Posttraumatic Epilepsy: Hemorrhage, Free Radicals and the Molecular Regulation of Glutamate
Department of Neurology & Psychiatry, Saint Louis University School of Medicine, 1402 South Grand Blvd., St. Louis, MI 63104, USA. Neurochemical Research
(Impact Factor: 2.59).
10/2008; 34(4):688-97. DOI: 10.1007/s11064-008-9841-3
Traumatic brain injury causes development of posttraumatic epilepsy. Bleeding within neuropil is followed by hemolysis and deposition of hemoglobin in neocortex. Iron from hemoglobin and transferring is deposited in brains of patients with posttraumatic epilepsy. Iron compounds form reactive free radical oxidants. Microinjection of ferric ions into rodent brain results in chronic recurrent seizures and liberation of glutamate into the neuropil, as is observed in humans with epilepsy. Termination of synaptic effects of glutamate is by removal via transporter proteins. EAAC-1 is within neurons while GLT-1 and GLAST are confined to glia. Persistent down regulation of GLAST production is present in hippocampal regions in chronic seizure models. Down regulation of GLAST may be fundamental to a sequence of free radical reactions initiated by brain injury with hemorrhage. Administration of antioxidants to animals causes interruption of the sequence of brain injury responses induced by hemorrhage, suggesting that such a strategy needs to be evaluated in patients with traumatic brain injury.
Available from: Eric R Miller
- "(D'Ambrosio et al., 2004a,b; Pitkänen and McIntosh, 2006; Statler et al., 2009; Hunt et al., 2009; Pitkänen et al., 2009, 2011; Curla et al., 2011; Bolkvadze and Pitkänen, 2012). Building on the substantial database of clinical, experimental, and pathological findings associated with TBI, biological mechanisms underlying PTE are actively being explored (D'Ambrosio et al., 1999; Norris and Scheff, 2009; Prince et al., 2009; Willmore and Ueda, 2009; Hunt et al., 2010, 2011; Kharatishvili and Pitkänen, 2010a; Mtchedlishvili et al., 2010; Kharlamov et al., 2011; Belousov et al., 2012; D'Ambrosio et al., 2013a,b; Hunt et al., 2013). Experimental models of TBI simulate human TBI with varying degrees of accuracy (Morales et al., 2005). "
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ABSTRACT: Posttraumatic epilepsy (PTE) has been modeled with different techniques of experimental traumatic brain injury (TBI) using mice and rats at various ages. We hypothesized that the technique of controlled cortical impact (CCI) could be used to establish a model of PTE in young adult rats. A total of 156 male Sprague-Dawley rats of 2-3 months of age (128 CCI-injured and 28 controls) was used for monitoring and/or anatomical studies. Provoked class 3-5 seizures were recorded by video monitoring in 7/57 (12.3%) animals in the week immediately following CCI of the right parietal cortex; none of the 7 animals demonstrated subsequent spontaneous convulsive seizures. Monitoring with video and/or video-EEG was performed on 128 animals at various time points 8-619 days beyond one week following CCI during which 26 (20.3%) demonstrated nonconvulsive or convulsive epileptic seizures. Nonconvulsive epileptic seizures of >10s were demonstrated in 7/40 (17.5%) animals implanted with 2 or 3 depth electrodes and usually characterized by an initial change in behavior (head raising or animal alerting) followed by motor arrest during an ictal discharge that consisted of high-amplitude spikes or spike-waves with frequencies ranging between 1 and 2Hz class 3-5 epileptic seizures were recorded by video monitoring in 17/88 (19%) and by video-EEG in 2/40 (5%) CCI-injured animals. Ninety of 156 (58%) animals (79 CCI-injured, 13 controls) underwent transcardial perfusion for gross and microscopic studies. CCI caused severe brain tissue loss and cavitation of the ipsilateral cerebral hemisphere associated with cell loss in the hippocampal CA1 and CA3 regions, hilus, and dentate granule cells, and thalamus. All Timm-stained CCI-injured brains demonstrated ipsilateral hippocampal mossy fiber sprouting in the inner molecular layer. These results indicate that the CCI model of TBI in adult rats can be used to study the structure-function relationships that underlie epileptogenesis and PTE.
