.
Language	English
Publishing date	2020-08-25
Publishing country	United States
Document type	Journal Article
ISSN	2666-3546
ISSN (online)	2666-3546
DOI	10.1016/j.bbih.2020.100132
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Article ; Online: Novel GluN2B-Selective NMDA Receptor Negative Allosteric Modulator Possesses Intrinsic Analgesic Properties and Enhances Analgesia of Morphine in a Rodent Tail Flick Pain Model.

Harris, Lynnea D / Regan, Michael C / Myers, Scott J / Nocilla, Kelsey A / Akins, Nicholas S / Tahirovic, Yesim A / Wilson, Lawrence J / Dingledine, Ray / Furukawa, Hiro / Traynelis, Stephen F / Liotta, Dennis C

ACS chemical neuroscience

2023 Volume 14, Issue 5, Page(s) 917–935

Abstract: Many cases of accidental death associated with drug overdose are due to chronic opioid use, tolerance, and addiction. Analgesic tolerance is characterized by a decreased response to the analgesic effects of opioids, requiring increasingly higher doses to ...

Abstract	Many cases of accidental death associated with drug overdose are due to chronic opioid use, tolerance, and addiction. Analgesic tolerance is characterized by a decreased response to the analgesic effects of opioids, requiring increasingly higher doses to maintain the desired level of pain relief. Overactivation of GluN2B-containing
MeSH term(s)	Animals ; Morphine ; Analgesics, Opioid/pharmacology ; Analgesics, Opioid/therapeutic use ; Receptors, N-Methyl-D-Aspartate/metabolism ; Rodentia/metabolism ; Analgesics/pharmacology ; Analgesics/therapeutic use ; Pain/drug therapy ; Pain/metabolism ; Analgesia ; Dose-Response Relationship, Drug
Chemical Substances	Morphine (76I7G6D29C) ; Analgesics, Opioid ; Receptors, N-Methyl-D-Aspartate ; Analgesics
Language	English
Publishing date	2023-02-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1948-7193
ISSN (online)	1948-7193
DOI	10.1021/acschemneuro.2c00779
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Article ; Online: Peripherally Restricted, Highly Potent, Selective, Aqueous-Soluble EP2 Antagonist with Anti-Inflammatory Properties.

Ganesh, Thota / Banik, Avijit / Dingledine, Ray / Wang, Wenyi / Amaradhi, Radhika

Molecular pharmaceutics

2018 Volume 15, Issue 12, Page(s) 5809–5817

Abstract: The prostaglandin ... ...

Abstract	The prostaglandin E
MeSH term(s)	Animals ; Anti-Inflammatory Agents/chemistry ; Anti-Inflammatory Agents/pharmacology ; Anti-Inflammatory Agents/therapeutic use ; Arthritis, Rheumatoid/drug therapy ; Arthritis, Rheumatoid/immunology ; Cell Line ; Dinoprostone/immunology ; Dinoprostone/metabolism ; Drug Evaluation, Preclinical ; Endometriosis/drug therapy ; Endometriosis/immunology ; Female ; Half-Life ; Inflammation Mediators/immunology ; Inflammation Mediators/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Neoplasms/drug therapy ; Neoplasms/immunology ; Rats ; Receptors, Prostaglandin/metabolism ; Receptors, Prostaglandin E, EP2 Subtype/antagonists & inhibitors ; Receptors, Prostaglandin E, EP2 Subtype/immunology ; Receptors, Prostaglandin E, EP2 Subtype/metabolism ; Receptors, Prostaglandin E, EP4 Subtype/metabolism ; Solubility ; Up-Regulation/drug effects ; Up-Regulation/immunology ; Water/chemistry
Chemical Substances	Anti-Inflammatory Agents ; Inflammation Mediators ; PTGER2 protein, human ; Receptors, Prostaglandin ; Receptors, Prostaglandin E, EP2 Subtype ; Receptors, Prostaglandin E, EP4 Subtype ; prostanoid D receptor 1, human ; Water (059QF0KO0R) ; Dinoprostone (K7Q1JQR04M)
Language	English
Publishing date	2018-11-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2138405-8
ISSN	1543-8392 ; 1543-8384
ISSN (online)	1543-8392
ISSN	1543-8384
DOI	10.1021/acs.molpharmaceut.8b00764
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Article ; Online: Prostaglandin receptor EP2 in the crosshairs of anti-inflammation, anti-cancer, and neuroprotection.

Jiang, Jianxiong / Dingledine, Ray

Trends in pharmacological sciences

2013 Volume 34, Issue 7, Page(s) 413–423

Abstract: Modulation of a specific prostanoid synthase or receptor provides therapeutic alternatives to nonsteroidal anti-inflammatory drugs (NSAIDs) for treating pathological conditions governed by cyclooxygenase-2 (COX-2 or PTGS2). Among the COX-2 downstream ... ...

Abstract	Modulation of a specific prostanoid synthase or receptor provides therapeutic alternatives to nonsteroidal anti-inflammatory drugs (NSAIDs) for treating pathological conditions governed by cyclooxygenase-2 (COX-2 or PTGS2). Among the COX-2 downstream signaling pathways, the prostaglandin E2 (PGE2) receptor EP2 subtype (PTGER2) is emerging as a crucial mediator of many physiological and pathological events. Genetic ablation strategies and recent advances in chemical biology provide tools for a better understanding of EP2 signaling. In the brain, the EP2 receptor modulates some beneficial effects, including neuroprotection, in acute models of excitotoxicity, neuroplasticity, and spatial learning via cAMP-PKA signaling. Conversely, EP2 activation accentuates chronic inflammation mainly through the cAMP-Epac pathway, likely contributing to delayed neurotoxicity. EP2 receptor activation also engages β-arrestin in a G-protein-independent pathway that promotes tumor cell growth and migration. Understanding the conditions under which multiple EP2 signaling pathways are engaged might suggest novel therapeutic strategies to target this key inflammatory prostaglandin receptor.
MeSH term(s)	Animals ; Anti-Inflammatory Agents/chemistry ; Anti-Inflammatory Agents/pharmacology ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Dinoprostone/metabolism ; Drug Design ; Humans ; Neuroprotective Agents/chemistry ; Neuroprotective Agents/pharmacology ; Receptors, Prostaglandin E, EP2 Subtype/drug effects ; Receptors, Prostaglandin E, EP2 Subtype/metabolism ; Signal Transduction/drug effects
Chemical Substances	Anti-Inflammatory Agents ; Antineoplastic Agents ; Neuroprotective Agents ; Receptors, Prostaglandin E, EP2 Subtype ; Dinoprostone (K7Q1JQR04M)
Language	English
Publishing date	2013-06-21
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	282846-7
ISSN	1873-3735 ; 0165-6147
ISSN (online)	1873-3735
ISSN	0165-6147
DOI	10.1016/j.tips.2013.05.003
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