While epilepsy can affect anyone at any age, it is roughly three times more prevalent in people over age 65. Prevalence and incidence of epilepsy will rise as the global population becomes increasingly older. Epilepsy in older people is associated with comorbidities such as neurodegeneration. We have previously demonstrated that administration of the antiseizure medicine (ASM), lacosamide (LCM), to young, corneally kindled mice was associated with increased levels of Ki-67 positive/NeuN-positive neurons relative to vehicle (VEH)-treated kindled or untreated sham-kindled animals in the dentate gyrus of dorsal hippocampus of the brain, suggesting beneficial effects of LCM on neurogenesis in young mice with chronic seizures (Zierath et al, IJMS 2023). We thus hypothesized that LCM administration to aged wild-type mice with chronic seizures could increase the number of Ki-67 positive/NeuN-positive hippocampal neurons, indicating neurogenesis. To test this hypothesis, I randomized mice aged >30 months-old to receive either LCM (4.5 mg/kg) or VEH treatment administered prior to each seizure stimulation. Mice were then kindled with a twice-daily 3 second, 60 Hz transcorneal stimulation over 15 days. After 27 stimulations to evoke consistent behavioral seizures, mice were euthanized, and brains collected for immunohistochemistry. Tissues were labeled for Ki-67, marking for neurogenesis, GFAP for astroglial cells, and NeuN, for mature neurons. Unlike in similarly treated young, kindled male mice, LCM administration significantly slowed male mouse kindling acquisition rate (p=0.0022) compared with VEH-treated littermates. There was no significant effect of LCM administration on kindling rate in aged female mice. Further, LCM was poorly tolerated in aged male but not female mice, revealing significant sexual dimorphism in ASM tolerability with chronic administration to aged mice. Ongoing immunohistochemistry is quantifying Ki-67 expression to further demonstrate whether LCM administration induces hippocampal neurogenesis in aged mice with chronic seizures.

Sudden unexpected death in epilepsy (SUDEP) is the most severe consequence of uncontrolled epilepsy. SUDEP is a multifactorial disease associated with serotonin (5-HT) imbalance and exacerbated neuroinflammation. Unfortunately, current preclinical animal models do not adequately explain all underlying causes of these events or their subsequent effects. Seizures are a common comorbidity in Alzheimer’s disease (AD), especially in patients with genetic variants in amyloid precursor protein (APP) and presenilin 1 (PSEN1) and 2 (PSEN 2). Clinical evidence suggests that seizures in AD patients worsen their cognitive decline and increase mortality rate compared to AD patients without seizures. Our lab demonstrated that 2-month-old mice with an APP/PS1 variant subjected to chronic evoked seizures resulted in premature mortality, heightened neuroinflammation, and altered 5-HT system enzyme expression prior to AD onset. These findings reveal a novel preclinical platform to test potential preventative agents for SUDEP. Given the relationship between seizures and AD, I aim to prevent seizure-induced premature mortality, and define 5-HT and neuroinflammatory changes in APP/PS1 mice treated with 2 investigational agents: lorcaserin, a selective 5-HT receptor agonist, and cannabidiol (CBD), a broad-spectrum anti-inflammatory and 5-HT modulator. I hypothesize that targeting seizure-induced neuroinflammation and the dysregulated 5-HT system with these compounds will decrease premature seizure-induced mortality. To assess this, 2-month-old APP/PS1 mice underwent corneal kindling procedure to evoke investigator-controlled chronic seizures and received lorcaserin (10 mg/kg) or CBD (100 mg/kg) via the intraperitoneal route. Then, I tracked survival during the chronic seizure period and performed molecular analysis to quantify neuroinflammatory proteins and 5-HT system enzyme expression. Our preliminary results show that mice treated with lorcaserin or CBD had a mortality rate of 10% compared to 75% in the untreated APP/PS1 mice. Future directions include using these compounds in other preclinical SUDEP models to confirm the translational potential of these medications to clinical use.

For people living with epilepsy (PWE), anti-seizure medicines (ASMs) are the primary treatment option. However, 30% of PWE are unable to control their seizures with ASMs because they have drug-resistant epilepsy (DRE). Pathological mechanisms that contribute to DRE are not currently understood. Nevertheless, both clinical and preclinical data indicate potential involvement of changes in the architecture of neuronal networks. I used a clinically relevant rat model of temporal lobe epilepsy, and novel medication in food delivery system to confirm DRE, or failure to reduce their baseline seizure frequency by 50% with two or more clinically used ASMs. I hypothesized that the DRE animals would have lowered neuronal cell density compared to the those with drug-sensitive epilepsy (DSE). All rats were euthanized at the end of a 6-week treatment period to process the brains for immunohistochemical labeling of mature neurons with the antibody, NeuN. Total percent staining area was quantified in the hippocampus, piriform cortex, and somatosensory cortex of brains. No differences in NeuN immunoreactivity were observed between DSE and DRE animals in any brain region. However, NeuN levels in animals with epilepsy, regardless of treatment outcome, trended lower than naïve animals without epilepsy in the CA1 and dentate gyrus regions of the hippocampus. Together, these data suggest that neuron density may not be driving pharmacoresistance. However, it is possible that the ratio between excitatory and inhibitory neurons may be disrupted in DRE. This underscores the need for future studies to quantify neuronal subtypes, providing a more nuanced understanding of the underlying mechanisms of pharmacoresistance. These studies play a crucial role in guiding future research into novel treatments designed for DRE.