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Discovery of Therapeutic Targets for Seizure Disorders Through Elucidation of the Neuroprotective Mechanisms of Uric Acid in Seizure Disorders

  • 고승연 (아주대학교 일반대학원)

초록/요약

Epilepsy is a chronic neurological disorder characterized by recurrent seizures, with drug- resistant epilepsy (DRE) and status epilepticus (SE) representing particularly challenging aspects of the disease. Uric acid (UA), a naturally occurring antioxidant, has recently garnered attention for its neuroprotective properties and potential role in neurological conditions. This dissertation investigates UA as both a biomarker for predicting the risk of DRE and as a therapeutic intervention to mitigate the neuronal damage associated with SE. The overarching aim of this research is to explore the potential of UA in improving outcomes for patients with epilepsy, focusing on both predictive and therapeutic aspects. In Chapter 1, a retrospective observational cohort study was conducted to evaluate the association between serum UA levels and the risk of DRE development. The findings demonstrated that higher pre-diagnostic serum UA levels were significantly correlated with a reduced risk of converting to DRE, while lower UA levels were associated with an increased risk. These results suggest that UA may serve as a predictive biomarker for identifying patients at a higher risk of developing DRE, which has important implications for personalized epilepsy management and early intervention strategies. Building on these insights, Chapter 2 focuses on investigating the therapeutic effects of UA in an in vivo model of SE, a life-threatening condition characterized by prolonged seizure activity that often leads to significant neuronal injury and long-term neurological consequences. Using a pilocarpine-induced SE model, post-SE administration of UA was shown to reduce oxidative stress and promote neuronal survival in the hippocampus. The reduction in oxidative damage was evidenced by decreased nitrotyrosine staining, indicative of UA’s ability to effectively scavenge reactive nitrogen species, particularly peroxynitrite. Furthermore, UA treatment led to a dose-dependent reduction in hippocampal neuronal death, particularly in the CA1 and CA3 subfields, which are highly susceptible to SE-induced injury. This neuroprotective effect has significant clinical relevance, as hippocampal atrophy and sclerosis are common outcomes of SE that contribute to the progression to chronic epilepsy and cognitive decline. To further elucidate the molecular mechanisms underlying UA’s neuroprotective effects, transcriptomic analysis of the hippocampus was conducted using RNA sequencing. The analysis revealed significant upregulation of genes involved in neuronal survival, synaptic plasticity, and metabolic regulation in response to UA treatment. Notably, the transcription factor Pou4f1 was upregulated in the high-dose UA group, suggesting that UA promotes neuroprotection by enhancing transcriptional programs that counteract apoptosis and support cellular recovery. Pathway enrichment analysis further highlighted the impact of UA on biological processes such as synaptic plasticity, calcium signaling, and axon guidance, all of which are crucial for maintaining neuronal integrity and promoting recovery after SE. In conclusion, this dissertation provides a comprehensive evaluation of the dual role of uric acid in epilepsy. Chapter 1 demonstrates UA’s potential as a predictive biomarker for DRE, while Chapter 2 highlights its therapeutic efficacy in mitigating neuronal injury during SE. Together, these findings suggest that UA has considerable promise as both a biomarker and a therapeutic agent in epilepsy, offering new opportunities for personalized treatment and improved patient outcomes. Future research should focus on translating these findings into clinical applications, including the development of UA-based biomarkers for epilepsy prognosis and the optimization of UA treatment protocols to mitigate neuronal injury and prevent long-term neurological sequelae.

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목차

1. Background 1
1.1 Rationale, Aims, and Thesis Outline 1
1.2 General Introduction on Epilepsy 2
1.3 General Introduction on Uric Acid 3
1.3.1 Uric Acid and Its Role in Neurological Disorders 3
1.4 Epilepsy and Uric Acid: The Rationale for Investigation 11
1.4.1 Current Epilepsy Treatments and Challenges 11
1.4.2 The intersection of epilepsy and UA 11
1.4.3 Uric Acid as a Novel Therapeutic Candidate 14
2. Chapter 1: In Silico Study on Uric Acid and Drug-Resistant Epilepsy 16
2.1 Introduction 16
2.2 Materials and Methods 20
2.2.1 Data Sources 20
2.2.2 Study Design and Definitions 20
2.2.3 Validation of Serum Uric Acid Levels in Predicting DRE 22
2.2.4 Statistical Analysis 22
2.2.5 Sensitivity Analysis 23
2.3 Results 24
2.3.1 Cohort Characteristics 24
2.3.2 Sensitivity Analyses 33
2.3.3 Validation Results 36
2.4 Discussion 39
3. Chapter 2: In Vivo Study on Neuroprotective Effects of Uric Acid 44
3.1 Introduction 44
3.2 Materials and Methods 48
3.2.1 Study Design 48
3.2.2 Animal Model 51
3.2.3 Induction of Status Epilepticus 51
3.2.4 Seizure Severity Assessment 53
3.2.5 Administration of Uric Acid 54
3.2.6 Induction of Hyperuricemia 55
3.2.7 Sample Collection and Serum Uric Acid Measurement 57
3.2.8 Tissue Sampling and Analysis 57
3.2.9 RNA Sequencing and Transcriptomic Analysis 60
3.3 Results 62
3.3.1 Neuroprotective Effects of UA preconditioning in seizure disorder 62
3.3.2 Therapeutic Effects of Post-SE Uric Acid Administration 80
3.4 Discussion 98
3.4.1 Hyperuricemia and Its Neuroprotective Mechanisms 100
3.4.2 Post-SE Uric Acid Administration: Therapeutic Outcomes 105
3.4.3 Future Aims and Perspectives 116
4. Conclusion 119
5. References 121

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