Alterations of GABAA and glutamate receptor subunits and heat shock protein in rat hippocampus following traumatic brain injury and in posttraumatic epilepsy

Kharlamov, Elena A.; Lepsveridze, Eka; Meparishvili, Maia; Solomonia, Revaz; Lü, Bo; Miller, Eric R.; Kelly, Kenneth G.; Mtchedlishvili, Zakaria

doi:10.1016/j.eplepsyres.2011.02.008

Cited by 72 publications

(57 citation statements)

References 163 publications

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“…Previous experimental studies showed that N-methyl-D-aspartate (NMDA) glutamate receptors contribute to several post-TBI pathologies that lead to functional impairments, including hypoperfusion due to failure in cerebrovascular autoregulation (7), edema via accumulation of intracellular Na 1 (8,9), glutamate-induced excitotoxicity (10), epileptogenesis (11), and cognitive decline (12). Similarly, inhibitory g-aminobutyric acid (GABA)-A receptor-mediated functions contribute to the development and expression of post-TBI aftermath, particularly to excitability related to acute seizures and epileptogenesis (11)(12)(13)(14). To date, no PET ligands have been available for assessment of the expression of NMDA or GABA-A receptors during the disease process.…”

mentioning

confidence: 99%

Ex Vivo Tracing of NMDA and GABA-A Receptors in Rat Brain After Traumatic Brain Injury Using ¹⁸F-GE-179 and ¹⁸F-GE-194 Autoradiography

et al. 2016

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In vivo imaging of N-methyl-D-aspartate (NMDA) glutamate receptor and γ-aminobutyric acid (GABA)-A receptor during progression of brain pathology is challenging because of the lack of imaging tracers with high affinity and specificity. Methods: We monitored changes in NMDA receptor and GABA-A receptor in a clinically relevant model of traumatic brain injury (TBI) induced by lateral fluid percussion in adult rats, using 2 new ligands for PET: 18 F-GE-179 for the open/active state of the NMDA receptor ion channel and 18 F-GE-194 for GABA-A receptor. Ex vivo brain autoradiography of radioligands was performed at subacute (5-6 d) and chronic (40-42 d) time points after TBI. Results: At 5-6 d after TBI, 18 F-GE-179 binding was higher in the cortical lesion area, in the lesion core, and in the hippocampus than in the corresponding contralateral regions; this increase was probably related to increased permeability of the blood-brain barrier. At 40-42 d after TBI, 18 F-GE-179 binding was significantly higher in the medial cortex, in the corpus callosum, and in the thalamus than in the corresponding contralateral regions. Five to 6 days after TBI, 18 F-GE-194 binding was significantly higher in the lesion core and significantly lower in the ipsilateral thalamus. By 40-42 d after TBI, the reduction in 18 F-GE-194 binding extended to the cortical lesion, including the perilesional cortex around the lesion core. The reduction in thalamic binding was more extensive at 40-42 d than at 5-6 d after TBI, suggesting a progressive decrease in thalamic GABA-A receptor density. Immunohistochemistry against GABA-A α1 subunit revealed a similar decrease to 18 F-GE-194 binding, particularly during the chronic phase. Conclusion: Our data support the validity of novel 18 F-GE-179 and 18 F-GE-194 radioligands for the detection of changes in active NMDA receptor and GABA-A receptor in the injured brain. These tools are useful for follow-up evaluation of secondary postinjury pathologies.

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confidence: 99%

Ex Vivo Tracing of NMDA and GABA-A Receptors in Rat Brain After Traumatic Brain Injury Using ¹⁸F-GE-179 and ¹⁸F-GE-194 Autoradiography

et al. 2016

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“…In kainate model, however, hippocampal expression of GluR1 expression was decreased at 1 month post-SE [ 83 ]. A decrease in GluR1 protein expression was also observed in the hippocampus at 3 months after TBI [ 36 ]. Some information is available on kainate receptor subunit GluR5.…”

Section: Ampa/kainate Receptorsmentioning

confidence: 88%

Are Alterations in Transmitter Receptor and Ion Channel Expression Responsible for Epilepsies?

Powell

Łukasiuk

O’Brien

et al. 2014

Issues in Clinical Epileptology: A View From the Bench

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Neuronal voltage-gated ion channels and ligand-gated synaptic receptors play a critical role in maintaining the delicate balance between neuronal excitation and inhibition within neuronal networks in the brain. Changes in expression of voltage-gated ion channels, in particular sodium, hyperpolarization-activated cyclic nucleotide-gated (HCN) and calcium channels, and ligand-gated synaptic receptors, in particular GABA and glutamate receptors, have been reported in many types of both genetic and acquired epilepsies, in animal models and in humans. In this chapter we review these and discuss the potential pathogenic role they may play in the epilepsies.