Epilepsy research 10/2015; 117:104-116. DOI:10.1016/j.eplepsyres.2015.09.009 · 2.02 Impact Factor
Available from: Keiko Kato
- "Implantation of cobalt into the cerebral cortex easy induces focal and secondarily generalized seizures in rodents, however, cobalt metal causes a large area of cortex to be lost, while the hippocampus containing the dentate gyrus appears intact (Chang et al., 2004). Microinjection of ferric ions into the rodent brain results in chronic recurrent seizures, which are brain injury responses induced by hemorrhage and free radical reactions observed in human posttraumatic epilepsy (Willmore and Ueda, 2009). "
Underlying Mechanisms of Epilepsy, 09/2011; , ISBN: 978-953-307-765-9
Available from: Ibolja Cernak
- "In this review, we focus on blast-induced neurotrauma (BINT), including mechanisms underlying brain damage and challenges imposed by this complex injury from both clinical and experimental perspectives . Whereas we do not consider the broader topic of traumatic brain injuries (TBIs) in the civilian population, there are a number of reviews from the past 5 years that consider this topic in detail, particularly from the perspectives of animal models (Cernak, 2005; Kazanis, 2005; LaPlaca et al, 2007; Manvelyan, 2006; Morales et al, 2005; Potts et al, 2009; Weber, 2007), and the understanding that we have gained from these models with regard to general pathobiology (Bramlett and Dietrich, 2007; Park et al, 2008; Povlishock and Katz, 2005; Werner and Engelhard, 2007), mechanisms of cell injury (Bayir and Kagan, 2008; Mazzeo et al, 2009; Raghupathi, 2004; Robertson, 2004; Sullivan et al, 2005; Yakovlev and Faden, 2004; Zhang et al, 2005), posttraumatic epilepsy (D'Ambrosio and Perucca, 2004; Dichter, 2009; Garga and Lowenstein, 2006; Pitkanen and McIntosh, 2006; Pitkanen et al, 2009; Willmore and Ueda, 2009), axonal injury (Bales et al, 2009; Buki and Povlishock, 2006; Hurley et al, 2004), behavior (Fujimoto et al, 2004; Schallert, 2006), proteomics (Ottens et al, 2007), biomarkers (Kochanek et al, 2008; Kovesdi et al, 2009), and neuroprotection (Bales et al, 2009; Beauchamp et al, 2008; Byrnes et al, 2009; Cook et al, 2009; Dichter, 2009; Dietrich et al, 2009; Forsyth et al, 2006; Gibson et al, 2008; Jain, 2008; Jennings et al, 2008; Kokiko and Hamm, 2007; Mammis et al, 2009; Margulies and Hicks, 2009; Marklund et al, 2006; Mechoulam and Shohami, 2007; Rogers and Wagner, 2006; Schouten, 2007; Schumacher et al, 2007; Stein, 2008; Stoica et al, 2009; Vink and Nimmo, 2009; Wang et al, 2006; Wise et al, 2005; Xiong et al, 2009). "
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ABSTRACT: This review considers the pathobiology of non-impact blast-induced neurotrauma (BINT). The pathobiology of traumatic brain injury (TBI) has been historically studied in experimental models mimicking features seen in the civilian population. These brain injuries are characterized by primary damage to both gray and white matter and subsequent evolution of secondary pathogenic events at the cellular, biochemical, and molecular levels, which collectively mediate widespread neurodegeneration. An emerging field of research addresses brain injuries related to the military, in particular blast-induced brain injuries. What is clear from the effort to date is that the pathobiology of military TBIs, particularly BINT, has characteristics not seen in other types of brain injury, despite similar secondary injury cascades. The pathobiology of primary BINT is extremely complex. It comprises systemic, local, and cerebral responses interacting and often occurring in parallel. Activation of the autonomous nervous system, sudden pressure-increase in vital organs such as lungs and liver, and activation of neuroendocrine-immune system are among the most important mechanisms significantly contributing to molecular changes and cascading injury mechanisms in the brain.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 10/2009; 30(2):255-66. DOI:10.1038/jcbfm.2009.203 · 5.41 Impact Factor
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