Early-Onset Convulsive Seizures Induced by Brain Hypoxia-Ischemia in Aging Mice: Effects of Anticonvulsive Treatments

Abstract

Aging is associated with an increased risk of seizures/epilepsy. Stroke (ischemic or hemorrhagic) and cardiac arrest related brain injury are two major causative factors for seizure development in this patient population. With either etiology, seizures are a poor prognostic factor. In spite of this, the underlying pathophysiology of seizure development is not well understood. In addition, a standardized treatment regimen with anticonvulsants and outcome assessments following treatment has yet to be established for these post-ischemic seizures. Previous studies have modeled post-ischemic seizures in adult rodents, but similar studies in aging/aged animals, a group that mirrors a higher risk elderly population, remain sparse. Our study therefore aimed to investigate early-onset seizures in aging animals using a hypoxia-ischemia (HI) model. Male C57 black mice 18-20-month-old underwent a unilateral occlusion of the common carotid artery followed by a systemic hypoxic episode (8% O2 for 30 min). Early-onset seizures were detected using combined behavioral and electroencephalographic (EEG) monitoring. Brain injury was assessed histologically at different times post HI. Convulsive seizures were observed in 65% of aging mice post-HI but not in control aging mice following either sham surgery or hypoxia alone. These seizures typically occurred within hours of HI and behaviorally consisted of jumping, fast running, barrel-rolling, and/or falling (loss of the righting reflex) with limb spasms. No evident discharges during any convulsive seizures were seen on cortical-hippocampal EEG recordings. Seizure development was closely associated with acute mortality and severe brain injury on brain histological analysis. Intra-peritoneal injections of lorazepam and fosphenytoin suppressed seizures and improved survival but only when applied prior to seizure onset and not after. These findings together suggest that seizures are a major contributing factor to acute mortality in aging mice following severe brain ischemia and that early anticonvulsive treatment may prevent seizure genesis and improve overall outcomes.

Neocortical injury–induced status epilepticus

“…[19][20][21] Co binds to oxygen-binding molecules and causes functional hypoxia, triggers neuronal death, and increases expression of vascular endothelial growth factor. 16,22 Hypoxia triggers seizures in vivo, 23,24 increases neuronal excitability in brain slices, and enhances the amplitude of excitatory postsynaptic currents. 24,25 In addition to these mechanisms, Co implantation in the motor cortex also decreases the density of inhibitory neurons and their terminals, thus creating a seizure focus.…”

Pilocarpine-Induced Status Epilepticus Is Associated with P-Glycoprotein Induction in Cardiomyocytes, Electrocardiographic Changes, and Sudden Death

“…Clinical and experimental studies have widely demonstrated that brain hypoxia-ischemia can induce seizures or epilepsy [ 16 , 17 , 18 , 19 , 20 ]. However, whether repetitive episodes of severe seizures as well as SE could induce chronic brain or systemic hypoxia-ischemia have been poorly investigated [ 21 , 22 ].…”

Susceptibility to hippocampal kindling seizures is increased in aging C57 black mice

“…It is presently unclear whether these jumps share common features with those previously observed from rats following extended amygdala or perforant path kindling ( Pinel and Rovner, 1978 , Michalakis et al, 1998 , Brandt et al, 2004 ). We speculate that these jumps likely represent a type of irritated motor response as they were not concurrent with other severe convulsive behaviors (such as barrel rotations and/or wild running) in comparison to jumping seizures observed in mouse models of brain ischemia ( El-Hayek et al, 2011 , Wang et al, 2015 , Wu et al, 2015 ).…”