| 1. |
- Carpenter, GH, et al.
(författare)
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Altered plasticity of the parasympathetic innervation in the recovering rat submandibular gland following extensive atrophy.
- 2009
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Ingår i: Experimental physiology. - : Wiley. - 0958-0670. ; 94:2, s. 213-9
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Tidskriftsartikel (refereegranskat)abstract
- Adult rat submandibular glands have a rich autonomic innervation, with parasympathetic and sympathetic nerves working in synergy rather than antagonistically. Ligation of the secretory duct rapidly causes atrophy and the loss of most acini, which are the main target cell for parasympathetic nerves. Following deligation, there is a recovery of gland structure and function, as assessed by autonomimetic stimulation. This study examines whether the parasympathetic nerves reattach to new target cells to form functional neuro-effector junctions. Under recovery anaesthesia, the submandibular duct of adult male rats was ligated via an intra-oral approach to avoid damaging the chorda-lingual nerve. Four weeks later, rats were either killed or anaesthetized and the ligation clip removed. Following a further 8 weeks, both submandibular ducts were cannulated under terminal anaesthesia. Salivary flows were then stimulated electrically (chorda-lingual nerve at 2, 5 and 10 Hz) and subsequently by methacholine (whole-body infusion at two doses). Glands were excised, weighed and divided for further in vitro studies or fixed for histological examination. Ligation of ducts caused 75% loss of gland weight, with the loss of most acinar cells. Of the remaining acini, only 50% were innervated despite unchanged choline acetyltransferase activity, suggesting few parasympathetic nerves had died. Following deligation, submandibular glands recovered half their weight and had normal morphology. Salivary flows from both glands (per unit of gland tissue) were similar when evoked by methacholine but greater from the deligated glands when evoked by nerve stimulation. This suggests that parasympathetic nerves had reattached to new target cells in the recovered glands at a greater ratio than normal, confirming reinnervation of the regenerating gland.
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| 2. |
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| 3. |
- Ekström, Jörgen, 1944, et al.
(författare)
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Regulatory Mechanisms and Salivary Gland Function
- 2011
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Ingår i: Salivary Gland Disorders: Diagnosis and Management. - Stuttgart, Germany : Georg Thieme Verlag. ; , s. 10-18
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- * Acinar cells secrete water and proteins.The isotonic saliva is modified by duct cells and becomes hypotonic. Immunoglobulin A from plasma cells is transported across the epithelial cells into the saliva.Contraction of myoepithelial cells increases luminal pressure and expels saliva. * The volume of saliva secreted and its protein composition varies between various types of gland.Minor glands continously secrete a protective mucin-rich film of saliva, while submandibular and parotid glands secrete their reflexly elicited watery saliva mainly during a meal. * Stimulation of various receptors (mechanoreceptors,gustatory receptors,thermoreceptors,olfactory receptors and noiceptors) triggers reflex secretion. * Salivary nuclei in the central nervous system are influenced by higher brain regions:sleep,fever and fear reduce or inhibit the outflow of impulses for secretion. * Parasympathetic innervation evokes secretion of proteins and large volumes of fluid, while sympathetic innervation of any of the secretory elements evokes secretion of proteins and small volumes of fluid. In reflex conditions, sympathetic activity occurs during ongoing parasympathetic activity and the two sets of nerves interact synergistically. * In acinar cells,Ca2+ causes mainly fluid secretion, while cAMP causes mainly protein secretion. The two pathways interact positively. The parasympathetic nerve uses different transmitters to activate the two pathways (acetylcholine for Ca2+ and vasoactive intestinal peptide for cAMP), while the sympathetic nerve activates the two pathways through the action of norepinephrine on α1(Ca2+) and β1(cAMP) adrenoreceptors. Agonists using cAMP also generate nitric oxid as an intracellular messenger, which contributes to the protein secretion. * Concomitant with secretion, gland blood flow increases due to parasympathetically induced vasodilation involving both cholinergic and vasoactive intestinal peptide transmission mechanisms. Sympathetic vasoconstrictor fibers are not activated during reflex