Abstracts

Rationale: Introduction: Nicotinamide adenine nucleotide (NAD) is a critical coenzyme for numerous metabolic functions and activates pathways that mediate cellular and mitochondrial protection (PMID: 29184484). Nicotinamide riboside (NR) is a naturally occurring form of Vitamin B3 that is readily converted to NAD in cells and exerts putative neuroprotective effects with minimal adverse effects (PMID: 24071780). We asked whether NR treatment could reduce the frequency of spontaneous recurrent seizures (SRS) and afford neuroprotective effects in the mouse pilocarpine model of epilepsy.




Methods: Methods: 4-week-old C57BL/6 were treated with 24 mM NR (PMID: 31934345) supplemented in their drinking water. Both NR (n=4) and nontreated control (n=3) mice were allowed to drink water ad libitum. After 3 weeks of treatment, control and experimental mice were given pilocarpine (275 mg/kg) via intraperitoneal injection to induce status epilepticus (SE). All mice were switched to untreated water after SE. Prefabricated head-mounts were surgically implanted onto all mice 5 weeks after pilocarpine induction and continuous video-EEG monitoring was initiated 6-8 days after implantation. Recording continued for 14 days after 2 or more Stage 3-5 Racine scale seizures were recorded in one day. After recording, mice from both groups were perfused and coronal brain slices obtained for histological analysis to test for differences in cell survival, inflammation, and pathological changes in the hippocampus.




Results: Results: For both NR-treated and control mice, SRS began within 1-3 days after initiation of video-EEG recording. Despite receiving NR only prior to SE, NR-treated mice exhibited a significant decrease in SRS over the 14-day recording period (2.2 ± 0.7 seizures/day versus control mice, 7.7 ± 1.8; p=0.02). However, no significant differences in seizure frequency were seen over the first week of recording between NR-treated (2.3 ± 0.7 seizures/day) and control mice (5.5 ± 2.1; p=0.16). By contrast, treatment effects were more pronounced during the 2^nd week of recording with NR and control mice experiencing 2.1 ± 0.9 and 10.0 ± 2.1 seizures/day, respectively (p=0.01).




Conclusions:

Conclusions & Future Directions: Treatment with NR prior to SE is effective at mitigating SRS in the mouse pilocarpine model of epilepsy. The mechanism(s) for these protective effects is(are) not known and are currently being investigated. Histological analysis is also being conducted to test whether SE-susceptible cell populations are spared in response to NR treatment and whether this might confer resilience against SRS. Additional studies will also investigate whether inflammation or other pathological changes are mitigated by NR treatment. In summary, our preliminary results indicate that NR supplementation may be a promising and cost-effective approach for epilepsy therapy.


Funding: None