Experimental animals’ seizures are often defined arbitrarily based on duration, which may lead to misjudgement of the syndrome and failure to develop a cure. We employed a functional definition of seizures based on the clinical practice of observing epileptiform electrocorticography and simultaneous ictal behaviour, and examined post-traumatic epilepsy induced in rats by rostral parasagittal fluid percussion injury and epilepsy patients evaluated with invasive monitoring. We showed previously that rostral parasagittal fluid percussion injury induces different types of chronic recurrent spontaneous partial seizures that worsen in frequency and duration over the months post injury. However, a remarkable feature of rostral parasagittal fluid percussion injury is the occurrence, in the early months post injury, of brief (<2 s) focal, recurrent and spontaneous epileptiform electrocorticography events (EEEs) that are never observed in sham-injured animals and have electrographic appearance similar to the onset of obvious chronic recurrent spontaneous partial seizures. Simultaneous epidural-electrocorticography and scalp-electroencephalography recordings in the rat demonstrated that these short EEEs are undetectable by scalp electrocorticography. Behavioural analysis performed blinded to the electrocorticography revealed that (i) brief EEEs lasting 0.8–2 s occur simultaneously with behavioural arrest; and (ii) while behavioural arrest is part of the rat's behavioural repertoire, the probability of behavioural arrest is greatly elevated during EEEs. Moreover, spectral analysis showed that EEEs lasting 0.8–2 s occurring during periods of active behaviour with dominant theta activity are immediately followed by loss of such theta activity. We thus conclude that EEEs lasting 0.8–2 s are ictal in the rat. We demonstrate that the assessment of the time course of fluid percussion injury-induced epileptogenesis is dramatically biased by the definition of seizure employed, with common duration-based arbitrary definitions resulting in artificially prolonged latencies for epileptogenesis. Finally, we present four human examples of electrocorticography capturing short (<2 s), stereotyped, neocortically generated EEEs that occurred in the same ictal sites as obvious complex partial seizures, were electrographically similar to rat EEEs and were not noted during scalp electroencephalography. When occurring in the motor cortex, these short EEEs were accompanied by ictal behaviour detectable with simultaneous surface electromyography. These data demonstrate that short (<2 s) focal recurrent spontaneous EEEs are seizures in both rats and humans, that they are undetectable by scalp electroencephalography, and that they are typically associated with subtle and easily missed behavioural correlates. These findings define the earliest identifiable markers of progressive post-traumatic epilepsy in the rat, with implications for mechanistic and prophylactic studies, and should prompt a re-evaluation of the concept of post-traumatic silent perio...
Previous studies have indicated that the generation of H2O2 may be a key step in the mechanism mediating the in vitro cytotoxicity of 3-hydroxykynurenine (3HK). An exposure protocol resulting in a delayed toxicity was utilized in order to further examine the role of H2O2 in the in vitro toxicity of 3HK in a neural hybrid cell line. 3HK-induced cell lysis was significantly attenuated by administration of catalase after termination of 3HK exposure and was abolished when intracellular peroxidase activity was elevated by pretreatment of cultures with horseradish peroxidase. In addition, a dose-dependent attenuation of 3HK toxicity was observed when cultures were exposed to 3HK in the presence of the iron chelator, desferrioxamine (DFO). Pretreatment with DFO also resulted in a significant attenuation of 3HK toxicity. These data suggest a direct role for H2O2 and metal ions in the cytotoxic action of 3HK and indicate that cell lysis results from the intracellular accumulation of toxic levels of H2O2.
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