Botulinum Toxin Confers Radioprotection in Murine Salivary Glands

Abstract

Purpose Xerostomia is a common radiation sequela, which has a negative impact on the quality of life of patients with head and neck cancer. Current treatment strategies offer only partial relief. Botulinum toxins (BTX) have been successfully used in treating a variety of radiation sequelae such as cystitis, proctitis, fibrosis, and facial pain. The purpose of this study was to evaluate the effect of BTX on radiation-induced salivary gland damage. Methods and Materials We used a previously established model for murine salivary gland irradiation (IR). The submandibular glands (SMGs) of C5BL/6 mice (n=6/group) were injected with saline or BTX 72 hours before receiving 15 Gy of focal irradiation. Saliva flow was measured 3, 7, and 28 days after treatment. The SMGs were collected for immunohistochemistry, confocal microscopy, and Western blotting. A cytokine array consisting of 40 different mouse cytokines was used to evaluate cytokine profiles after radiation treatment. Results Irradiated mice showed a 50% reduction in saliva flow after 3 days, whereas mice preinjected with BTX had 25% reduction in saliva flow (P<.05). Cell death detected by TUNEL staining was similar in SMG sections of both groups. However, neutrophil infiltrate, detected by myeloperoxidase staining, was 3-fold lower for the BTX treated mice. A cytokine array showed a 2-fold upregulation of LPS-induced chemokine (LIX/CXCL5) 3 days after IR. BTX pretreatment reduced LIX levels by 40%. At 4 weeks after IR, the saline (control) group showed a 40% reduction in basal SMG weight, compared with 20% in the BTX group. Histologically, BTX-pretreated glands showed relative preservation of acinar structures after radiation. Conclusions These data suggest that BTX pretreatment ameliorates radiation-induced saliva dysfunction. Moreover, we demonstrate a novel role for CXCL5 in the acute phase of salivary gland damage after radiation. These results carry important clinical implications for the treatment of xerostomia in patients with head and neck cancer.

Inhibition of the Continuum of Radiation-Induced Normal Tissue Injury by a Redox-Active Mn Porphyrin

“…4). In accordance with previous studies, radiation treatment significantly decreased salivation in saline-treated mice (13, 24–26). In this study, the lowest doses of MnBuOE (0.6/0.3 or 0.2/0.1 mg/kg) gave the highest level of protection against xerostomia.…”

Effect of ischemic preconditioning on radiation damage to the submandibular gland in rats

“…The potential mechanism involved might be related to the reduction in inflammatory infiltration, which has been reported in various organs, including the liver, intestine, and heart [4–6,10]. In addition, Zeidan et al [33] only observed a significant increase at the level of myeloperoxidase on the 3rd day after irradiation in mouse submandibular glands. Zhang et al [34] also observed that only the myeloperoxidase activity peaked on the 3rd day after radiation damage to the intestinal epithelial cells and decreased to nearly normal levels on the 7th day.…”

Salivary side effects after radioiodine treatment for differentiated papillary thyroid carcinoma: Long‐term study

“…A review of natural and synthetic compounds suggested that more studies were needed, and at the time, it was better to use natural compounds over synthetic 13,40‐43 . Botulinum toxin seems to confer radioprotective properties to salivary glands in Murine subjects by reducing glandular atrophy and periductal fibrosis during classic external radiation 44 . Botulinum toxin would be an interesting preventive treatment for patients receiving radioiodine to prevent adverse side effects.…”