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“…Mossy fiber sprouting is localized to areas near the injury epicenter after focal injury (29) and is less severe and sparser after TBI than, for example, in chemoconvulsant models of TLE, but its presence, however limited, is a consistent feature of both models. Other cellular outcomes identified in both TLE and PTE models include an increase in postinjury granule cell progenitor proliferation and a reorganization of GABA A receptors in granule cells (33,(37)(38)(39)(40). Increased adult neurogenesis has been hypothesized to contribute to aberrant mossy fiber connectivity and an eventual increase in seizure susceptibility but may also contribute to cognitive recovery shortly after TBI (40,41).…”

Section: Convergence Of Cellular Changes In Pte and Tle Modelsmentioning

confidence: 99%

“…Increased adult neurogenesis has been hypothesized to contribute to aberrant mossy fiber connectivity and an eventual increase in seizure susceptibility but may also contribute to cognitive recovery shortly after TBI (40,41). Reorganization of GABA A receptors might also serve a compensatory function, particularly since model-and location-dependent increases or decreases in receptor function have been observed (37)(38)(39). As for most other outcomes, cellular changes are correlated with epileptogenesis, but definitive studies to determine whether there is a causal role for these events in PTE development are lacking.…”

Section: Convergence Of Cellular Changes In Pte and Tle Modelsmentioning

confidence: 99%

How and Why Study Posttraumatic Epileptogenesis in Animal Models?

Smith

2016

Epilepsy Curr

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Over 2 million people are treated medically each year in the United States after sustaining a traumatic brain injury (TBI) (1), and posttraumatic epilepsy (PTE), which is often intractable to medical treatment, is a common long-term consequence of TBI. Epilepsy affects 1% to 2% of the population (2), but the overall incidence of epilepsy after moderate-to-severe closedhead injury is 7% to 39% and is over 50% after penetrating injury (3)(4)(5). Approximately 20% of all symptomatic epilepsies result from TBI (6), making PTE one of the most prevalent types of epilepsy. Although a number of seizure types can develop after brain trauma, PTE manifests as temporal lobe epilepsy (TLE, either neocortical or mesial) in 35 to 62% of trauma patients (7-9). As with other forms of acquired epilepsy, spontaneous recurrent seizures associated with PTE develop with a latency ranging from weeks to many years after the initial injury. This seizure-free period after TBI is thought to represent the period of epileptogenesis, during which the brain undergoes physiological, anatomic, cellular, and molecular changes that lead to a state of chronically increased seizure susceptibility. In principle, this delay between the TBI and development of PTE also represents a window of opportunity during which strategies might be employed to inhibit the reactive plasticity in the brain that leads to PTE, but no antiepileptogenic therapies have been successfully developed to date. This review focuses on key pathophysiological changes in the brain associated with posttraumatic epileptogenesis, animal models used to study those changes, and efforts to identify predictive biomarkers of PTE and to employ candidate treatments to prevent PTE.TBI results in acute cell death, axon injury, vascular damage, and accompanying excitotoxicity shortly after injury. Secondary damage, occurring within days of the primary injury, including or resulting from hypoxia/ischemia, delayed necrotic and apoptotic cell death, oxidative stress, gliosis, edema, blood brain barrier disruption, and inflammation may exacerbate initial damage. Putative homeostatic repair mechanisms, including angiogenesis, synaptic reorganization, and neurogenesis can engage over time and are hypothesized to compensate for functional loss resulting from the initial injury; they are also associated with PTE. By their very nature, brain injuries are highly variable across patients, and this heterogeneity is reflected in a wide variety of epileptogenic responses to injury. Injury severity and location, the presence of seizures shortly after injury, intracranial hemorrhage, cortical contusion, the level of postinjury consciousness impairment, age, and sex have all been implicated as potential factors associated with increased risk of developing PTE after brain trauma (4, 5, 10). Many of the cellular events that occur after TBI also occur after insults used to induce epilepsy in animal models, and rodent models of PTE have been developed with the goal of identifying those factors associated with the e...

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Alterations of GABAA and glutamate receptor subunits and heat shock protein in rat hippocampus following traumatic brain injury and in posttraumatic epilepsy

Cited by 72 publications

References 163 publications

Ex Vivo Tracing of NMDA and GABA-A Receptors in Rat Brain After Traumatic Brain Injury Using ¹⁸F-GE-179 and ¹⁸F-GE-194 Autoradiography

Ex Vivo Tracing of NMDA and GABA-A Receptors in Rat Brain After Traumatic Brain Injury Using ¹⁸F-GE-179 and ¹⁸F-GE-194 Autoradiography

Are Alterations in Transmitter Receptor and Ion Channel Expression Responsible for Epilepsies?

How and Why Study Posttraumatic Epileptogenesis in Animal Models?

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Alterations of GABAA and glutamate receptor subunits and heat shock protein in rat hippocampus following traumatic brain injury and in posttraumatic epilepsy

Cited by 72 publications

References 163 publications

Ex Vivo Tracing of NMDA and GABA-A Receptors in Rat Brain After Traumatic Brain Injury Using 18F-GE-179 and 18F-GE-194 Autoradiography

Ex Vivo Tracing of NMDA and GABA-A Receptors in Rat Brain After Traumatic Brain Injury Using 18F-GE-179 and 18F-GE-194 Autoradiography

Are Alterations in Transmitter Receptor and Ion Channel Expression Responsible for Epilepsies?

How and Why Study Posttraumatic Epileptogenesis in Animal Models?

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Product

Resources

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Ex Vivo Tracing of NMDA and GABA-A Receptors in Rat Brain After Traumatic Brain Injury Using ¹⁸F-GE-179 and ¹⁸F-GE-194 Autoradiography

Ex Vivo Tracing of NMDA and GABA-A Receptors in Rat Brain After Traumatic Brain Injury Using ¹⁸F-GE-179 and ¹⁸F-GE-194 Autoradiography