Biology subjects

Dingledine, R.

Publications and source records attributed to Dingledine, R..

4 recordsLinked to original sources

bioRxiv2025

CCR2 antagonism identifies blood-borne monocytes as a target for prevention of cognitive deficits after seizures

Seizure-associated cognitive co-morbidities can substantially reduce the quality of life in people with epilepsy. Neuroinflammation is an invariant feature of all chronic neurologic diseases, including epilepsy, and acute brain insults, including status epilepticus (SE). The generalized seizures of SE trigger a robust inflammatory response involving astrocytosis, erosion of the blood-brain barrier (BBB), activation of brain-resident microglia, and recruitment of blood-borne CCR2+ monocytes into the brain. We have shown that blocking monocyte recruitment into the brain via global Ccr2 knockout or systemic CCR2 antagonism with a small molecule alleviates multiple deleterious SE-induced pathologies, including BBB damage, microgliosis, neuronal damage, and monocyte brain invasion in the days following pilocarpine-induced SE. This study aimed to determine if fleeting CCR2 antagonism improves SE-associated cognitive impairments in the long term. Here, we show that the brief antagonism of CCR2 eliminates the profound deficit in working memory in the Y-maze and retention memory in the novel object recognition test but does not attenuate anxiety-like behavior in the open field arena. Microgliosis and astrocytosis were observed in brain sections from SE mice after the behavioral tests, and CA1 hippocampal astrocytosis mildly correlated with performance in the Y-maze. Notably, SE mice exposed to the vehicle showed robust neuronal loss in the cortex and CA1 region of the hippocampus, and mice treated with the CCR2 antagonist showed less neurodegeneration in both the cortex and hippocampus. Our results indicate that monocyte brain infiltration after SE opens a window for preventing cognitive co-morbidities and neurodegeneration with an orally available CCR2 antagonist. HighlightsO_LICCR2 antagonism provides protection against seizure-associated cognitive deficits. C_LIO_LIA therapeutic window to alleviate SE-associated cognitive decline has been identified. C_LIO_LISelective immune modulation might be used to treat epilepsy co-morbidities. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/655010v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@1f8060org.highwire.dtl.DTLVardef@25408aorg.highwire.dtl.DTLVardef@1b03589org.highwire.dtl.DTLVardef@18ad3fc_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Tofacitinib effects profound seizure suppression through mimicking EZH2 antagonism of a pro-inflammatory gene network in epilepsy.

All current drug treatments for epilepsy, a neurological disorder affecting over 50 million people(1, 2) merely treat symptoms, and a third of patients do not respond to medication. There are no disease modifying treatments that may be administered briefly to patients to enduringly eliminate spontaneous seizures and reverse cognitive deficits(3, 4). Applying network approaches to rodent models and human temporal lobectomy samples at both whole tissue and single-nuclei resolutions, we observe the well-characterized pattern of rapid induction and subsequent quenching exhibited of the JAK/STAT pathway within days of epileptogenic insult. This is followed by a resurgent activation weeks to months later with the onset of spontaneous seizures. Targeting the first wave of activation after epileptic insult does not prevent disease. However, brief inhibition of the second wave with CP690550 (Tofacitinib) (5, 6) enduringly suppresses seizures, rescues deficits in spatial memory, and alleviates epilepsy-associated histopathological alterations. Seizure suppression lasts for at least 2 months after the final dose. Using discovery-based transcriptomic analysis across models of epilepsy and validation of putative mechanisms with human data, we demonstrate a powerful approach to identifying disease modifying targets; this may be useful for other neurological disorders. With this approach, we find that reignition of inflammatory JAK/STAT3 signaling in chronic epilepsy opens a window for disease modification with the FDA-approved, orally available drug CP690550.

neuroscience↗

bioRxiv2019

A Systems Approach Identifies Enhancer of Zeste Homolog 2 (EZH2) as a Protective Factor in Epilepsy

