Document text
Principal Investigator: Nicholas Varvel
Organization: EMORY UNIVERSITY
Fiscal Year: 2024
Award: $504,623
Funding agency: National Institute of Neurological Disorders and Stroke
Project Summary
Accumulating evidence in humans and in animal models indicates that inflammation of the brain that
develops after status epilepticus (SE) may play a determinant role in long-term detrimental consequences,
independent of an infection or auto-immune cause. The pathophysiological interactions among the various
inflammatory molecules, and the sequence of events leading to their induction, have not yet been dissected.
Previous work pointed to a role for cyclooxygenase-2 (COX-2) pathways in SE-induced inflammation, and
showed that the EP2 receptor mediates much of the COX-2 effect. Our recent work suggests that PGE2
released from neurons after SE activates EP2 receptors on nearby neurons and myeloid cells, and that EP2
activation on neurons and myeloid cells might cause opposing effects. We hypothesize that EP2 activation
on neurons after SE is neuroprotective, whereas EP2 activation on microglia or invading monocytes results
in cytokine synthesis and subsequent development of epilepsy. Here we use a novel HaloTag technology to
target neurons and myeloid cells separately with EP2 antagonists and agonists to test this hypothesis. Our
specific aims are: 1. To test the hypothesis that pharmacologic block of EP2 receptors on neurons and
myeloid cells has opposing effects after SE. 2. To test the hypothesis that blocking EP2 receptors on myeloid
cells interferes with the process of epileptogenesis. 3. To test the hypothesis that EP2-mediated
neuroprotection involves neuronal EP2 receptors, utilizes a cAMP rather than β-arrestin pathway, and
requires CX3CL1 (fractalkine). To address these aims we employ in vitro culture models and in vivo SE
models with novel EP2 antagonists and agonists targeted by HaloTag to neurons or microglia.
Immunohistochemical, western blot, qRT-PCR, cell viability, EEG and behavioral assays are performed.
Terms: <3'5'-cyclic ester of AMP><ABCD-3><Ablation><Acquired brain injury><Address><Adenosine Cyclic 3',5'-Monophosphate><Adenosine Cyclic Monophosphate><Adenosine Cyclic Monophosphate-Dependent Protein Kinases><Adenosine, cyclic 3',5'-(hydrogen phosphate)><Agonist><Ammon Horn><Amygdala><Amygdaloid Body><Amygdaloid Nucleus><Amygdaloid structure><Animal Model><Animal Models and Related Studies><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-epileptogenic><Anti-inflammatory><Antiepileptogenic><Appearance><Astrocytes><Astrocytus><Astroglia><Autoimmune><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Behavioral Assay><Biology><Blood - brain barrier anatomy><Blood monocyte><Blood-Brain Barrier><Brain><Brain Inflammation><Brain Injuries><Brain Nervous System><C3Xkine><COX-2 protein><COX2 enzyme><CX(3)C protein><CX3CL1><CX3CL1 gene><CXC3><CXC3C><Cell Body><Cell Survival><Cell Viability><Cells><Chemokine (C-X3-C Motif) Ligand 1><Chlorohemin><Chronic><Cognitive deficits><Convulsants><Cornu Ammonis><Coupled><Cre driver><Cyclic AMP><Cyclic AMP-Dependent Protein Kinases><Cyclo-Oxygenase-2><DOH-CB-PGE1><Development><Dimensions><Dinoprostone><Disease><Disorder><EEG><Electroencephalogram><Electroencephalography><Elements><Encephalitis><Encephalon><Epilepsy><Epileptic Seizures><Epileptics><Epileptogenesis><Event><FKN protein><Ferriheme Chloride><Ferriprotoporphyrin IX Chloride><Fore-Brain><Forebrain><Fractalkine><Frequencies><Generalized Status Epilepticus><HPGF><Hemato-Encephalic Barrier><Hemin><Hepatocyte-Stimulating Factor><Hippocampus><Hortega cell><Hour><Human><Hybridoma Growth Factor><IFN-beta 2><IFNB2><IL-6><IL6 Protein><Immunoblotting><In Vitro><Incidence><Induced Neurons><Infection><Infiltration><Inflammation><Inflammatory><Interleukin-6><Interruption><Invaded><Knock-out><Knockout><Ligands><MGI-2><Marrow monocyte><Mediating><Membrane><Mice><Mice Mammals><Microglia><Modeling><Modern Man><Modification><Molecular><Murine><Mus><Myelogenous><Myeloid><Myeloid Cells><Myeloid Differentiation-Inducing Protein><N Methyl D aspartic Acid><N methyl D aspartate><N-Methyl-D-aspartate><N-Methylaspartate><NMDA><Nerve Cells><Nerve Degeneration><Nerve Unit><Nervous System Diseases><Nervous System Disorder><Neural Cell><Neurocyte><Neurologic Disorders><Neurological Disorders><Neuron Degeneration><Neuronal Injury><Neurons><ORFs><Open Reading Frames><Oral><Outcome><PGE Receptors><PGE2><PGE2 Receptors><PGE2 alpha><PGE2alpha><PGH Synthase 2><PGHS2><PHS II><PKA><Pathway interactions><Peptides><Pilocarpine><Plasmacytoma Growth Factor><Play><Process><Prosencephalon><Prostaglandin E Receptor><Prostaglandin E2><Prostaglandin E2 alpha><Prostaglandin E2alpha><Prostaglandin G/H Synthase 2><Prostaglandin H2 Synthase 2><Prostaglandin Receptor><Prostaglandin-Endoperoxide Synthase 2><Protein Coding Region><Protein Kinase A><Proteins><Protohemin><Quantitative RTPCR><Quantitative Reverse Transcriptase PCR><Reaction><Receptor Protein><Reporting><Rodent><Rodentia><Rodents Mammals><Role><SCYD1><Seizure Disorder><Seizures><Series><Small Inducible Cytokine D1><Status Epilepticus><Technology><Testing><Transgenes><Western Blotting><Western Immunoblotting><Work><adenosine 3'5' monophosphate><amygdaloid nuclear complex><antagonism><antagonist><arrestin B><astrocytic glia><beta-arrestin><bloodbrain barrier><brain damage><brain-injured><butaprost><cAMP><cAMP-Dependent Protein Kinases><cell type><cognitive defects><cyclo-oxygenase II><cyclooxygenase 2><cytokine><developmental><epilepsia><epileptogenic><excitotoxic><excitotoxicity><genetic approach><genetic strategy><gitter cell><hippocampal><iNeuron><in vivo><interferon beta 2><kainate><man><membrane structure><mesoglia><microglial cell><microgliocyte><model of animal><monocyte><neural degeneration><neural inflammation><neurodegeneration><neurodegenerative><neuroinflammation><neuroinflammatory><neurological degeneration><neurological disease><neuron injury><neuron toxicity><neuronal><neuronal degeneration><neuronal toxicity><neuropathologic><neuropathological><neuropathology><neuroprotection><neuroprotective><neurotoxicity><novel><pathway><perivascular glial cell><pharmacologic><prevent><preventing><primary outcome><prostaglandin H synthase-2><protein blotting><qRTPCR><receptor><social role><transgene><virtual><β-arrestin>