| 1. |
- Dankis, Martin, et al.
(författare)
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Acute inhibitory effects of antidepressants on lacrimal gland secretion in the anesthetized rat
- 2021
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Ingår i: Investigative Ophthalmology and Visual Science. - : Association for Research in Vision and Ophthalmology (ARVO). - 0146-0404. ; 62:7
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Tidskriftsartikel (refereegranskat)abstract
- 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 reflex-evoked 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. Copyright 2021 The Authors
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| 2. |
- Dankis, Martin
(författare)
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Characterization of secretory mechanisms in lacrimal and salivary glands
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Dry mouth and dry eyes are multifactorial morbidities that can lead to a severely reduced quality of life. Approximately 20% of the population suffers from ocular or oral dryness. In the pursuit of pharmacological treatments of these troublesome symptoms, we sought to identify new targets and characterize underlying mechanisms that modulate lacrimal and salivary secretion. Xerogenic and xerophthalmic effects of antidepressants were examined in a rat in vivo model. Centrally mediated secretion was stimulated by applying citric acid to the tongue or by administration of menthol to the surface of the eye, and peripherally induced secretion was mediated by i.v. injection of the muscarinic agonist methacholine. The xerogenic effects of the tricyclic antidepressant clomipramine, the selective serotonin reuptake inhibitor citalopram, and serotonin-noradrenaline reuptake inhibitor venlafaxine were shown to be centrally mediated. In contrast, only clomipramine attenuated the peripherally stimulated response, while it was ameliorated by citalopram and venlafaxine. Likewise, the xerophthalmic effects of clomipramine and citalopram were centrally mediated. Further, similar to what was displayed in the salivary investigation, clomipramine attenuated peripherally stimulated lacrimation. However, citalopram exhibited no peripheral hyposecretory effects. In conclusion, in contrast with the common perception, modern antidepressant compounds such as selective serotonin reuptake inhibitors do not feature peripherally mediated anticholinergic properties. These findings verify the more suitable therapeutic profile of modern antidepressants and support the use of local parasympathomimetic treatment of drug induced dry mouth and dry eyes. Lacrimal gland secretory mechanisms and the effects of cholinergic and purinergic mediators were studied in primary monocultures and co-cultures of rat lacrimal gland cells. The primary culture isolation procedure was validated by monitoring the cultures immunochemically. After four weeks, a monoculture of myoepithelial cells was established which was shown to be sustained throughout the six-week isolation process. Prior to this, at 2-3 weeks, a co-culture of acinar and myoepithelial cells was evident. In conjunction, lacrimal gland tissue and primary cell cultures were studied morphologically for identification of cholinergic receptors. Immunohistochemical investigation of both myoepithelial cells and lacrimal gland tissues showed expression of a heterogenous muscarinic receptor population, indicating a multifaceted presence of functional receptors. However, no alterations in intracellular calcium were observed in myoepithelial cells, following stimulation with cholinergic modulators. This finding indicated a functional cholinergic dependence on intercellular interactions with acinar cells and an alternative cholinergic signal transduction pathway that excludes calcium. Based on the monoculture results, we next established a primary co-culture of rat lacrimal gland acinar and myoepithelial cells. In these studies, myoepithelial cells displayed a latent calcium response to cholinergic stimuli. This response was attributed to purinergic intercellular interactions, likely via ATP released from acini cells. In conclusion, the current findings show that antidepressant-induced hyposecretion is mainly centrally mediated. We established and validated sustainable isolation procedures for monocultures of primary myoepithelial cells, in which co-cultures of acinar and myoepithelial cells arise midway. Furthermore, we showed that lacrimal gland secretion can be multifaceted, highlighting the importance of investigating effects of selective muscarinic and purinergic modulatory compounds in the efforts of developing new treatments for dry eyes and dry mouth.
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| 3. |
- Dankis, Martin, et al.
(författare)
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Novel Insights Into Muscarinic and Purinergic Responses in Primary Cultures of Rat Lacrimal Gland Myoepithelial Cells.
- 2021
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Ingår i: Investigative ophthalmology & visual science. - : Association for Research in Vision and Ophthalmology (ARVO). - 1552-5783. ; 62:12
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Tidskriftsartikel (refereegranskat)abstract
- 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.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 [Ca2+] responses upon activation of muscarinic receptors. For methodological verification, purinergic functional responses were also studied.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 [Ca2+]. However, activation of purinergic receptors by the non-selective purinergic agonist ATP (10-8-10-3 M) caused a concentration-dependent increase in intracellular [Ca2+] that could be blocked by the P2 antagonists PPADS and suramin.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 [Ca2+] 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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| 4. |
- Walladbegi, Java, et al.
(författare)
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Moderate temperature reduction is sufficient for prevention of 5-fluorouracil-induced oral mucositis: an experimental in vivo study in rats
- 2023
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Ingår i: Cancer Chemotherapy and Pharmacology. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 91:1, s. 67-75
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Tidskriftsartikel (refereegranskat)abstract
- 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 3–5days, 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.
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