secretion, but in response to a severe drop in mean arterial blood pressure. * Recent studies have drawn attention to the role of gastrointestinal hormones (gastrin,cholecystokinin and melatonin) in protein secretion and synthesis, engaging nitric oxide intracellularly. * Sensory nerves, using substance P and calcitonin gene-related peptide as transmitters, innervate ducts and blood vessels and may evoke pain,glandular swelling and glandular inflammation. * Both nerves and hormones such as estrogen and testosterone have long-term trophic effects on glandular metabolism and gland weight. Parasympathetic nonadrenergic,noncholinergic transmission mechanisms are particularly important for maintaining gland weight. * Neural regulation of the receptor sensitivity of the secretory cells to stimulating agents is a further example of trophic effects. Loss of the nerve supply is followed by denervation supersensitivity. * Xerogenic drugs act centrally or peripherally, or at both levels. Antipsychotic agents are well-known xerogenic drugs, but clozapine causes sialorrhea. Local activation of the minor glands may be an advantageous approach to the treatment of dry mouth.
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| 4. |
- Ekström, Jörgen, 1944, et al.
(författare)
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RP-HPLC-ESI-MS characterization of novel peptide fragments related to rat parotid secretory protein in parasympathetic induced saliva.
- 2009
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Ingår i: Journal of separation science. - : Wiley. - 1615-9314 .- 1615-9306. ; 32:17, s. 2944-52
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Tidskriftsartikel (refereegranskat)abstract
- Two peptides (MW 1211.7 and 928.5 Da) were detected by RP-HPLC-ESI-MS analysis of parotid saliva secreted upon continuous parasympathetic stimulation. The peptide with the higher mass (PSPFr-A) corresponded to the N-terminal dodecapeptide (Fragment 1-12) of rat parotid secretory protein (PSP), while the peptide with the lower mass (PSPFr-B) corresponded to the 4-12 fragment of the same protein. During stimulation, the PSPFr-A secretion increased, while the PSPFr-B secretion decreased (HPLC-ESI-MS). In the presence of cycloheximide, PSPFr-A was not demonstrated, while the PSPFr-B secretion decreased. In the presence of aprotinin, the PSPFr-B secretion was almost abolished, while the PSPFr-A secretion increased to higher levels than those observed in the absence of the inhibitor. In vitro perfusion, with artificial solution, of stimulated rat parotid glands excluded that the fragments were derived from the circulation. Neither peptide occurred in enriched granule preparations from unstimulated glands. The results suggest that at least two pathways - granular and vesicular - are responsible for the generation of the two peptides. PSPFr-A is the first cleavage product in both pathways. PRPFr-B is probably generated from granular PSPFr-A only and, at the end of the granule mediated pathway, by the action of an enzyme of the serine protease class.
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| 5. |
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| 6. |
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| 7. |
- Khosravani, Nina, et al.
(författare)
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Facial nerve section induces transient changes in sensitivity to methacholine and in acetylcholine synthesis in the rat parotid gland.
- 2006
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Ingår i: Arch Oral Biol. ; 51:9, s. 736-39
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Tidskriftsartikel (refereegranskat)abstract
- Nerves exert long-term influences on the salivary glands as e.g. revealed by increases in sensitivity to secretagogues following nerve degeneration. The objective was to study the effect of unilateral facial nerve section on the sensitivity of the parotid secretory cells 2-3 weeks postoperatively, i.e. at a time when the sensitisation is thought to be fully developed. Comparisons were made between pair of glands. However, no increase in the secretory response to increasing intravenous doses of methacholine of the duct-cannulated gland on the operated side was found; neither were any decrease in the acetylcholine synthesizing capacity of the gland found. In contrast, a slight supersensitivity had developed 1 week postoperatively supporting the idea of a functional influence of the facial nerve on the secretory cells under normal conditions. Furthermore, the results combined with the previous finding of ours of decreased acetylcholine synthesis in the parotid gland 1 week after facial nerve section, suggest a rapid restitution of the nervous influence on the secretory cells between 1 and 2-3 weeks postoperatively.
