Correlation between the expression of the iNOS, caspase-3 and α-SMA genes in the parotid glands of albino rats following the administration of two antihistamines from two different generations.

BACKGROUND: Several medications, including antihistamines, can alter salivary gland function, causing dry mouth or xerostomia. Antihistamines are commonly used for treating allergic rhinitis. OBJECTIVES: The aim of the present study was to compare and correlate the effects of first-generation vs. second-generation H1-antihistamines on the parotid glands of rats. MATERIAL AND METHODS: Twelve adult male albino rats were used; 4 rats served as a control group (group I) and the remaining rats were divided into 2 groups: group II received promethazine hydrochloride; and group III received cetirizine dihydrochloride for 3 weeks. The parotid salivary glands were dissected, and examined histologically and analyzed histomorphometrically for the acinar area percentage. In addition, mRNA gene expression of iNOS, caspase-3 and α-SMA was assessed using quantitative realtime polymerase chain reaction (qRT-PCR). Finally, all the obtained data was statistically analyzed. RESULTS: Histologically, group I showed the typical architecture of the gland. In group II, degenerative changes were noticed, including acinar degeneration and shrinkage with widened connective tissue septa, intracellular vacuolization, and increased inflammatory cell infiltration. In group III, similar histological features were detected as in group II, but to a lesser extent. Histomorphometric results revealed significant differences in the acinar area percentage between various groups. In addition, qRT-PCR results showed a significant increase in iNOS expression in both groups II and III as compared to group I, caspase-3 gene expression was significantly increased in group II, while in group III, it increased non-significantly. Finally, α-SMA gene expression non-significantly decreased in both groups II and III. A significant positive correlation was observed between caspase-3 and iNOS gene expression, while an inverse correlation was noticed between caspase-3 and α-SMA gene expression. CONCLUSIONS: The administration of antihistamines resulted in changes in the rat salivary glands, which could be due to the induction of oxidative stress and the resultant apoptotic effect. These changes were suggested to occur mainly through action on muscarinic receptors; yet, action on histamine receptors could not be excluded. However; these effects were less marked with the second-generation antihistamine.

Effect of cevimeline and different concentration of gum arabic on parotid salivary gland function in methotrexate-induced xerostomia: a comparative study.

OBJECTIVE: This study assessed the effect of cevimeline and different concentrations of gum arabic on the parotid gland of rats being given xerostomia-inducing methotrexate. METHODS: One hundred twenty-five rats were divided into five equal groups of twenty-five each. The rats in Group I received basic diets, while those in Groups II, III, IV, and V received 20 mg/kg MTX as a single intraperitoneal dose on day one. Group III received 10 mg/kg CVM dissolved in saline orally and daily, and the other two groups received a 10% W/V aqueous suspension of GA. Therefore, Group IV received 2 ml/kg suspension orally and daily, while Group V received 3 ml/kg suspension orally and daily. After 9 days, the parotid glands were dissected carefully and prepared for hematoxylin and eosin (H&E) staining as a routine histological stain and caspase-3 and Ki67 immunohistochemical staining. Quantitative data from α-Caspase-3 staining and Ki67 staining were statistically analysed using one-way ANOVA followed by Tukey's multiple comparisons post hoc test. RESULTS: Regarding caspase-3 and Ki67 immunohistochemical staining, one-way ANOVA revealed a significant difference among the five groups. For Caspase-3, the highest mean value was for group II (54.21 ± 6.90), and the lowest mean value was for group I (15.75 ± 3.67). The other three groups had mean values of 31.09 ± 5.90, 30.76 ± 5.82, and 20.65 ± 3.47 for groups III, IV, and V, respectively. For Ki67, the highest mean value was for group I (61.70 ± 6.58), and the lowest value was for group II (18.14a ± 5.16). The other three groups had mean values of 34.4 ± 9.27, 48.03 ± 8.40, and 50.63 ± 8.27 for groups III, IV, and V, respectively. CONCLUSION: GA, rather than the normally used drug CVM, had a desirable effect on the salivary glands of patients with xerostomia.

Local anesthetics inhibit muscarinic acetylcholine receptor-mediated calcium responses and the recruitment of ß-arrestin in HSY human parotid cells.

