JAK/STAT pathway regulation of GABAA receptor expression after differing severities of experimental TBI

Raible, Daniel J.; Frey, Lauren C.; Angel, Yasmin Cruz Del; Carlsen, Jessica; Hund, Dana; Russek, Shelley J.; Smith, Bret N.; Brooks‐Kayal, Amy R.

doi:10.1016/j.expneurol.2015.07.001

Cited by 56 publications

(45 citation statements)

References 49 publications

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“…The JAK/STAT pathway has been shown to be a critical mediator of LTD, and is known to be activated after many types of epileptogenic injuries including TBI, SE, HI, and stroke . The JAK/STAT pathway regulates expression of genes critical for essential physiologic functions, including cell proliferation, differentiation, neurogenesis, learning and memory, and regulation of the γ‐aminobutyric acid (GABA) type A receptor (GABA A R) subunit expression.…”

Section: Potential Molecular Biomarkers Of Comorbiditiesmentioning

confidence: 99%

“…Using the controlled cortical impact (CCI) model of posttraumatic epilepsy in mice, the JAK/STAT pathway has been shown to be differentially activated depending on the severity of brain injury, and to correlate with the presence and severity of subsequent cognitive comorbidities. The degree of impact generated during CCI correlates with postinjury lesion size, levels of several GABA A R subunits, activation of the JAK/STAT pathway, and functional neurologic outcomes . Specifically, the levels of phosphorylated STAT3 (pSTAT3) were differentially increased in the injured hippocampus 6 h after CCI depending of the severity of injury (Fig.…”

Section: Potential Molecular Biomarkers Of Comorbiditiesmentioning

confidence: 99%

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WONOEP appraisal: Biomarkers of epilepsy‐associated comorbidities

et al. 2016

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Neurologic and psychiatric comorbidities are common in patients with epilepsy. Diagnostic, predictive, and pharmacodynamic biomarkers of such comorbidities do not exist. They may share pathogenetic mechanisms with epileptogenesis/ictogenesis, and as such are an unmet clinical need. The objectives of the subgroup on biomarkers of comorbidities at the XIII Workshop on the Neurobiology of Epilepsy (WONOEP) were to present the state-of-the-art recent research findings in the field that highlighting potential biomarkers for comorbidities in epilepsy. We review recent progress in the field, including molecular, imaging, and genetic biomarkers of comorbidities as discussed during the WONOEP meeting on August 31-September 4, 2015, in Heybeliada Island (Istanbul, Turkey). We further highlight new directions and concepts from studies on comorbidities and potential new biomarkers for the prediction, diagnosis, and treatment of epilepsy-associated comorbidities. The activation of various molecular signaling pathways such as the "Janus Kinase/Signal Transducer and Activator of Transcription," "mammalian Target of Rapamycin," and oxidative stress have been shown to correlate with the presence and severity of subsequent cognitive abnormalities. Furthermore, dysfunction in serotonergic transmission, hyperactivity of the hypothalamic-pituitary-adrenocortical axis, the role of the inflammatory cytokines, and the contributions of genetic factors have all recently been regarded as relevant for understanding epilepsy-associated depression and cognitive deficits. Recent evidence supports the utility of imaging studies as potential biomarkers. The role of such biomarker may be far beyond the diagnosis of comorbidities, as accumulating clinical data indicate that comorbidities can predict epilepsy outcomes. Future research is required to reveal whether molecular changes in specific signaling pathways or advanced imaging techniques could be detected in the clinical settings and correlate with epilepsy-associated comorbidities. A reliable biomarker will allow a more accurate diagnosis and improved treatment of epilepsy-associated comorbidities.

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Section: Potential Molecular Biomarkers Of Comorbiditiesmentioning

confidence: 99%

Section: Potential Molecular Biomarkers Of Comorbiditiesmentioning

confidence: 99%

WONOEP appraisal: Biomarkers of epilepsy‐associated comorbidities

et al. 2016

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“…mossy fiber sprouting) leads to recurrent excitation of DGCs and disrupts the normal information processing of the hippocampus. Synaptic inhibition of DGCs is also altered after TBI, and GABA A receptors (GABA A R's) undergo functional changes in models of TBI and epilepsy (Boychuk et al, 2016; Hunt et al, 2011; Mtchedlishvili et al, 2010; Raible et al, 2012; Raible et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

Differential effects of rapamycin treatment on tonic and phasic GABAergic inhibition in dentate granule cells after focal brain injury in mice

