파킨슨병 마우스 모델에서 NOX4-related Signal을 통한 산화스트레스 조절 및 해마 신경재생의 증가 = Regulation of Oxidative Stress and Promotion of Hippocampal Neurogenesis via NOX4-related Signal in Parkinson’s Disease Mouse Model

다국어 초록 (Multilingual Abstract)

Parkinson’s disease (PD) is characterized by progressive dopaminergic neurodegeneration, α-synuclein aggregation, and disrupted hippocampal neurogenesis, largely driven by astrocyte-derived oxidative stress mediated by NADPH oxidase 4 (NOX4). Current pharmacotherapies offer only symptomatic relief without halting disease progression or restoring neuronal regeneration. In this study, we examined the neuroprotective and neuroregenerative effects of two plant-derived antioxidant extracts—saffron-derived antioxidant (SDA; Crocus sativus extract) and Passiflora incarnata L. (PI) by assessing their ability to modulate astrocytic redox signaling in an MPTP-induced mouse model of PD. Male C57BL/6J mice received MPTP and were treated orally with SDA or PI (50 mg/kg/day) for five weeks, with resveratrol (RES; 50 mg/kg/day) as a positive control. Behavioral tests assessed motor strength and coordination, while histological and molecular analyses evaluated dopaminergic neuron survival, α-synuclein pathology, hippocampal neurogenesis markers (Ki67, DCX, BrdU/NeuN), Synaptic plasticity markers (PSD95, synaptophysin), and astrocytic oxidative mediators (NOX4, MPO, OPN). Both SDA and PI significantly preserved dopaminergic neurons, reduced α-synuclein accumulation, and improved motor function. Treatment also restored hippocampal neurogenesis and synaptic integrity, accompanied by marked suppression of astrocytic NOX4, MPO, and OPN expression. Notably, SDA exerted stronger effects on motor recovery, whereas PI more effectively promoted neuronal differentiation within the dentate gyrus. These findings identify SDA and PI as potent astrocyte-targeted redox modulators that mitigate NOX4-driven oxidative neuroinflammation, preserve hippocampal plasticity, and promote neuroprotection. Collectively, this work provides compelling preclinical evidence supporting SDA and PI as safe, disease-modifying phytotherapeutics for Parkinson’s disease and related neurodegenerative disorders.

목차 (Table of Contents)

• List of tables iii
• List of figures iv
• List of abbreviations vii
• Abstract ix
• I. Introduction 1
• II. Materials and Methods 4
• 2.1 Animals and Experimental Design 4
• 2.2 Behavioral Assessments of MPTP-induced Parkinson’s disease mouse model 6
• 2.3 Histological and Immunohistochemical Evaluation 6
• 2.4 Western Blot 8
• 2.5 Statistics 9
• III. Results 12
• 3.1 SDA and PI protect dopaminergic neurons, attenuate α-synuclein pathology, and improve motor performance in MPTP-induced PD mice 12
• 3.2 SDA and PI restore hippocampal neurogenesis impaired by MPTP toxicity 14
• 3.3 SDA and PI restore synaptic plasticity markers and hippocampal connectivity 15
• 3.4 SDA and PI promote neuronal over astrocytic differentiation of newly generated cells 16
• 3.5 SDA and PI suppress NOX4, MPO, and OPN expression in the hippocampus 17
• 3.6 Differential NOX4–MPO–OPN coupling between astrocytes and neurons in response to SDA and PI 18
• 3.7 SDA and PI preserve mitochondrial integrity and inhibit apoptosis in the hippocampus of MPTP-induced PD mice 19
• IV. Discussion 50
• V. References 55
• VI. Supplement 61
• 국문요약 62
• 감사의 글 64