Purpose The current idea of how oral mucositis (OM) develops is primarily based on hypotheses and the early events which precede clinically established OM remain to be demonstrated. Cryotherapy (CT) continues to have considerable promise in clinical settings to reduce chemotherapy-induced OM. Although being effective, the knowledge is scarce regarding the ideal temperature for prevention of OM. Thus, the present study had two main objectives: (i) to develop an animal model to investigate the early events of OM; (ii) to study at what cooling temperature these early events could be abolished. Methods Male Sprague–Dawley rats were anaesthetized and given an intravenous bolus dose with the cytostatic drug fluorouracil (5-FU). During the first hour following injection with 5-FU, the oral cavity of the rats was cooled to a mucosal temperature at the range of 15–30 ○C, or left uncooled (35 ○C), serving as control. After 3–5 days, the rats were euthanized, and the buccal mucosa was excised. Subsequently, mucosal thickness and expression of IL-6 and TNF-α were analyzed with immunohistochemistry and enzyme-linked immunosorbent assay (ELISA). Results Five days following treatment with 5-FU, a statistically significant thickening of the oral mucosa occurred, and a distinct expression of both IL-6 and TNF-α were observed. The cryo-treated groups (15–30 °C) displayed statistically significantly thinner mucosa as compared to the control group (35 °C). The ELISA showed an increase in expression of the proinflammatory cytokines IL-6 and TNF-α in tissues exposed to 5-FU that were treated with increasing temperatures (15–30 °C). Conclusion Bolus i.v. injection with 5-FU in rats can be used to create a functional animal model for chemotherapy-induced OM. Further, moderate temperature reduction is sufficient to reduce the early events which may precede clinically established OM.
PURPOSE.Patients that medicate with antidepressants commonly report dryness of eyes. The cause is often attributed to the anticholinergic properties of the drugs. However, regulation of tear production includes a substantial reflex-evoked component and is regulated via distinct centers in the brain. Further, the anticholinergic component varies greatly among antidepressants with different mechanisms of action. In the current study it was wondered if acute administration of antidepressants can disturb production of tears by affecting the afferent and/or central pathway. METHODS.Tear production was examined in vivo in anesthetized rats in the presence or absence of the tricyclic antidepressant (TCA) clomipramine or the selective serotonin reuptake inhibitor (SSRI) escitalopram. The reflex-evoked production of tears was measured by challenging the surface of the eye with menthol (0.1 mM) and cholinergic regulation was examined by intravenous injection with the nonselective muscarinic agonist methacholine (1-5 μg/kg). RESULTS.Acute administration of clomipramine significantly attenuated both reflexevoked and methacholine-induced tear production. However, escitalopram only attenuated reflex-evoked tear production, while methacholine-induced production of tears remained unaffected. CONCLUSIONS.This study shows that antidepressants with different mechanisms of action can impair tear production by attenuating reflex-evoked signaling. Further, antimuscarinic actions are verified as a likely cause of lacrimal gland hyposecretion in regard to clomipramine but not escitalopram. Future studies on antidepressants with different selectivity profiles and mechanisms of action are required to further elucidate the mechanisms by which antidepressants affect tear production.
Purpose The functional characteristics of receptors that regulate lacrimal gland myoepithelial cells are still somewhat unclear. To date, mainly muscarinic receptors have been of interest; however, further knowledge is needed regarding their expression and functional roles. For this purpose, primary cultures of rat lacrimal gland myoepithelial cells were established and examined functionally. Methods Rat lacrimal glands were excised, minced, and further digested, yielding mixtures of cells that were seeded in culturing flasks. After 4-6 weeks, primary monocultures of myoepithelial cells were established, verified by immunocytochemistry. The cells were stained for all muscarinic receptor subtypes (M1–M5) and examined functionally regarding intracellular [Ca 2+ ] responses upon activation of muscarinic receptors. For methodological verification, purinergic functional responses were also studied. Results Expression of muscarinic receptor subtypes M2-M5 was detected, whereas expression of muscarinic M1 receptors could not be shown. Activation of muscarinic receptors by the non-selective muscarinic agonist methacholine (3 × 10 −11 –10 −3 M) did not cause a significant increase in intracellular [Ca 2+ ]. However, activation of purinergic receptors by the non-selective purinergic agonist ATP (10 −8 –10 −3 M) caused a concentration-dependent increase in intracellular [Ca 2+ ] that could be blocked by the P2 antagonists PPADS and suramin. Conclusions Primary cultures of rat lacrimal gland myoepithelial cells were established that displayed a heterogeneous expression of muscarinic receptors. Purinergic functional responses demonstrated a viable cell population. Upon treatment with methacholine, no significant increase in intracellular [Ca 2+ ] could be detected, indicating that cholinergic activation of myoepithelial cells occurs via other intracellular messengers or is dependent on interaction with other cell types.
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