Targeting Multiple Aspects of Neuroinflammation for Epilepsy

Author

Nelufar Yasmen, University of Tennessee Health Science Center

Date of Award

12-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Pharmaceutical Sciences

Research Advisor

Jianxiong Jiang, PhD

Committee

Marie Dennis M Leo, PhD; Wei Li, PhD; Mohammad Moshahid Khan, PhD; Helena Parfenova, PhD

Keywords

Seizure; Epilepsy; Neuroinflammation

Abstract

Epilepsy is considered as one of the most prevailing neurological conditions and worldwide approximately 65 million people are suffering from epilepsy. It has complex mechanistic features and is manifested by unprovoked seizures. There are over 30 antiseizure drugs (ASDs) available to treat seizures, however, about one-third of people with epilepsy continue to experience seizures that are resistant to treatment. These ASDs primarily focus on the relief of seizure symptoms but are unable to treat the underlying pathophysiological mechanisms such as neuroinflammation which causes exacerbation of seizure activity and contributes to the devastating consequences of seizures. Researchers showed a crucial connection between seizures and neuroinflammation, worsening each other and causing a critical cycle that impacts neuronal damage and neuronal activity. Reduction in neuroinflammation has been shown to decrease seizure activity and neurodegeneration which indicates neuroinflammation might offer a potential to prevent epilepsy and associated comorbidities.

This study focuses on microsomal prostaglandin E synthase-1 (mPGES-1) which is the last step enzyme responsible for synthesizing prostaglandin E2 (PGE2), a key inflammatory mediator, a molecule that plays a central role in driving the inflammatory process. Previous studies have shown that seizure can induce mPGES-1 robustly in a prompt manner. Genetic deletion of mPGES-1 in mice demonstrated neuroprotection and reduction of seizures followed by chemoconvulsant seizures. This suggests the potential of mPGES-1 as a target to treat epilepsy and pharmacological inhibition of mPGES-1 might provide beneficial effects against neuroinflammation. In this study, PBCH, an mPGES-1 inhibitor was used in a pilocarpine-induced status epilepticus (SE) mice model. The treatment abolished SE-induced PGE2 levels in the brain and showed negligible effect on cyclooxygenases (COX) which validated the specificity of the inhibitor to mPGES-1. Inhibition of mPGES-1 after SE also diminished pro-inflammatory cytokines and reduced activation of glial cells in the hippocampus. In addition, treatment with PBCH largely 10 reduced neuronal damage across several brain regions. These results highlight the potential of pharmacological inhibition of mPGES-1 as an adjunctive treatment to mitigate SE-induced brain inflammation and injury, even after hours of the onset of SE

Following, another inflammatory pathway TLR4/NF-κB was explored which involved sialic acid- binding immunoglobulin-like lectin E (Siglec-E). As an immunosuppressive molecule, Siglec-E modulates inflammatory responses through interaction with sialic acid ligands. Siglec-E shows negative regulation on the TLR4 receptor which dampens the activation of NF-κB as well it also can dampen the activation of microglia to reduce inflammation. Recent studies suggest that Siglec-E might play a role in neurotoxicity, brain inflammation, and neuronal excitability. Thus, activation of Siglec-E could modulate inflammatory responses which potentially reduce the severity and progression of seizures. To investigate, we used several conventional seizure models including pentylenetetrazol (PTZ)-induced seizures, flurothyl-induced seizures, kainic acid- induced seizures, pilocarpine-induced seizures,6 Hz-induced seizures, and maximum electroshock seizures (MES). Interestingly we found inverse results, global genetic deletion of iglec-E increased seizure latency in PTZ-induced and flurothyl-induced seizures compared to wildtype (WT) mice. Electroencephalogram (EEG) measurements further confirmed and validated that Siglec-E knockout (KO) mice exhibited lower electrographic seizures in the PTZ-induced seizure model. Additionally, in kainic acid-induced and pilocarpine-induced seizures, Siglec-E KO mice displayed lower behavioral seizure scores. Similarly, 6 Hz-induced seizures and MES models showed lower seizure severity in KO mice. These results suggest that Siglec-E has a possible role in seizure generation and reduction of seizures in KO mice, indicating its potential as a therapeutic target for epilepsy.

Targeting mPGES-1 and modulating Siglec-E provide promising prospects for developing new effective treatments. These strategies are addressing both seizure control and underlying 11 neuroinflammation which could lead to more broad and effective treatment strategies for epilepsy and potentially might reveal additional therapeutic targets.

Declaration of Authorship

Declaration of Authorship is included in the supplemental files.

DOI

10.21007/aetd.cghs.2024.0015

Recommended Citation

Yasmen, Nelufar , "Targeting Multiple Aspects of Neuroinflammation for Epilepsy" (2024). Alternative Theses and Dissertations (AETDs). Paper 15. http://dx.doi.org/10.21007/aetd.cghs.2024.0015.
https://dc.uthsc.edu/aetd/15