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| 8. |
- Khosravani, Nina, et al.
(författare)
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Intraoral stimulation of salivary secretion with the cholinesterase inhibitor physostigmine as a mouth spray: A pilot study in healthy volunteers.
- 2007
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Ingår i: Archives of oral biology. - : Elsevier BV. - 0003-9969. ; 52:11, s. 1097-101
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Tidskriftsartikel (refereegranskat)abstract
- Dry mouth produces a deterioration in oral health and impairs quality of life. There is a need for a novel approach to the pharmacological treatment of dry mouth. With a view to enhancing the cholinergic drive on minor salivary glands, whilst at the same time minimising adverse systemic effects, the cholinesterase inhibitor physostigmine was therefore sprayed, in a fixed volume, onto the oral mucosa of seven healthy subjects. Three concentrations (0.5%, 1% and 2%) were tested. The mean salivary output over time (0-105min) was higher than that of placebo (p<0.05), as the area under the curve increased by 61%, 91% and 66% at physostigmine 0.5%, 1% and 2%, respectively. Two subjects experienced nausea at the highest physostigmine concentration, thus reflecting systemic effects. Heart rate, blood pressure and respiration were unaffected by the physostigmine treatment.
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| 9. |
- Khosravani, Nina, et al.
(författare)
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Local treatment of dry mouth by the cholinesterase inhibitor physostigmine
- 2008
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Ingår i: 8th European Symposium on Saliva, Eeegmond oon Zee, Netherlands,14-17 june 2008.
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Konferensbidrag (refereegranskat)abstract
- The feeling of mouth moistness is associated with the continuous secretion of mucin from submucosal minor glands, rather than with deficits in the watery saliva intermittently secreted from the major glands (Sreebny & Broich, 1988). Animal studies show physostigmine, applied on the oral mucosa, to enhance the cholinergic tone in the submucosal mucin-producing glands underlying the physostigmine-exposed mucosa (Ekström & Helander, 2002). Topical application of physostigmine, aiming at stimulating minor glands while at the same time minimising systemic cholinergic effects, would therefore be an advantageous approach to the treatment of mouth dryness. Presently, twenty subjects suffering from dry mouth participated, in a crossover double blind, randomized study. Physostigmine was applied onto the inside of the lips, at different doses (0.9 mg, 1.8 mg, 3.6 mg and 7.2 mg), while the vehicle served as placebo; the solution (300 ul) was distributed with the tongue. As significantly marked relief of the dry-mouth-feeling (score reduction by 25). Placebo, caused just a transient, initial, decrease in scores (by 7). Since doses above 1.8 mg were assiciated with signs of systemic effects, predominantly gastrointestinal discomfort, the dose 1.8 mg was used for objective assessment of secretion in those subjects previously tested. The volumes of saliva collected after physostigmine were significantly larger than those after placebo; the mean AUC-value (above baseline) over 180 min was almost 5 times that of placebo. Thus, physostigmine locally applied seems promising in the treatment of dry mouth.
