Effect of adenovirus-mediated overexpression of PTEN on brain oxidative damage and neuroinflammation in a rat kindling model of epilepsy

Abstract

Background:Epilepsy is a chronic and severe neurological disorder. Phosphatase and tensin homolog deleted on chromosome ten (PTEN)-deficient mice exhibit learning and memory deficits and spontaneous epilepsy. The aim of this study was to investigate the role of PTEN in brain oxidative damage and neuroinflammation in a rat model of epilepsy.Methods:An adenovirus (Ad)-PTEN vector was constructed, and status epilepticus (SE) was induced in 41 model rats using lithium chloride-pilocarpine. Thirty-six SE rats were then allocated into the Ad-PTEN, Ad-LacZ, and SE groups, those were administered intracerebroventricular injections of Ad-PTEN, Ad-enhanced green fluorescent protein, and phosphate buffer saline, respectively. The normal group was comprised of healthy Sprague-Dawley rats. Nissl staining was conducted to evaluate neuronal damage, and immunohistochemistry was conducted to observe the morphology of cells in the hippocampal CA1 region and the distribution of ionized calcium-binding adaptor molecule 1 (Iba1) and ED1 (rat homologue of human CD68). Levels of apoptosis-related proteins, inflammatory-related factors, and oxidative stress-related markers (reactive oxygen species [ROS], glutathione [GSH], superoxide dismutase [SOD], and malondialdehyde [MDA]) were measured. Comparisons between multiple groups were conducted using one-way analysis of variance (ANOVA), and pairwise comparisons after ANOVA were conducted using the Tukey multiple comparisons test.Results:After SE induction, PTEN expression in the rat brain exhibited a four-fold decrease (P = 0.000) and the expression of both Iba1 and ED1 increased. Furthermore, significant neuronal loss, oxidative damage, and neuroinflammation were observed in the SE rat brain. After intracerebroventricular injection of Ad-PTEN, PTEN expression exhibited a three-fold increase (P = 0.003), and the expression of both Iba1 and ED1 decreased. Additionally, neurons were restored and neuronal apoptosis was inhibited. Furthermore, ROS and MDA levels decreased, GSH level and SOD activity increased, and neuroinflammation was reduced.Conclusion:Our study demonstrated that brain oxidative damage and neuroinflammation in SE rats were ameliorated by intracerebroventricular injection of Ad-PTEN.

Anticonvulsant Effects of Topiramate and Lacosamide on Pilocarpine-Induced Status Epilepticus in Rats: A Role of Reactive Oxygen Species and Inflammation

“…All these changes could increase the neuronal network excitability and diminish cell survival and seizure threshold. These data correspond to clinical and experimental studies in which there have been increased levels of IL-1β and TNF-α demonstrated in patients with temporal lobe epilepsy and humans exposed to SE [4,12], as well as in animals with SE [13].…”

Pentoxifylline prevents epileptic seizure via modulating HMGB1/RAGE/TLR4 signalling pathway and improves memory in pentylenetetrazol kindling rats

“…Besides its immune modulatory and pro‐inflammatory potential, HMGB1 interacts with TLR4 on neutrophils to induce oxidative stress 6 . The HMGB1 induced oxidative stress results in a progressive neuronal damage 7,8 . The HMGB1‐mediated activation of TLR4/RAGE pathway is one of the contributing factors to epileptogenesis.…”

Genetic and molecular features of seizure-freedom following surgical resections for focal epilepsy: A pilot study

“…Candidate genes were selected with the goal of capturing several proposed mechanisms underlying postoperative seizure pathophysiology from prior literature. To conserve statistical power in this pilot study, we selected a total of 10 genes across genes that were either previously studied in the setting of surgical epilepsy seizure outcomes (DEPDC5, NBEA, SCN1A) (6), or studied as potential mechanisms for the cause or maintenance of the epileptogenic zone in focal epilepsy (6,(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). These mechanisms included: neuroinflammatory causes of epileptogenesis (IL1A, C3) (17), calcium regulation and its role in induction and maintenance of epilepsy (CALHM1) (17, 21), mTOR pathway regulation in focal epileptogenesis (DEPDC5, PTEN) (6,15,18,20,22), monogenic causes of focal epilepsy (SCN1A, GABBRA1, LGI1) (16,17,23), established genetic causes of epileptic encephalopathies (NBEA) (6,18), and pharmaco-resistance mediating maintenance of seizures (ABCB1) (14,23,24).…”