Complex neurological conditions can give rise to large scale transcriptomic changes that drive disease progression. It is likely that alterations in one or a few transcription factors or cofactors underlie these transcriptomic alterations. Identifying the driving transcription factors/cofactors is a non-trivial problem and a limiting step in the understanding of neurological disorders. Epilepsy has a prevalence of 1% and is the fourth most common neurological disorder. While a number of anti-seizure drugs exist to treat seizures symptomatically, none is curative or preventive. This reflects a lack of understanding of disease progression. We used a novel systems approach to mine transcriptome profiles of rodent and human epileptic brain samples to identify regulators of transcriptional networks in the epileptic brain. We find that Enhancer of Zeste Homolog 2 (EZH2) regulates differentially expressed genes in epilepsy across multiple rodent models of acquired epilepsy. EZH2 undergoes a prolonged upregulation in the epileptic brain. A transient inhibition of EZH2 immediately after seizure induction robustly increases spontaneous seizure burden weeks later. Thus, EZH2 upregulation is a protective response mounted after a seizure. These findings are the first to characterize a role for EZH2 in opposing epileptogenesis and debut a bioinformatic approach to identify nuclear drivers of complex transcriptional changes in disease.\n\nAuthor SummaryEpilepsy is the fourth most common neurological disorder and has been described since the time of Hippocrates. Despite this, no treatments exist to stop epilepsy progression. This is fundamentally due to the complex nature of the disease. Epilepsy is associated with hundreds if not thousands of gene expression changes in the brain that are likely driven by a few key master regulators called transcription factors and cofactors. Finding the aberrantly acting factors is a complex problem that currently lacks a satisfactory solution. We used a novel datamining tool to define key master regulators of gene expression changes across multiple epilepsy models and patient samples. We find that a nuclear enzyme, EZH2, regulates a large number of genes in the rodent and patient epileptic brain and that its function is protective. Thus, inhibiting EZH2 greatly exacerbates seizure burden. This is the first report of a novel datamining tool to define drivers of large-scale gene changes and is also the first report of EZH2 induction as an endogenous protective response in the epilepsy.

neuroscience↗

bioRxiv2018

Opposing effects of prostaglandin receptor EP2 signaling in mouse immune cells and neurons after status epilepticus

A multidimensional inflammatory response ensues after status epilepticus (SE), driven partly by cyclooxygenase-2 mediated activation of prostaglandin EP2 receptors. Here we identify those effects of EP2 antagonism that are reproduced by conditional ablation of EP2 receptors in immune myeloid cells and forebrain neurons. Removal of myeloid cell EP2 dampened induction of hippocampal IL-6, prevented erosion of the blood-brain barrier, accelerated weight regain, and relieved ptosis following SE. Elimination of EP2 receptor from neurons enhanced neuronal injury, elevated hippocampal induction of the pro-inflammatory cytokines, TNF and Ccl2, promoted deterioration of the blood-brain barrier, delayed weight recovery, and worsened animal posture and activity. Taken together these data highlight the complexities in neuroinflammatory signaling, wherein activation of EP2 receptors in innate immune cells is deleterious but neuronal EP2 signaling is protective. Effective treatments targeting brain prostaglandin signaling pathways should be cell targeted to be optimally effective.\n\nSignificance StatementSeizures reduce quality of life, promote the development of epilepsy, and can be fatal. We previously identified inflammation, via prostaglandin receptor EP2 activation, as a driver of undesirable seizure-induced effects. However, the relevant EP2-expressing cell types remain unclear. We identify innate immune cells as a driver of the EP2-related negative consequences of seizures, whereas neuronal EP2 signaling is protective. Genetic removal of EP2 from immune cells was beneficial, accelerating weight gain and limiting behavioral deficits. Elimination of EP2 from neurons was harmful, worsening behavioral deficits and promoting neuronal damage. These findings enhance our understanding of the complex inflammatory processes engaged after seizures and will assist in the development of beneficial therapies to enhance quality of life in individuals susceptible to seizures.

neuroscience↗