Page 72 - 2025中醫藥與天然藥物聯合學術研討會-中醫藥與天然藥物的挑戰Ｘ機遇與未來大會手冊

Targeting Brain Energy Deficiency

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Yi-juang Chern*

1 Institute of Biomedical Sciences, Academia Sinica, Taiwan
* E-mail: bmychern@ibms.sinica.edu.tw

Abstract
Alzheimer’s disease (AD) is the most common neurodegenerative disorder in aging societies
(including Taiwan), yet current treatments offer limited efficacy and are often accompanied by

serious side effects. Adenosine, a critical regulator of mitochondrial function and brain
homeostasis, is found at abnormal levels in AD brains, making its transport pathway a
promising therapeutic target. We identified the equilibrative nucleoside transporter 1 (ENT1)

as a key regulator of adenosine balance and isolated T1-11, an adenosine analog from Gastrodia
elata, subsequently developing J4, a stable and orally active ENT1 inhibitor suitable for large-
scale synthesis. J4 was tested in four experimental models of AD, with treatment initiated after
disease onset. Behavioral assays, including the Morris Water Maze, demonstrated significant
improvement in learning and memory. Biochemical analyses revealed that J4 reduced amyloid-

β and phosphorylated tau accumulation, alleviated oxidative stress and neuroinflammation,
restored mitochondrial and glucose metabolic function, and improved sleep disturbances.
Collectively, these findings indicate that J4 exerts broad neuroprotective effects across multiple

pathological domains of AD and may represent a disease-modifying therapeutic strategy. Given
its efficacy, oral bioavailability, chemical stability, and ease of synthesis, J4 holds strong
potential for clinical development as a cost-effective treatment for AD.

Keywords: Alzheimer’s disease; Adenosine; ENT1

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