Biology subjects

Ferguson, P. J.

Publications and source records attributed to Ferguson, P. J..

4 recordsLinked to original sources

bioRxiv2023

Neuroprotective Effects of Naltrexone in a Mouse Model of Post-Traumatic Epilepsy

Traumatic Brain Injury (TBI) induces neuroinflammatory responses that can initiate epileptogenesis, which develops into epilepsy. Recently, we identified the anti-convulsive effects of naltrexone, a mu-opioid receptor (MOR) antagonist. While blocking opioid receptors can reduce inflammation, it is unclear if post-TBI epileptogenesis can be prevented by blocking MORs. Here, we tested if naltrexone prevents neuroinflammation and epileptogenesis post-TBI. TBI was induced by a modified Marmarau Weight-Drop (WD) method applied to four-week-old C57BL/6J male mice. Mice were given the pro-convulsant pentylenetetrazol (PTZ) on day two post-injury while telemetry-monitored mice received PTZ on day five. Naltrexone/vehicle treatment started two hours after PTZ. Integrated EEG-video (vEEG) recorded interictal events and spontaneous seizures for three months. Molecular, histological and neuroimaging techniques were used to evaluate neuroinflammation and neurodegeneration both acutely and chronically. Peripheral immune responses were assessed through serum chemokine/cytokine measurements. We observed increases in MOR expression, nitro-oxidative stress, mRNA expression of inflammatory cytokines, microgliosis, neurodegeneration, and white matter damage in the neocortex of TBI mice. vEEG revealed increased interictal events in TBI mice, with 71% developing epilepsy. Naltrexone ameliorated neuroinflammation and neurodegeneration, reduced interictal events and prevented epilepsy, illustrating that naltrexone is a promising drug to prevent TBI-associated neuroinflammation and epileptogenesis in post-traumatic epilepsy.

neuroscience↗

bioRxiv2023

Selective neuroimmune modulation by type I interferon drives neuropathology and neurologic dysfunction following traumatic brain injury

Accumulating evidence suggests that type I interferon (IFN-I) signaling is a key contributor to immune cell-mediated neuropathology in neurodegenerative diseases. Recently, we demonstrated a robust upregulation of type I interferon-stimulated genes in microglia and astrocytes following experimental traumatic brain injury (TBI). The specific molecular and cellular mechanisms by which IFN-I signaling impacts the neuroimmune response and neuropathology following TBI remains unknown. Using the lateral fluid percussion injury model (FPI) in adult male mice, we demonstrated that IFN /{beta} receptor (IFNAR) deficiency resulted in selective and sustained blockade of type I interferon-stimulated genes following TBI as well as decreased microgliosis and monocyte infiltration. Phenotypic alteration of reactive microglia also occurred with diminished expression of molecules needed for MHC class I antigen processing and presentation following TBI. This was associated with decreased accumulation of cytotoxic T cells in the brain. The IFNAR-dependent modulation of the neuroimmune response was accompanied by protection from secondary neuronal death, white matter disruption, and neurobehavioral dysfunction. These data support further efforts to leverage the IFN-I pathway for novel, targeted therapy of TBI.

neuroscience↗

bioRxiv2019

Modulation of post-traumatic immune response using anti-IL-1 therapy for improved visual outcomes

The purpose of this study was to characterize acute changes in inflammatory pathways in the mouse eye following a blast-mediated TBI (bTBI) model, and to determine if modulation of these pathways could protect the structure and function of retinal ganglion cells (RGC). bTBI was induced in C57BL/6J male mice by exposure to three 20 PSI blast waves, with an interblast interval of one hour. Acute cytokine expression in retinal tissue was measured through real-time quantitative polymerase chain reaction (RT-qPCR) 4 hours post-blast. Increased retinal expression of lL-1{beta}, IL-1, IL-6, and TNF was observed in bTBI mice exposed to blast when compared to shams, which was associated with activation of microglia and macroglia reactivity, assessed via immunohistochemistry with IBA-1 and GFAP, respectively, 1 week post-blast. Inhibition of the IL-1 pathway was accomplished using anakina, an IL-1RI antagonist. Retinal function and structure were evaluated 4 weeks post-injury using pattern electroretinogram (PERG) and optical coherence tomography (OCT), respectively. After bTBI, anakinra treatment resulted in a preservation of RGC function and RGC structure when compared to saline treated bTBI mice. Optic nerve integrity analysis demonstrated a tred of decreased suggesting that IL-1 blockade also prevents axonal damage after blast. Blast exposure results in increased retinal inflammation including upregulation of pro-inflammatory cytokines and activation of resident microglia and macroglia. This may partially explain the RGC loss we observed in this model as blockade of the acute inflammatory response after injury with the IL-1R1 antagonist anakinra resulted in preservation of RGC function and structure.\n\nSignificance StatementBlast-mediated traumatic brain injury (bTBI) affects military members and civilians as a direct result of combat, workplace accidents, or intentional terrorist attacks. The retina is a central nervous system (CNS) tissue that is vulnerable to blast exposure. Individuals with bTBI often report visual dysfunction, but the mechanisms of ocular injury are poorly understood. This study demonstrates that damaging neuroinflammation contributes to retinal injury following blast-mediated TBI. We also identified anakinra, an anti-IL-1 therapy currently utilized for other diseases, as a potential pharmacologic agent that could prevent ocular damage after blast. These findings will aide in the development of novel treatments for vision preservation.

neuroscience↗

bioRxiv2018

In trans variant calling reveals enrichment for compound heterozygous variants in genes involved in neuronal development and growth.

Compound heterozygotes occur when different mutations at the same locus on both maternal and paternal chromosomes produce a recessive trait. Here we present the tool VarCount for the quantification of mutations at the individual level. We used VarCount to characterize compound heterozygous coding variants in patients with epileptic encephalopathy and in the 1000 genomes participants. The Epi4k data contains variants identified by whole exome sequencing in patients with either Lennox-Gastaut Syndrome (LGS) or Infantile Spasms (IS), as well as their parents. We queried the Epi4k dataset (264 trios) and the phased 1000 genomes data (2504 participants) for recessive variants. To assess enrichment, transcript counts were compared between the Epi4k and 1000 genomes participants using minor allele frequency (MAF) cutoffs of 0.5% and 1.0%, and including all ancestries or only probands of European ancestry. In the Epi4k participants, we found enrichment for rare, compound heterozygous mutations in six genes, including three involved in neuronal growth and development - PRTG (p=0.00086, 1% MAF, combined ancestries), TNC (p=0.0221% MAF, combined ancestries), and MACF1 (p=0.0245, 0.5% MAF, EU ancestry). Due the total number of transcripts considered in these analyses, the enrichment detected was not significant after correction for multiple testing and higher powered or prospective studies are necessary to validate the candidacy of these genes. However, PRTG, TNC, and MACF1 are potential novel recessive epilepsy genes and our results highlight that compound heterozygous mutations should be considered in sporadic epilepsy.

neuroscience↗