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| 10. |
- Khosravani, Nina
(författare)
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On The Innervation of Salivary Glands and Treatment of Dry Mouth - An Experimental and Clinical Study
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Detailed knowledge of the innervation of the parotid gland is essential in basic studies on various neuroglandular phenomena as well as in various types of orofacial surgery. The innervation is more complex than usually depicted in Textbooks. Using the rat as experimental model, it was shown that not only the classical auriculo-temporal nerve but also the facial nerve contributed to the cholinergic innervation of the gland, and that facial nerve-mediated impulses, reflexly elicited, evoked secretion of saliva. In humans, aberrant regenerating parasympathetic nerve fibres of the facial nerve may, therefore, be a potential contributor to Frey´s syndrome, characterized by sweating and redness over the parotid region. Little is known about the sensory innervation of salivary glands. A co-localization of the neuropeptides substance P and calcitonin gene-related peptide signals sensory nerve fibres in the salivary glands. Though the auriculo-temporal nerve trunk carries sensory fibres from the trigeminal ganglion, denervation experiments showed that those sensory substance P- and calcitonin gene-related fibres that innervate the gland use other routes. The comparison of a number of various types of glands in the ferret revealed large differences in the acetylcholine synthesis, the mucin-producing sublingual, zygomatic and molar glands showing a synthesizing capacity, expressed per gland weight, 3-4 times higher than that of the serous parotid gland and the sero-mucous submandibular gland, implying a high cholinergic tone in the mucin-producing glands. The acetylcholine formation was due to the specific action of choline acetyltransferase, and denervation experiments showed this enzyme to be confined to the nerves. Thus, no support for an extra-neuronal synthesis of acetylcholine by the activity of choline acetyltransferase was found. Dry mouth jeopardizes the oral health. A new approach to the treatment of dry mouth was tested in healthy subjects and in patients suffering from salivary gland hypofunction. The cholinesterase inhibitor physostigmine prevents the breakdown of acetylcholine released from cholinergic nerve endings: acetylcholine accumulates and either evokes an effector response or enhances it. Physostigmine was applied locally on the oral mucosa aiming at activating hundreds of underlying, submucosal minor glands (producing lubricating mucin), while at the same time minimising systemic cholinergic effects. A dose-finding showed that it was possible to obtain a long-lasting secretion of saliva in the two study groups concomitant with a long-lasting relief from oral dryness (as revealed by Visual Analogue Scale-scoring) in the group of dry mouth patients at a dose level, where side-effects were absent or in the form of mild gastro-intestinal discomfort. The local drug application, directed towards the minor salivary glands, seems promising and may develop into a therapeutic option in the treatment of dry mouth. Keywords: Parotid gland, denervation, acetylcholine synthesis, otic ganglion, auriculo-temporal nerve, facial nerve, neuropeptides, salivary gland hypofunction, physostigmine.
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| 11. |
- Khosravani, Nina, et al.
(författare)
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The cholinesterase inhibitor physostigmine for the local treatment of dry mouth: a randomized study.
- 2009
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Ingår i: European journal of oral sciences. - : Wiley. - 1600-0722 .- 0909-8836. ; 117:3, s. 209-17
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Tidskriftsartikel (refereegranskat)abstract
- Application of physostigmine to the oromucosal surface with the aim of stimulating underlying mucin-producing glands while reducing cholinergic systemic effects might be a strategy for treating dry mouth. Subjects suffering from dry mouth and with hyposalivation participated in a crossover, double-blind, randomized study. A gel containing physostigmine (0.9, 1.8, 3.6, and 7.2 mg) or placebo was applied to the inside of the lips and distributed with the tongue. The feeling of dryness was assessed using a visual analogue scale (VAS) (where a score of 100 = extremely dry) and systemic effects were registered. Based on assessments of efficacy and safety, the dose of 1.8 mg of physostigmine was selected for use in the second part of the study to make objective measurements of saliva volumes. Physostigmine (1.8 mg) produced long-lasting (120 min) relief (evident as a score reduction of 25 on the VAS) in the feeling of dryness. Judging from AUC values related to baseline over 180 min, the improvement for both mouth and lips in response to physostigmine was six times greater than that to placebo. At higher doses of physostigmine, gastrointestinal discomfort predominantly occurred. The volume of saliva collected in response to physostigmine was five times higher over 180 min than that collected in response to placebo. Physostigmine, applied locally, therefore appears to be a promising modality for dry-mouth treatment.
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| 12. |
- Khosravani, Nina, et al.
