Modification of Post-traumatic Seizure Susceptibility by Controlled Endotoxemia
Abstract number :
3.008
Submission category :
1. Basic Mechanisms / 1A. Epileptogenesis of acquired epilepsies
Year :
2024
Submission ID :
30
Source :
www.aesnet.org
Presentation date :
12/9/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Andrey Mazarati, PhD – University of California, Los Angeles
Jesus-Servando Medel-Matus, PhD – University of California, Los Angeles
Cindy Santiago-Castaneda, PhD – Albert Einstein College of Medicine
Julia Frostholm, Student – University of California, Los Angeles
Bovornpat Suriyapakorn, PharmD – University of Minnesota
Aristea S. Galanopoulou, MD, PhD – Albert Einstein College of Medicine
Lisa Coles, PhD – University of Minnesota
Don Shin, BSc – University of California, Los Angeles
Anna Maria Katsarou, MD – Albert Einstein College of Medicine
Wei Liu, MD – Department of Neurosurgery, Ruijin Hospital
Christopher Martinez Aguirre, PhD – Albert Einstein College of Medicine
Raman Sankar, MD, PhD – University of California, Los Angeles
Solomon L. Moshé, MD – Albert Einstein College of Medicine and Montefiore Medical Center
Rationale: Lateral fluid percussion injury (LFPI) leads to post-traumatic epilepsy (PTE) in 25-50% of rats. LFPI disrupts intestinal barrier, resulting in the escape of gut bacterial products, including lipopolysaccharide (LPS, a.k.a. endotoxin) into the blood. We reported that plasma LPS levels during the 1st post-LFPI week were in the inverse correlation with the risk of PTE as detected 6+ months after LFPI (PMID: 33893636) and proposed that mild post-LFPI endotoxemia might exert an anti-PTE effect via LPS conditioning. We tested this hypothesis by examining effects of exogenously administered LPS on PTE and on pro- and anti-inflammatory mediators.
Methods: Eight-week-old Sprague-Dawley rats underwent either LFPI or sham-LFPI, followed immediately by one-week subcutaneous delivery of LPS (100 ug/kg/day), from either E. Coli (EC), or Akkermansia (Ak), or of saline (SAL), via an osmotic minipump. 6-12 rats per group were used for enzyme linked immunosorbent assays (ELISA) in the hippocampus (HIP) and parietal cortex (PC), to detect pro-inflammatory (Interleukin [IL]-1beta, IL-6, tumor necrosis factor, iNOS), and anti-inflammatory (IL-4, IL-10, CD163, transforming growth factor beta [TGFb], triggering receptor expressed on myeloid cells 2 [TREM2]) mediators. Separate rats underwent 4 weeks of video-EEG 7-8 mos after LFPI/sham LFPI to detect spontaneous seizures, followed by kindling of basolateral amygdala.
Results: TGFb and TREM2 were increased in PC and HIP ipsilateral to LFPI in animals of all groups except for TGFb in SAL LFPI. IL-4 was suppressed after EC-LPS in the HIP and PC ipsilateral to LFPI. Seizures occurred in 2 out of 10 SAL, 1 out of 8 Ak-LPS and 0 out of 10 EC-LPS rats (p >0.05). Sham rats (n=12) kindled after 14-20 trials. SAL-LFPI rats (n=10) kindled after 4-27 trials (p=0.41 vs. sham) with 4 kindled faster (p< 0.05) and 3- slower (p >0.05) than shams, as compared to lower and upper limits respectively of shams’ 95% confidence interval of median (CIM). EC-LPS rats (n=10) kindled after 10-23 trials (p=0.3 vs. sham and SAL), with 1 kindled faster, 5- within and 4- slower than shams’ 95% CIM (p >0.05). Ak-LPS rats (n=8) kindled after 15-27 trials (p=0.03 vs. sham, p=0.09 vs. SAL), with 4 kindled slower, and 4- within shams’ 95% CIM (p >0.05). With the EC-LPS and Ak-LPS data combined, the number of fast-kindled rats (1 out of 18) was lower than in the SAL group (4 out of 10, p< 0.05), and the number of slow-kindled rats (8 out of 18) was higher than among shams (1 out of 12, p< 0.05).
Conclusions: Facilitation and delay of kindling after LFPI in certain rats might reflect susceptibility and resistance to epileptogenesis respectively. Both types of LPS, especially Ak-LPS, counteracted LFPI-induced facilitation of kindling. ELISA findings suggest that anti-epileptogenic effects of LPS may involve TGFb and TREM2 in brain areas relevant to the injury and to PTE during an early post-LFPI period, which (period) is thought to be critical to epileptogenesis.
Funding: DoD W81XWH2210210, W81XWH2210510, NINDS NS127524; N. and V. Harinarayan Charitable Fund (UCLA); Heffer Funds (Albert Einstein College of Medicine).
Basic Mechanisms