Imaging Brain Inflammation: If We Can See It, Maybe We Can Treat It

French, Jacqueline

doi:10.5698/1535-7597-16.1.24

Cited by 5 publications

(6 citation statements)

References 11 publications

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“…Neuroinflammation and neurodegeneration are emerging as new mechanistic targets for drug development for neurological disorders ( Ba et al, 2014 ; French, 2016 ). SE-induced changes in the brain result in the proliferation and migration of glia (gliosis) and neurons (neurogenesis) to compensate for the neuronal loss ( Beamer et al, 2012 ; Puttachary et al, 2016a , 2016b ).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of disease-modifying effect of saracatinib (AZD0530), a Src/Fyn tyrosine kinase inhibitor, in the rat kainate model of temporal lobe epilepsy

Sharma

Carlson

Gregory-Flores

et al. 2021

Neurobiology of Disease

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We have recently demonstrated the role of the Fyn-PKCδ signaling pathway in status epilepticus (SE)-induced neuroinflammation and epileptogenesis in experimental models of temporal lobe epilepsy (TLE). In this study, we show a significant disease-modifying effect and the mechanisms of a Fyn/Src tyrosine kinase inhibitor, saracatinib (SAR, also known as AZD0530), in the rat kainate (KA) model of TLE. SAR treatment for a week, starting the first dose (25 mg/kg, oral) 4 h after the onset of SE, significantly reduced spontaneously recurring seizures and epileptiform spikes during the four months of continuous video-EEG monitoring. Immunohistochemistry of brain sections and Western blot analyses of hippocampal lysates at 8-day (8d) and 4-month post-SE revealed a significant reduction of SE-induced astrogliosis, microgliosis, neurodegeneration, phosphorylated Fyn/Src-419 and PKCδ-tyr311, in SAR-treated group when compared with the vehicle control. We also found the suppression of nitroxidative stress markers such as iNOS, 3-NT, 4-HNE, and gp91 phox in the hippocampus, and nitrite and ROS levels in the serum of the SAR-treated group at 8d post-SE. The qRT-PCR (hippocampus) and ELISA (serum) revealed a significant reduction of key proinflammatory cytokines TNFα and IL-1β mRNA in the hippocampus and their protein levels in serum, in addition to IL-6 and IL-12, in the SAR-treated group at 8d in contrast to the vehicle-treated group. These findings suggest that SAR targets some of the key biomarkers of epileptogenesis and modulates neuroinflammatory and nitroxidative pathways that mediate the development of epilepsy. Therefore, SAR can be developed as a potential disease-modifying agent to prevent the development and progression of TLE.

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Section: Discussionmentioning

confidence: 99%

Mechanisms of disease-modifying effect of saracatinib (AZD0530), a Src/Fyn tyrosine kinase inhibitor, in the rat kainate model of temporal lobe epilepsy

Sharma

Carlson

Gregory-Flores

et al. 2021

Neurobiology of Disease

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“…Neuroinflammation is emerging as a new mechanistic target for drug development, and it also serves as a biomarker for neuroimaging in various neurodegenerative diseases (Abi-Dargham and Horga, 2016; Albrecht et al, 2016; French 2016; Gershen et al, 2015). The microglia are considered as resident macrophages and they mediate neuroinflammation and hyperexcitability in neurons (Block, 2014; Davis and Carson, 2012; Devinsky et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Role of the Fyn-PKCδ signaling in SE-induced neuroinflammation and epileptogenesis in experimental models of temporal lobe epilepsy

Sharma

Carlson

Puttachary

et al. 2018

Neurobiology of Disease

127

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Status epilepticus (SE) induces neuroinflammation and epileptogenesis, but the mechanisms are not yet fully delineated. The Fyn, a non-receptor Src family tyrosine kinase (SFK), and its immediate downstream target, PKCδ are emerging as potential mediators of neuroinflammation. In order to first determine the role of Fyn kinase signaling in SE, we tested the efficacy of a SFK inhibitor, saracatinib (25mg/kg, oral) in C57BL/6J mouse kainate model of acute seizures. Saracatinib pretreatment dampened SE severity and completely prevented mortality. We further utilized fyn and fyn mice (wildtype control for the fyn mice on same genetic background), and the rat kainate model, treated with saracatinib post-SE, to validate the role of Fyn/SFK in SE and epileptogenesis. We observed significant reduction in SE severity, epileptiform spikes, and electrographic non-convulsive seizures in fyn mice when compared to fyn mice. Interestingly, significant reductions in phosphorylated pSrc-416 and PKCδ (pPKCδ-507) and naive PKCδ were observed in fyn mice as compared to fyn mice suggesting that PKCδ signaling is a downstream mediator of Fyn in SE and epileptogenesis. Notably, fyn mice also showed a reduction in key proinflammatory mediators TNF-α, IL-1β, and iNOS mRNA expression; serum IL-6 and IL-12 levels; and nitro-oxidative stress markers such as 4-HNE, gp91, and 3-NT in the hippocampus. Immunohistochemistry revealed a significant increase in reactive microgliosis and neurodegeneration in the hippocampus and hilus of dentate gyrus in fyn mice in contrast to fyn mice. Interestingly, we did not observe upregulation of Fyn in pyramidal neurons of the hippocampus during post-SE in fyn mice, but it was upregulated in hilar neurons of the dentate gyrus when compared to naïve control. In reactive microglia, both Fyn and PKCδ were persistently upregulated during post-SE suggesting that Fyn-PKCδ may drive neuroinflammation during epileptogenesis. Since disabling the Fyn kinase prior to SE, either by treating with saracatinib or fyn gene knockout, suppressed seizures and the subsequent epileptogenic events, we further tested whether Fyn/SFK inhibition during post-SE modifies epileptogenesis. Telemetry-implanted, SE-induced, rats were treated with saracatinib and continuously monitored for a month. At 2h post-diazepam, the saracatinib (25mg/kg) or the vehicle was administered orally and repeated twice daily for first three days followed by a single dose/day for the next four days. The saracatinib post-treatment prevented epileptogenesis in >50% of the rats and significantly reduced spontaneous seizures and epileptiform spikes in the rest (one animal did not respond) when compared to the vehicle treated group, which had >24 seizures in a month. Collectively, the findings suggest that Fyn/SFK is a potential mediator of epileptogenesis and a therapeutic target to prevent/treat seizures and epileptogenesis.

