Transient and permanent arterial occlusions modeling poststroke epilepsy in aging rats

Abstract

The pathophysiological mechanisms of epileptogenesis following ischemic stroke in the aged brain are not well understood, largely due to limited developments in animal modeling of poststroke epilepsy (PSE). A recent study in our laboratory (Kelly et al., 2018) using transient (3 h) unilateral middle cerebral artery (MCA) and common carotid artery (CCA) occlusion (MCA/CCAo) in 4- and 20-month-old Fischer (F344) rats resulted in epileptic seizures in both age groups; age and infarction factors independently had effects on seizure frequency. We hypothesized that permanent unilateral MCA/CCAo, a simpler model, was capable of producing results comparable to those of transient MCA/CCAo. In this study, we performed permanent MCA/CCAo and compared it to transient MCA/CCAo in 76 4-, 12-, and 20-month-old F344 rats; 41 (54%) animals experienced early, unexpected mortality. The remaining 35 (46%) animals had depth electrodes implanted. Prior to implantation of depth electrodes, 9 (26%) of these 35 animals (26%) were monitored periodically by video alone before video-EEG monitoring (17,837 h total) to assess the potential development of PSE. No EEG recordings were obtained from 12- or 20-month-old transient occlusion or 20-month-old permanent occlusion animals due to premature deaths. Five animals (14%) demonstrated epileptic seizure activity after MCA/CCAo: one 4-month-old transient occlusion animal, one 4-month-old permanent occlusion animal, and three 12-month-old permanent occlusion animals. Of these 5 animals, all but the 4-month-old permanent animal demonstrated 1-4 Hz spike-wave discharges variably associated with inactivity or frank motor arrest, and 2 animals (4- and 12-month-old permanent) demonstrated generalized ictal EEG discharges associated with grade 5 convulsive activity. All animals monitored with video-EEG demonstrated generalized 7-9 Hz spike-wave discharges, innate in F344 animals and distinct from lesion-induced epileptic seizures. Gross inspection of brains revealed variability in lesion presence and size among age groups and occlusion types. Comparison of infarct volumes of permanent MCA/CCAo animals (2.9 ± 1.29 mm³, n = 6) with those of transient MCA/CCAo animals (1.7 ± 0.31 mm³, n = 3) was not significant (p = 0.44) due to the small sample size. Timm staining revealed no evidence of mossy fiber sprouting in 7 animals tested, only one of which was known to be epileptic (4-month-old transient). These results provide evidence of focal nonconvulsive electrographic ictal discharges and behavioral seizures in both permanent and transient MCA/CCAo animals lesioned at 4- or 12-months-of-age and support the use of arterial ligation as a viable method for modeling PSE.

Keywords: Aging; Cortical infarction; Middle cerebral artery and common carotid artery occlusion; Poststroke epilepsy; Poststroke seizures; Video-EEG.