OBJECTIVES: Local anesthetics act on G protein-coupled receptors (GPCRs); thus, their potential as allosteric modulators of GPCRs has attracted attention. Intracellular signaling via GPCRs involves both G-protein- and ß-arrestin-mediated pathways. To determine the effects of local anesthetics on muscarinic acetylcholine receptors (mAChR), a family of GPCRs, we analyzed the effects of local anesthetics on mAChR-mediated Ca2+ responses and formation of receptor-ß-arrestin complexes in the HSY human parotid cell line. METHODS: Ca2+ responses were monitored by fura-2 spectrofluorimetry. Ligand-induced interactions between mAChR and ß-arrestin were examined using a ß-arrestin GPCR assay kit. RESULTS: Lidocaine reduced mAChR-mediated Ca2+ responses but did not change the intracellular Ca2+ concentration in non-stimulated cells. The membrane-impermeant lidocaine analog QX314 and procaine inhibited mAChR-mediated Ca2+ responses, with EC50 values of 48.0 and 20.4 µM, respectively, for 50 µM carbachol-stimulated Ca2+ responses. In the absence of extracellular Ca2+, the pretreatment of cells with QX314 reduced carbachol-induced Ca2+ release, indicating that QX314 reduced Ca2+ release from intracellular stores. Lidocaine and QX314 did not affect store-operated Ca2+ entry as they did not alter the thapsigargin-induced Ca2+ response. QX314 and procaine reduced the carbachol-mediated recruitment of ß-arrestin, and administration of procaine suppressed pilocarpine-induced salivary secretion in mice. CONCLUSION: Local anesthetics, including QX314, act on mAChR to reduce carbachol-induced Ca2+ release from intracellular stores and the recruitment of ß-arrestin. These findings support the notion that local anesthetics and their derivatives are starting points for the development of functional allosteric modulators of mAChR.

Parotid hypersalivation after inferior salivatory nucleus glutamate/NMDA receptor excitation in the rat.

Although salivation is essential during eating behavior, little is known about the brainstem centers that directly control the salivary glands. With regard to the inferior salivatory nucleus (ISN), the site of origin of the parasympathetic preganglionic cell bodies that innervate the parotid glands, previous anatomical studies have located it within the rostrodorsal medullary reticular formation. However, to date there is no functional data that shows the secretory nature of the somas grouped in this region. To activate only the somas and rule out the activation of the efferent fibers from and the afferent fibers to the ISN, in exp. 1, NMDA neurotoxin was administered to the rostrodorsal medullary region and the secretion of saliva was recorded during the following hour. Results showed an increased secretion of parotid saliva but a total absence of submandibular-sublingual secretion. In exp. 2, results showed that the hypersecretion of parotid saliva after NMDA microinjection was completely blocked by the administration of atropine (a cholinergic blocker) but not after administration of dihydroergotamine plus propranolol (α and ß-adrenergic blockers, respectively). These findings suggest that the somata of the rostrodorsal medulla are secretory in nature, controlling parotid secretion via a cholinergic pathway. The data thus functionally supports the idea that these cells constitute the ISN.

Maternal Fluoride Exposure Exerts Different Toxicity Patterns in Parotid and Submandibular Glands of Offspring Rats.

There is currently a controversial and heated debate about the safety and ethical aspects of fluoride (F) used for human consumption. Thus, this study assessed the effects of prenatal and postnatal F exposure of rats on the salivary glands of their offspring. Pregnant rats were exposed to 0, 10, or 50 mg F/L from the drinking water, from the first day of gestation until offspring weaning (42 days). The offspring rats were euthanized for the collection of the parotid (PA) and submandibular (SM) glands, to assess the oxidative biochemistry and to perform morphometric and immunohistochemical analyses. F exposure was associated with a decrease in the antioxidant competence of PA in the 10 mg F/L group, contrasting with the increase observed in the 50 mg F/L group. On the other hand, the antioxidant competence of the SM glands was decreased at both concentrations. Moreover, both 10 and 50 mg F/L groups showed lower anti-α-smooth muscle actin immunostaining area in SM, while exposure to 50 mg F/L was associated with changes in gland morphometry by increasing the duct area in both glands. These findings demonstrate a greater susceptibility of the SM glands of the offspring to F at high concentration in comparison to PA, reinforcing the need to adhere to the optimum F levels recommended by the regulatory agencies. Such findings must be interpreted with caution, especially considering their translational meaning.

Safety of High-Dose Botulinum Toxin Injections for Parotid and Submandibular Gland Radioprotection.

Botulinum Toxin injections into salivary glands (SG) up to a total dose of 100 units IncobotulinumtoxinA (IncoA) represent the treatment of choice for sialorrhea. However, BTX might also protect SG against sialotoxic radioligand cancer therapies. The radioligand Actinium-225-PSMA effectively targets Prostate Cancer (PCa) metastases but inevitably destroys SG due to unintended gland uptake. A preliminary case series with regular-dose IncoA failed to reduce SG PSMA-radioligand uptake. We therefore increased IncoA dosage in combination with transdermal scopolamine until a clinically relevant SG PSMA-radioligand uptake reduction was achieved. Ten consecutive men with metastasized PCa refractory to all other cancer therapies received gradually increasing IncoA dosages as part of a compassionate use PSMA-radioligand-therapy trial. The parotid gland received six and the submandibular gland three injection points under ultrasound control, up to a maximum of 30 units IncoA per injection point. A maximum total dose of 250 units IncoA was applied with up to 170 units per parotid and 80 units per submandibular gland. Treatment was well tolerated and all side-effects were non-serious. The most frequent side-effect was dry mouth of mild severity. No dysphagia, facial weakness, chewing difficulties or systemic side-effects were observed. SG injections with IncoA up to a total dose of 250 units are safe when distributed among several injection-points under ultrasound control by an experienced physician. These preliminary findings lay the basis for future trials including BTX as major component for SG protection in established as well as newly emerging radioligand cancer therapies.

