Fenfluramine Attenuates Retinal Microglial Activation but Does Not Rescue Structural and Vascular Deficits in a Rat Model of Dravet Syndrome

Zhang, Yajuan; Qian, Weixin; Li, Miao; Zou, Ying-Ying; Lu, Zhonghua; Huang, Zhihui; Naumann, Robert K.; Wang, Hong

doi:10.3390/ijms27135752

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Fenfluramine Attenuates Retinal Microglial Activation but Does Not Rescue Structural and Vascular Deficits in a Rat Model of Dravet Syndrome

by

Yajuan Zhang

^1,2

,

Weixin Qian

^2,3

,

Miao Li

^2,4,

Ying-Ying Zou

⁴,

Zhonghua Lu

²

,

Zhihui Huang

¹,

Robert K. Naumann

^2,* and

Hong Wang

^1,2,*

¹

School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China

²

The Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, 1068 Xueyuan Blvd, Shenzhen 230027‌, China

³

Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 518055‌, China

⁴

Department of Pathology and Pathophysiology, Faculty of Basic Medical Sciences, Kunming Medical University, Kunming 650500, China

^*

Authors to whom correspondence should be addressed.

Int. J. Mol. Sci. 2026, 27(13), 5752; https://doi.org/10.3390/ijms27135752 (registering DOI)

Submission received: 10 May 2026 / Revised: 11 June 2026 / Accepted: 17 June 2026 / Published: 25 June 2026

(This article belongs to the Special Issue Molecular Insights in Neuro-Ophthalmology)

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Abstract

Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy caused by SCN1A haploinsufficiency. While brain pathology has been extensively studied, the retina remains underexplored. This study investigated retinal structural, functional, vascular, and cellular changes in a Scn1a^+/− rat model of DS. Anatomical quantification revealed thinning of the retinal nerve fiber layer and thickening of the outer plexiform layer. Electroretinography (ERG) showed selectively reduced oscillatory potential amplitudes, suggesting dysfunction of neurovascular coupling. Consistent with these findings, immunohistochemistry demonstrated aberrant vascular morphology, including increased vessel curvature and reduced branching density. In addition, we observed robust microglial activation in the outer and inner plexiform layers; however, astrocyte morphology remained largely unchanged. Fenfluramine, an approved anti-seizure drug for DS, attenuated microglial activation but failed to rescue retinal structural or vascular deficits, indicating a dissociation between its anti-inflammatory and disease-modifying effects. Our findings suggest that multimodal retinal assessment could serve as a noninvasive biomarker platform for monitoring disease progression and therapeutic response in DS.

Keywords: Dravet syndrome; fenfluramine; retina; electroretinograph; microglia

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MDPI and ACS Style

Zhang, Y.; Qian, W.; Li, M.; Zou, Y.-Y.; Lu, Z.; Huang, Z.; Naumann, R.K.; Wang, H. Fenfluramine Attenuates Retinal Microglial Activation but Does Not Rescue Structural and Vascular Deficits in a Rat Model of Dravet Syndrome. Int. J. Mol. Sci. 2026, 27, 5752. https://doi.org/10.3390/ijms27135752

AMA Style

Zhang Y, Qian W, Li M, Zou Y-Y, Lu Z, Huang Z, Naumann RK, Wang H. Fenfluramine Attenuates Retinal Microglial Activation but Does Not Rescue Structural and Vascular Deficits in a Rat Model of Dravet Syndrome. International Journal of Molecular Sciences. 2026; 27(13):5752. https://doi.org/10.3390/ijms27135752

Chicago/Turabian Style

Zhang, Yajuan, Weixin Qian, Miao Li, Ying-Ying Zou, Zhonghua Lu, Zhihui Huang, Robert K. Naumann, and Hong Wang. 2026. "Fenfluramine Attenuates Retinal Microglial Activation but Does Not Rescue Structural and Vascular Deficits in a Rat Model of Dravet Syndrome" International Journal of Molecular Sciences 27, no. 13: 5752. https://doi.org/10.3390/ijms27135752

APA Style

Zhang, Y., Qian, W., Li, M., Zou, Y.-Y., Lu, Z., Huang, Z., Naumann, R. K., & Wang, H. (2026). Fenfluramine Attenuates Retinal Microglial Activation but Does Not Rescue Structural and Vascular Deficits in a Rat Model of Dravet Syndrome. International Journal of Molecular Sciences, 27(13), 5752. https://doi.org/10.3390/ijms27135752

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Fenfluramine Attenuates Retinal Microglial Activation but Does Not Rescue Structural and Vascular Deficits in a Rat Model of Dravet Syndrome

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