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Article

Chronic Administration with FAD012 (3,5-Dimethyl-4-hydroxycinnamic Acid) Maintains Cerebral Blood Flow and Ameliorates Swallowing Dysfunction After Chronic Cerebral Hypoperfusion in Rats

by
Takashi Asano
1,
Hirokazu Matsuzaki
1,
Meiyan Xuan
2,
Bo Yuan
1,
Jun Takayama
2,
Takeshi Sakamoto
2 and
Mari Okazaki
1,*
1
Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan
2
Laboratory of Organic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(7), 3277; https://doi.org/10.3390/ijms26073277
Submission received: 14 February 2025 / Revised: 26 March 2025 / Accepted: 29 March 2025 / Published: 1 April 2025
(This article belongs to the Collection Feature Papers in Molecular Neurobiology)
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Abstract

Dysphagia is a serious complication of stroke, yet effective pharmacological treatments remain limited. This study investigated the effects of FAD012 (3,5-dimethyl-4-hydroxy cinnamic acid), a synthetic derivative of ferulic acid (FA), on cerebral damage and swallowing dysfunction in a rat model of bilateral common carotid artery occlusion (2VO). Sprague–Dawley rats were orally administered FAD012 (3 or 10 mg/kg), FA (10 mg/kg), or 0.5% carboxymethyl cellulose (CMC, suspension vehicle) starting one week before 2VO. Two weeks after 2VO surgery, which was performed under isoflurane anesthesia, reflex swallowing was assessed by electromyographic recordings of the mylohyoid muscle under urethane anesthesia. Two weeks after 2VO, cerebral blood flow (CBF) declined to approximately 40% of baseline, and the number of reflex swallowing responses was significantly reduced in the CMC group. Additionally, 2VO induced O2− production, apoptotic cell death in the striatum, and a reduction in tyrosine hydroxylase expression. Substance P (SP) levels in the laryngopharyngeal mucosa, positively regulated by dopaminergic signaling in the basal ganglia, also decreased. FAD012 (10 mg/kg) effectively prevented the 2VO-induced reduction in CBF, enhanced the reflex swallowing, and preserved the dopamine-SP system. Notably, FAD012 exerted significantly stronger effects than FA at the same dose. These findings suggest that FAD012 maintains CBF under cerebral hypoperfusion and enhances the swallowing reflex by maintaining neuronal function in the striatal and laryngopharyngeal regions of 2VO rats.
Keywords: 3,5-dimethyl-4-hydroxycinnamic acid (ferulic acid derivative 012, FAD012); ferulic acid (FA); cerebral hypoperfusion (2VO); dysphagia (swallowing dysfunction); oxidative stress; substance P (SP); nigrostriatal dopamine-SP system 3,5-dimethyl-4-hydroxycinnamic acid (ferulic acid derivative 012, FAD012); ferulic acid (FA); cerebral hypoperfusion (2VO); dysphagia (swallowing dysfunction); oxidative stress; substance P (SP); nigrostriatal dopamine-SP system
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MDPI and ACS Style

Asano, T.; Matsuzaki, H.; Xuan, M.; Yuan, B.; Takayama, J.; Sakamoto, T.; Okazaki, M. Chronic Administration with FAD012 (3,5-Dimethyl-4-hydroxycinnamic Acid) Maintains Cerebral Blood Flow and Ameliorates Swallowing Dysfunction After Chronic Cerebral Hypoperfusion in Rats. Int. J. Mol. Sci. 2025, 26, 3277. https://doi.org/10.3390/ijms26073277

AMA Style

Asano T, Matsuzaki H, Xuan M, Yuan B, Takayama J, Sakamoto T, Okazaki M. Chronic Administration with FAD012 (3,5-Dimethyl-4-hydroxycinnamic Acid) Maintains Cerebral Blood Flow and Ameliorates Swallowing Dysfunction After Chronic Cerebral Hypoperfusion in Rats. International Journal of Molecular Sciences. 2025; 26(7):3277. https://doi.org/10.3390/ijms26073277

Chicago/Turabian Style

Asano, Takashi, Hirokazu Matsuzaki, Meiyan Xuan, Bo Yuan, Jun Takayama, Takeshi Sakamoto, and Mari Okazaki. 2025. "Chronic Administration with FAD012 (3,5-Dimethyl-4-hydroxycinnamic Acid) Maintains Cerebral Blood Flow and Ameliorates Swallowing Dysfunction After Chronic Cerebral Hypoperfusion in Rats" International Journal of Molecular Sciences 26, no. 7: 3277. https://doi.org/10.3390/ijms26073277

APA Style

Asano, T., Matsuzaki, H., Xuan, M., Yuan, B., Takayama, J., Sakamoto, T., & Okazaki, M. (2025). Chronic Administration with FAD012 (3,5-Dimethyl-4-hydroxycinnamic Acid) Maintains Cerebral Blood Flow and Ameliorates Swallowing Dysfunction After Chronic Cerebral Hypoperfusion in Rats. International Journal of Molecular Sciences, 26(7), 3277. https://doi.org/10.3390/ijms26073277

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