Effects of Cevimeline on the Immunolocalization of Aquaporin-5 and the Ultrastructure of Salivary Glands in Sjögren’s Syndrome Model Mice

Abstract

Summary: Sjögren's syndrome (SS) is an autoimmune disorder whose main symptoms include xerostomia and dry eyes. It has been demonstrated that abnormal expression of aquaporin (AQP)-5 in the parotid and submandibular glands in SS model mice was corrected by cevimeline. In the present study, we orally administered cevimeline hydrochloride (cevimeline) to female MRL/l mice, which are widely used as a model for SS, to immunohistochemically investigate the localization of AQP-5 in the salivary glands. We also assessed the ultrastructure of acinar cells in the submandibular glands. AQP-5 was expressed in the apical and lateral cell membranes of acinar cells in the parotid and submandibular glands of normal mice, but not in the sublingual glands. In contrast, AQP-5 was expressed not only in the cell membranes in the apical domains but also in the cytoplasm in the SS model mice, indicating that the localization of AQP-5 was disordered in the SS model mice. After administration of cevimeline, AQP-5 was predominantly localized in the cellular apical domains of the acinar cells. Electron microscopy revealed that administration of cevimeline to the SS model mice and normal mice markedly reduced the number of secretory granules, increased the area of the rough endoplasmic reticulum, and expanded the intercellular gaps in the cells of the submandibular acini. Condensed vacuoles were also observed in the Golgi apparatuses, indicating that secondary enhancement of secretion and production of saliva had occurred. Consequently, the results of the present study demonstrate that the administration of cevimeline to the SS model mice increased salivary secretion in the submandibular glands. Furthermore, cevimeline transiently normalized the localization of AQP-5 expression in the parotid and submandibular glands.

<em>Ixeris dentata </em>extract regulates salivary secretion through the activation of aquaporin-5 and prevents diabetes-induced xerostomia

“…Aquaporins are proteins that form water-specific channels for water secretion. Among the various aquaporins (AQP1–AQP10), 30 AQP5 is expressed in the apical, basal and lateral membranes 21 of acinar cells in rat SMGs 21 , 31 and is as an essential protein for salivary gland secretion. 20 Hyposalivation is caused not only by changes in whole-body fluid homeostasis, but also by the reduction of membrane water-permeability from the loss of AQP5 in salivary gland acinar cells.…”

Dysfunction of Lacrimal and Salivary Glands in Sjögren′s Syndrome: Nonimmunologic Injury in Preinflammatory Phase and Mouse Model

“…Soyfoo et al [78] reported that the 8-week-old female NOD mice without inflammation and normal age-matched BALB/c(normal) mice showed a similar distribution of AQP5 （ primarily at the apical membrane of the salivary gland acini ） , whereas in acini from the submandibular glands (but not from the parotid glands) from 24-week-old NOD mice with inflammation, AQP5 staining was reduced at the apical membrane but was increased at the basal membrane compared to normal mice, in which a significant decrease in pilocarpine-stimulated salivary flow was observed. On the other hand, Nishimura et al [79] reported that AQP-5 was expressed in the apical and lateral cell membranes of acinar cells in the parotid and submandibular glands of normal mice, but not in the sublingual glands, whereas AQP-5 was expressed not only in the cell membranes of acinar cells in the apical domains but also in the cytoplasm in the female MRL/lpr mouse, a model for not only RA-like disease but also sSjS in human. There are some differences in distribution/expression of AQPs.…”

Involvement of Aquaporins in the Pathogenesis, Diagnosis and Treatment of Sjögren’s Syndrome

“…Three-time daily intake of 30 mg of cevimeline or of three- to four-time daily intake of pilocarpine represent therapeutic options, with limited side effects, for the treatment of xerostomia in SS patients and head and neck irradiated patients [ 80 ]. At a molecular level, cevimeline was shown to prevent radiation-induced xerostomia and radiation-induced decrease in AQP5 expression in mice submandibular glands [ 83 ], and normalized AQP5 localization to the apical membrane of SG acinar cells in SS mice [ 84 , 85 ]. The effects of bethanechol, a carbamate ester resistant to cholinesterase, acting on M3 muscarinic receptors has been tested in patients with radiotherapy-induced xerostomia, but additional studies are required to assess the beneficial effects of the drug in the treatment of saliva hypofunction of other origins, including pSS [ 86 ].…”