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“…6 In addition to axonal loss and demyelination, decreases in FA obtained from the basic tensor model may reflect the presence of crossing fibers or increases in extracellular diffusion due to edema or inflammation. 7,8 Given recent data suggesting that inflammation may play a role in the pathogenesis of TLE, 9 better understanding of the neurobiology of decreased FA in temporal and extratemporal regions could help to guide treatments in patients with TLE or other epilepsy syndromes. 9 In recent years, a number of advanced diffusion methods have emerged that extend beyond the tensor model and may provide more sensitive and/or specific measures of cerebral pathology in TLE.…”

mentioning

confidence: 99%

“…7,8 Given recent data suggesting that inflammation may play a role in the pathogenesis of TLE, 9 better understanding of the neurobiology of decreased FA in temporal and extratemporal regions could help to guide treatments in patients with TLE or other epilepsy syndromes. 9 In recent years, a number of advanced diffusion methods have emerged that extend beyond the tensor model and may provide more sensitive and/or specific measures of cerebral pathology in TLE. 6,[10][11][12][13] Diffusion kurtosis imaging (DKI), which is a statistical method that probes non-Gaussian diffusion and estimates diffusion heterogeneity, 14 has been applied in several studies of children 12 and adults 10,11 with TLE.…”

mentioning

confidence: 99%

Restriction spectrum imaging reveals decreased neurite density in patients with temporal lobe epilepsy

et al. 2016

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Objective Diffusion tensor imaging (DTI) has become a popular tool for delineating the location and extent of white matter injury in temporal lobe epilepsy (TLE). However, DTI yields nonspecific measures that are confounded by changes occurring within both the intracellular and extracellular environments. This study investigated whether an advanced diffusion method, restriction spectrum imaging (RSI) could provide a more robust measure of white matter injury in TLE relative to DTI due to RSI’s ability to separate intra-axonal diffusion (i.e., neurite density; ND) from diffusion associated with extra-axonal factors (e.g., inflammation; crossing fibers). Methods RSI and DTI scans were obtained on 21 patients with TLE and 11 age-matched controls. RSI-derived maps of ND, isotropic hindered (IH) and free (IF) water, and crossing fibers (CF) were compared to DTI-derived fractional anisotropy (FA) maps. Voxelwise and tract-based analyses were performed comparing patients with TLE to controls on each diffusion metric. Results Reductions in FA were seen primarily in frontotemporal white matter in TLE and were most pronounced proximal to the seizure focus. Reductions in ND corresponded to those seen in the FA maps; however, ND reductions were greater in magnitude, more lateralized to the epileptogenic hemisphere, and showed a broader pattern. Increases in IF/IH and effects from CFs also contributed to reduced FA in the ipsilateral parahippocampal cingulum and fornix, with decreases in IH extending into extratemporal regions. Reduced ND of the uncinate fasciculus was associated with longer disease duration, whereas FA was not associated with any clinical variables. Significance RSI may provide a more specific measure of white matter pathology in TLE, distinguishing regions primarily affected by axonal/myelin loss from those where CFs and increases in extracellular water also play a role. By providing a more specific measure of axonal/myelin loss, RSI-derived ND may better reflect overall white matter burden in epilepsy.

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Imaging Brain Inflammation: If We Can See It, Maybe We Can Treat It

Cited by 5 publications

References 11 publications

Mechanisms of disease-modifying effect of saracatinib (AZD0530), a Src/Fyn tyrosine kinase inhibitor, in the rat kainate model of temporal lobe epilepsy

Mechanisms of disease-modifying effect of saracatinib (AZD0530), a Src/Fyn tyrosine kinase inhibitor, in the rat kainate model of temporal lobe epilepsy

Role of the Fyn-PKCδ signaling in SE-induced neuroinflammation and epileptogenesis in experimental models of temporal lobe epilepsy

Restriction spectrum imaging reveals decreased neurite density in patients with temporal lobe epilepsy

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