Posttraumatic Epilepsy: Hemorrhage, Free Radicals and the Molecular Regulation of Glutamate

Abstract

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.

Relationship between increase in astrocytic GLT-1 glutamate transport and late-LTP

“…If this is true, the ability to form and express some types of memories will depend upon the healthiness of the plasticity of glutamate transport. It is also likely that the regulation of glutamate uptake plays a role in many processes in addition to memory formation (e.g., addiction, stress, and seizure prevention) (Yang et al 2005;Willmore and Ueda 2009;Reissner and Kalivas 2010). Equally likely, abnormalities in the plasticity of glutamate uptake will be found to underlie several pathologies of brain function (e.g., epilepsy, ALS, Alzheimer's disease, HIV-1-associated dementia, and Huntington's disease) (Maragakis and Rothstein 2001;Benarroch 2010;Mookherjee et al 2011).…”

Long-Term Consequences of Traumatic Brain Injury: Current Status of Potential Mechanisms of Injury and Neurological Outcomes

“…156,157 A recently proposed mechanism for development of PTE is that iron compounds deposited in brains of TBI patients form reactive free radical oxidants, leading to release of glutamate and subsequent abnormal neuronal excitation. 157,158 Comprehensive gene expression and gene network analyses have also clarified molecular events associated with PTE and reported up-regulation of phosphatase A2 and lipid metabolism, which may be related to seizure propagation. 139,158 Importantly, administration of antioxidants appears to cause an interruption of the generation of chronic seizures induced by hemorrhage.…”

“…139,158 Importantly, administration of antioxidants appears to cause an interruption of the generation of chronic seizures induced by hemorrhage. 157 …”

A rare case of epilepsy and acute pancreatitis induced by severe paraquat poisoning

“…It can cause a large number of free radicals in vivo by paraquat. Free radicals can cause epileptic seizures (1). Elevated pancreatic enzymes have been found in patients with severe paraquat poisoning, and pancreatitis has been observed in the autopsies of paraquat poisoning patients (2).…”