Suppression of Inflammatory and Fibrotic Signals by Cinnamon (Cinnamomum cassia) and Cinnamaldehyde in Cyclophosphamide-Induced Overactive Bladder in Mice

Lih-Lian Chen; Mei-Hsien Lee; Chia-Lin Chang; Kuo-Tong Liou; Shu-Hsiang Liu; Chang-Ming Chern; Hui-I Chen; Yuh-Chiang Shen; Yea-Hwey Wang

doi:10.1155/2021/5205759

Suppression of Inflammatory and Fibrotic Signals by Cinnamon (Cinnamomum cassia) and Cinnamaldehyde in Cyclophosphamide-Induced Overactive Bladder in Mice

Evid Based Complement Alternat Med. 2021 Dec 22:2021:5205759. doi: 10.1155/2021/5205759. eCollection 2021.

Authors

Lih-Lian Chen^{1

2}, Mei-Hsien Lee^{1

3

4}, Chia-Lin Chang⁵, Kuo-Tong Liou^{6

7}, Shu-Hsiang Liu⁸, Chang-Ming Chern^{9

10

11}, Hui-I Chen¹, Yuh-Chiang Shen^{1

8

12}, Yea-Hwey Wang⁸

Affiliations

¹ Ph.D. Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University, Taipei City, Taiwan.
² Department of Traditional Chinese Medicine, En Chu Kong Hospital, New Taipei City, Taiwan.
³ Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei City, Taiwan.
⁴ Center for Reproductive Medicine & Sciences, Taipei Medical University Hospital, Taipei City, Taiwan.
⁵ Research Institute of Biotechnology, Hungkuang University, Taichung City, Taiwan.
⁶ Department of Medicine, Mackay Medical College, New Taipei City, Taiwan.
⁷ Department of Chinese Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei City, Taiwan.
⁸ School of Nursing, College of Nursing, National Taipei University of Nursing and Health Sciences, Taipei City, Taiwan.
⁹ Taipei Municipal Gan-Dau Hospital, Taipei City, Taiwan.
¹⁰ Division of Neurovascular Disease, Neurological Institute, Taipei Veterans General Hospital, Taipei City, Taiwan.
¹¹ Institute of Brain Science, School of Medicine, National Yang-Ming University, Taipei City, Taiwan.
¹² National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei City, Taiwan.

Abstract

Cinnamon (Cinnamomum cassia) is a well-known traditional Chinese medicine used to treat nocturia by tonifying and warming the kidney. Our recent clinical study found that overactive bladder (OAB) patients treated with cinnamon powder (CNP) patches exhibited significantly ameliorated OAB symptoms without significant side effects, but the mechanism of action is unclear. To explore the beneficial effects and action mechanisms of CNP and its major active component cinnamaldehyde (CNA) in an OAB-related murine model, cyclophosphamide- (CYP-) induced OAB injury was performed on male ICR mice in the presence or absence of CNP and CNA, as well as solifenacin, a clinical drug for OAB as a reference. Twenty-four-hour micturition patterns (frequency of urination and volume of urine per time), as well as histopathological examination, immunohistochemistry (IHC), and Western blotting of the bladder, were analyzed for mechanism elucidation. Administration of CYP (300 mg/kg, i.p.) induced typical OAB pathophysiological changes, including increased frequency of urination and reduced volume of urine. CYP-induced mice displayed strong edema of the bladder and hemorrhagic cystitis, accompanied by loss of normal corrugated folds and decreased muscarinic receptors (M2/M3) in the urothelium, and disordered/broken structures of the lamina propria and detrusor. These changes were correlated with increased leukocyte (CD11b) infiltration colocalized with inflammatory (pp65 NFκB, macrophage migration inhibitory factor (MIF)/Toll-like receptor 4 (TLR4)) and fibrotic (stem cell factor (SCF)/c-Kit, α-smooth muscle actin (α-SMA)/β-catenin) signals. Treatment with CNP (600 mg/kg, p.o.) and CNA (10-50 mg/kg, p.o.), but not solifenacin (50 mg/kg), 30 min after CYP induction significantly ameliorated CYP-induced dysfunction in micturition patterns and pathophysiological changes. CNP and CNA further suppressed MIF/TLR4-associated inflammatory and SCF/c-Kit-related fibrotic signaling pathways. Our findings indicate that suppression of inflammatory and fibrotic signals contributes to the crucial mechanism in the improvement of CYP-induced OAB by CNP and CNA.