Poststroke seizures and epilepsy have been described in numerous clinical and population studies. In contrast, the pathophysiological events of injured brain that establish poststroke epileptogenesis are not well understood because there is no standard animal model of poststroke epilepsy. In the elderly, stroke is the dominant cause of epilepsy yet the modeling of poststroke epilepsy in aged animals has had only limited study. Recent pilot studies in our laboratory indicate that transient (3 hr) unilateral (left-sided) middle cerebral artery (MCA) and common carotid artery (CCA) occlusion (MCA/CCAO) results in poststroke epilepsy less frequently in 4 mo old male Fischer 344 (F344) rats than in 20 mo old animals within 2 months of lesioning. Based on these findings, our central hypothesis is that MCA/CCAO can result in epileptic seizures that are more frequently expressed with advancing age. This hypothesis will be tested by extending our pilot studies to 4, 12, and 20 mo old male F344 rats and performing either transient (Specific Aim #1) or permanent (Specific Aim #2) unilateral MCA/CCAO followed by 4 months of intermittent video-electroencephalogram (EEG) monitoring, morphometry of the infarct core, and assessment of neurons and glia within penumbral and remote areas using stereological techniques.
These Specific Aims will characterize the relationship of ischemia/infarction, with or without reperfusion injury, to advancing animal age and the expression of poststroke epileptogenesis during long-term monitoring. The short-term goal of this proposal is to establish the critical experimental components of a physiologically relevant model of poststroke epilepsy in the elderly. The long-term goal of these studies is to provide a mechanistic delineation of poststroke epileptogenesis that can enable translation to clinical trials designed to prevent or halt the development of poststroke epilepsy in the elderly. ? ? The proposed research project is intended to establish an animal model to study how stroke can result in epileptic seizures in the elderly. By developing a reliable model of poststroke epilepsy, improved insight and understanding can be gained in knowing why stroke can result in seizures and epilepsy in some patients but not in others - approximately 15-20% of elderly patients will develop epilepsy following a stroke. Specifically, this study is focused on describing and analyzing some of the important electrical and anatomical changes that occur in the young, mid-aged, and aged brain following a stroke that potentially lead to the development of seizures in the short term and/or epilepsy in the long term. By identifying critical changes that occur in the brain after stroke, it may be possible to develop new and markedly improved medications to prevent or limit the development of epileptic seizures. The proposed studies are designed to ultimately shift the focus of therapies from the control of symptoms, i.e., treating seizures once epilepsy has been established, to prevention and cure. Use of standard antiepileptic (antiseizure) medications immediately following a stroke may prevent seizures in the short term, but they are ineffective in preventing the establishment of epilepsy in others. It is hoped that the proposed research can produce a reliable model of poststroke epilepsy in the elderly that will ultimately evolve into the development of new and effective medications that can be given to patients following stroke to prevent or limit the development of epileptic seizures. ? ? ? ?
| Kelly, Kevin M; Jukkola, Peter I; Yin, Guo et al. (2018) Poststroke epilepsy following transient unilateral middle cerebral and common carotid artery occlusion in young adult and aged F344 rats. Epilepsy Res 141:38-47 |
