Temporal lobe epilepsy (TLE) is a prevalent, often drug resistant form of acquired epilepsy that frequently presents with co-morbid cognitive dysfunction. There is a pressing need to identify novel targets for the effective treatment of TLE and associated cognitive symptoms. Oxidative stress has been identified as a contributing factor to the cognitive decline associated with aging and neurodegenerative diseases such as Alzheimer's disease (AD) [4,5]. Most recently, oxidative stress has been shown to contribute to seizure-induced neuronal death and has been implicated in the progression of TLE [6,7,8]. However, to what degree oxidative stress products contribute to cognitive decline in TLE is unknown. Isoketals (IsoKs) and neuroketals (NeuroKs) are highly reactive ?-ketoaldehydes (?-Ks), formed via the non-enzymatic, free radical induced, peroxidation of arachidonic acid and docosahexaenoic acid, respectively . They are highly enriched in brain and can irreversibly adduct to lysine residues, readily crosslink proteins leading to cell dysfunction and injury [11,12. Elevated ?-K levels have been detected in pathological conditions such as atherosclerosis, chronic inflammation, and AD [9,10,42]. Importantly, scavenging of ?-Ks has been shown to attenuate spatial working memory deficits in a mouse model of AD . The overarching goals of this proposal are to determine if ?-Ks are increased during epileptogenesis and whether they contribute to learning and memory deficits associated with epileptogenesis. If so, a potential mechanism i.e. adduction of Nav1.1. will be studied. Additionally, this proposal will determine if scavenging of these highly reactive aldehydes is anti-epileptogenic and/or neuroprotective. If successful, the studies proposed herein have the potential to elucidate a novel mechanism of seizure induced cognitive dysfunction and provide a therapeutic avenue to prevent learning and memory deficits associated with the epilepsies. Conducting these studies will be the sole responsibility of the applicant and will allow for the development of a valuable st of skills. Specifically, the applicant will learn methods in mass spectrometry, cognitive behaviora testing, immunohistochemistry, electroencephalography, data analysis &interpretation, and scientific presentation. Results from these experiments are expected to generate multiple publications in high caliber journals. Thus, completion of this project will provide the applicant with requisite skills for the foundation of a productive career in research.
If successful, the studies proposed herein have the potential to elucidate a novel mechanism of seizure induced cognitive dysfunction and provide a therapeutic avenue to prevent learning and memory deficits associated with the epilepsies. Additionally, studies will determine if the therapeutic is anti-epileptic and/or neuroprotective.
|Pearson, Jennifer N; Patel, Manisha (2016) The role of oxidative stress in organophosphate and nerve agent toxicity. Ann N Y Acad Sci 1378:17-24|
|Pearson, Jennifer N; Rowley, Shane; Liang, Li-Ping et al. (2015) Reactive oxygen species mediate cognitive deficits in experimental temporal lobe epilepsy. Neurobiol Dis 82:289-97|