Butler

Boychuk

Smith

2016

Experimental Neurology

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The cascade of events leading to post-traumatic epilepsy (PTE) after traumatic brain injury (TBI) remains unclear. Altered inhibition in the hippocampal formation and dentate gyrus is a hallmark of several neurological disorders, including TBI and PTE. Inhibitory synaptic signaling in the hippocampus is predominately driven by γ-aminobutyric acid (GABA) neurotransmission, and is prominently mediated by postsynaptic type A GABA receptors (GABAAR's). Subsets of these receptors involved in tonic inhibition of neuronal membranes serve a fundamental role in maintenance of inhibitory state, and GABAAR-mediated tonic inhibition is altered functionally in animal models of both TBI and epilepsy. In this study we assessed the effect of mTOR inhibition on hippocampal hilar inhibitory interneuron loss and synaptic and tonic GABAergic inhibition of dentate gyrus granule cells (DGCs) after controlled cortical impact (CCI), to determine if mTOR activation after TBI modulates GABAAR function. Hilar inhibitory interneuron density was significantly reduced 72 hours after CCI injury in the dorsal two-thirds of the hemisphere ipsilateral to injury compared to the contralateral hemisphere and sham controls. Rapamycin treatment did not alter this reduction in cell density. Synaptic and tonic current measurements made in DGCs at both 1-2 and 8-13 weeks post-injury indicated reduced synaptic inhibition and THIP-induced tonic current density in DGCs ipsilateral to CCI injury at both time points post-injury, with no change in resting tonic GABAAR-mediated currents. Rapamycin treatment did not alter the reduced synaptic inhibition observed in ipsilateral DGCs 1-2 weeks post-CCI injury, but further reduced synaptic inhibition of ipsilateral DGCs at 8-13 weeks post-injury. The reduction in THIP-induced tonic current after injury, however, was prevented by rapamycin treatment at both time points. Rapamycin treatment thus differentially modifies CCI-induced changes in synaptic and tonic GABAAR-mediated currents in DGCs.

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“…Following TBI, WP1066 treatment improved the degree of recovery of vestibular motor function after injury. In addition, reducing JAK/STAT pathway activation after severe experimental TBI reversed the decrease in the GABAAR α1 protein levels and improved motor recovery [133]. BDNF- and seizure-dependent phosphorylation of STAT3 stimulates the binding of inducible cAMP early repressor protein (ICER) to phosphorylated CREB at the Gabra1:CRE site.…”

Section: Interruption Of Jak-stat Pathway In Epileptogenesismentioning

confidence: 99%

Novel therapeutic approaches for disease-modification of epileptogenesis for curing epilepsy

Clossen

Reddy

2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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This article describes the recent advances in epileptogenesis and novel therapeutic approaches for the prevention of epilepsy, with a special emphasis on the pharmacological basis of disease-modification of epileptogenesis for curing epilepsy. Here we assess animal studies and human clinical trials of epilepsy spanning 1982–2016. Epilepsy arises from a number of neuronal factors that trigger epileptogenesis, which is the process by which a brain shifts from a normal physiologic state to an epileptic condition. The events precipitating these changes can be of diverse origin, including traumatic brain injury, cerebrovascular damage, infections, chemical neurotoxicity, and emergency seizure conditions such as status epilepticus. Expectedly, the molecular and system mechanisms responsible for epileptogenesis are not well defined or understood. To date, there is no approved therapy for the prevention of epilepsy. Epigenetic dysregulation, neuroinflammation, and neurodegeneration appear to trigger epileptogenesis. Targeted drugs are being identified that can truly prevent the development of epilepsy in at-risk people. The promising agents include rapamycin, COX-2 inhibitors, TRK inhibitors, epigenetic modulators, JAK-STAT inhibitors, and neurosteroids. Recent evidence suggests that neurosteroids may play a role in modulating epileptogenesis. A number of promising drugs are under investigation for the prevention or modification of epileptogenesis to halt the development of epilepsy. Some drugs in development appear rational for preventing epilepsy because they target the initial trigger or related signaling pathways as the brain becomes progressively more prone to seizures. Additional research into the target validity and clinical investigation is essential to make new frontiers in curing epilepsy.

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JAK/STAT pathway regulation of GABAA receptor expression after differing severities of experimental TBI

Cited by 56 publications

References 49 publications

WONOEP appraisal: Biomarkers of epilepsy‐associated comorbidities

WONOEP appraisal: Biomarkers of epilepsy‐associated comorbidities

Differential effects of rapamycin treatment on tonic and phasic GABAergic inhibition in dentate granule cells after focal brain injury in mice

Novel therapeutic approaches for disease-modification of epileptogenesis for curing epilepsy

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