DNA Damage and Repair in the Brain: Implications for Seizure-Induced Neuronal Injury, Endangerment, and Neuroprotection
Continuous seizures can be induced in rodents using several methods, including focal or systemic chemoconvulsants or electrical stimulation of particular neural networks. Injurious durations of seizure activity result in neuronal death in vulnerable brain regions, including the hippocampal CA1 and CA3 subfields and hilus; the entorhinal, perirhinal, and piriform cortices; and the amygdala, regardless of the method employed to evoke the seizures (Ben-Ari et al. 1986; Du et al. 1995; Fujikawa 1996; Fujikawa et al. 2000a, b; Henshall et al. 2000; Kondratyev et al. 2001; Motte et al. 1998; Schwob et al. 1980; Sloviter et al. 1996; Sperk et al. 1983). Other neuronal populations, including those located in striatum, in the hippocampal CA2 subfield, and in the hippocampal dentate granule cell layer, are resistant to seizure-evoked injury. It is unclear why particular endangered populations die in the aftermath of injurious seizures, whereas other populations survive. One plausible explanation is that injury-resistant populations are either inherently endowed with or more efficiently engage protective cellular mechanisms.
Although the exact factors mediating the transition from cell endangerment to cell death following seizures are unknown, it is generally accepted that seizure-induced cellular damage significantly contributes to injury (i.e., frank neuronal death). It is well established that the cellular damage caused by continuous seizures increases with seizure duration, and it is generally believed that seizures lasting in excess of 30 min in duration are required to elicit injury (Fujikawa 1996; Henshall et al. 2000; Kondratyev and Gale 2001) (Fig. 16.1a). Such seizures are thus considered to be “injurious.” Shorter seizure durations, although likely to evoke some degree of cellular damage, are subthreshold for inducing cell death and are thus defined here as being “noninjurious.” Given that endangered neurons survive noninjurious seizure durations (i.e., durations not eliciting frank neuronal death), it is plausible that the cellular damage elicited by these seizures does not reach the threshold necessary for triggering cell death and/or compensatory repair processes are both activated in response to and sufficient for survival.
KeywordsFluorescence Resonance Energy Transfer Nucleotide Excision Repair Ischemic Precondition Base Excision Repair Seizure Duration
The authors thank Drs Susette Mueller and Xuehua Xu from the Lombardi Comprehensive Cancer Center Microscopy & Imaging Shared Resource for their contribution to obtaining confocal imaging and FRET analysis. The authors thank Dr Maryam Khafizova for technical assistance with neuronal cultures and immunocytochemistry. The previously unpublished studies presented here were supported by the NIH grants MH 02040, NS 048974 and subcontract to AG019165 (AK), T32-NS041231, and the NIH predoctoral fellowship NS 046199 (SC).
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