(författare)
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The facial nerve and its influence on the parotid gland.
- 2006
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Ingår i: 3rd International Symposium on salivary glands in honor of Niels Stensen, eds Murakami M, Suigya A, Riva A, Okazaki Conference Center, NINS, Japan, October 20-24.
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Konferensbidrag (refereegranskat)
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| 13. |
- Khosravani, Nina, et al.
(författare)
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The otic ganglion in rats and its parotid connection: cholinergic pathways, reflex secretion and a secretory role for the facial nerve.
- 2006
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Ingår i: Exp Physiol. ; 91:1, s. 239-47
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Tidskriftsartikel (refereegranskat)abstract
- Otic ganglionectomy in rats was found to have affected the parotid gland more profoundly than section of the auriculotemporal nerve as assessed by reduction in gland weight (by 33 versus 20%) and total acetylcholine synthesizing capacity (by 88 versus 76%) 1 week postoperatively and, when assessed on the day of surgery under adrenoceptor blockade, by reflex secretion (by 99 versus 88%). The facial nerve contributed to the acetylcholine synthesizing capacity of the gland. Section of the nerve only, at the level of the stylomastoid foramen, reduced the acetylcholine synthesis by 15% and, combined with otic ganglionectomy, by 98% or, combined with section of the auriculotemporal nerve, by 82%. The facial nerve was secretory to the gland, and the response was of a cholinergic nature. The nerve conveyed reflex secretion of saliva and caused secretion of saliva upon stimulation. Most of the facial secretory nerve fibres originated from the otic ganglion, since after otic ganglionectomy (and allowing for nerve degeneration) the secretory response to facial nerve stimulation was markedly reduced (from 23 to 4 microl (5 min)(-1)). The persisting secretory response after otic ganglionectomy, exaggerated due to sensitization, and the residual acetylcholine synthesizing capacity (mainly depending on the facial nerve) showed that a minor proportion of pre- and postganglionic nerve fibres relay outside the otic ganglion. The great auricular nerve, which like the facial nerve penetrates the gland, caused no secretion of saliva upon stimulation. Avulsion of the auriculotemporal nerve was more effective than otic ganglionectomy in reducing the acetylcholine synthesizing capacity (by 94 versus 88%) and as effective as otic ganglionectomy in abolishing reflex secretion (by 99%). When aiming at parasympathetic denervation, avulsion may be the preferable choice, since it is technically easier to perform than otic ganglionectomy.
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| 14. |
- Khosravani, Nina, et al.
(författare)
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The peptidergic innervation of the rat parotid gland: effects of section of the auriculo-temporal nerve and/or of otic ganglionectomy.
- 2008
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Ingår i: Archives of oral biology. - : Elsevier BV. - 0003-9969. ; 53:3, s. 238-42
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Tidskriftsartikel (refereegranskat)abstract
- The origin/pathways of peptidergic nerves contributing to the parotid gland contents of vasoactive intestinal peptide (VIP), substance P and calcitonin gene-related peptide (CGRP) were investigated by performing surgery on one side of the rat. Comparisons (based on total amount of peptide) were made between the gland on the operated side and the contralateral gland 7 days postoperatively. Otic ganglionectomy showed that almost all of the parotid gland contents of VIP (98%) and substance P (98%) were due to the otic connection, while this was true for only a minor portion (32%) of the CGRP-gland content. Section of the auriculo-temporal nerve showed that almost all of the VIP- and substance P-containing nerve fibres reached the parotid gland via this nerve, as judged by a reduction in the VIP-content by 88% and in the substance P-content by 93%, while the CGRP-content was only reduced by 37%. Section of the auriculo-temporal nerve combined with otic ganglionectomy did not reduce the gland contents of CGRP and substance P further than just otic ganglionectomy. Thus, the auriculo-temporal nerve is not likely to innervate the parotid gland with CGRP- and/or substance P-containing nerve fibres from the trigeminal ganglion.
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