Effects of long-term fluoride exposure are associated with oxidative biochemistry impairment and global proteomic modulation, but not genotoxicity, in parotid glands of mice.

BACKGROUND: Fluoride has become widely used in dentistry because of its effectiveness in caries control. However, evidence indicates that excessive intake interferes with the metabolic processes of different tissues. Thus, this study aimed to investigate the effects of long-term exposure to F on the parotid salivary gland of mice, from the analysis of oxidative, proteomic and genotoxic parameters. MATERIALS AND METHODS: The animals received deionized water containing 0, 10 or 50 mg/L of F, as sodium fluoride, for 60 days. After, parotid glands were collected for analysis of oxidative biochemistry, global proteomic profile, genotoxicity assessment and histopathological analyses. RESULTS: The results revealed that exposure to fluoride interfered in the biochemical homeostasis of the parotid gland, with increased levels of thiobarbituric acid reactive species and reduced glutathione in the exposed groups; as well as promoted alteration of the glandular proteomic profile in these groups, especially in structural proteins and proteins related to oxidative stress. However, genotoxic assessment demonstrated that exposure to fluoride did not interfere with DNA integrity in these concentrations and durations of exposure. Also, it was not observed histopathological alterations in parotid gland. CONCLUSIONS: Thus, our results suggest that long-term exposure to fluoride promoted modulation of the proteomic and biochemical profile in the parotid glands, without inducing damage to the genetic component. These findings reinforce the importance of rationalizing the use of fluorides to maximize their preventative effects while minimizing the environmental risks.

INitial Steps of Insulin Action in Parotid Glands of Male Wistar Rats.

The parotid gland is the largest salivary gland. It produces watery saliva, rich in proteins (amylase, lysozymes, and antibodies). Due to the gland's morphological cytoarchitecture composed of only serous acini, it contributes almost 50% of total salivary volume upon stimulation. It has been reported that the prevalence of saliva secretion impairments, periodontitis, delayed wound healing, and xerostomia increase in diabetic patients. Herein we evaluated the acute effects of insulin on insulin receptor phosphorylation status and its substrates IRS-1 and IRS-2 in the parotid glands of adult male Wistar rats, using Western blot analyses. We confirmed an acute effect of insulin on IR/IRS/PI3K/Akt and MAPK intracellular pathway activation in the parotid glands of male Wistar rats similar to the classical metabolic targets of the hormone, like the liver.

Development of a functional salivary gland tissue chip with potential for high-content drug screening.

Radiation therapy for head and neck cancers causes salivary gland dysfunction leading to permanent xerostomia. Limited progress in the discovery of new therapeutic strategies is attributed to the lack of in vitro models that mimic salivary gland function and allow high-throughput drug screening. We address this limitation by combining engineered extracellular matrices with microbubble (MB) array technology to develop functional tissue mimetics for mouse and human salivary glands. We demonstrate that mouse and human salivary tissues encapsulated within matrix metalloproteinase-degradable poly(ethylene glycol) hydrogels formed in MB arrays are viable, express key salivary gland markers, and exhibit polarized localization of functional proteins. The salivary gland mimetics (SGm) respond to calcium signaling agonists and secrete salivary proteins. SGm were then used to evaluate radiosensitivity and mitigation of radiation damage using a radioprotective compound. Altogether, SGm exhibit phenotypic and functional parameters of salivary glands, and provide an enabling technology for high-content/throughput drug testing.

Ethanol binge drinking during pregnancy and its effects on salivary glands of offspring rats: oxidative stress, morphometric changes and salivary function impairments.

OBJECTIVES: To investigate the biochemical and morphological effects of ethanol (EtOH) binge drinking during pregnancy on parotid glands (PG), submandibular glands (SMG), and saliva of offspring rats. METHODS: Pregnant Wistar rats (n = 8) were exposed to EtOH consumption (3 g/kg/day - 20 % w/v) for three consecutive days. The saliva of 40-day-old offspring rats was collected to determine amylase activity and total protein concentration. PG and SMG were collected to performe oxidative biochemistry, morphometric and immunohistochemistry analyses (Student's t-test, p < .05). RESULTS: EtOH consumption during pregnancy significantly decreased the total protein concentration and decreased amylase activity. In the PG, the EtOH group showed increased lipid peroxidation and decreased antioxidant capacity against peroxyl. In the SMG, the EtOH group showed increased lipid peroxidation and NOx metabolite levels. PG exposed to EtOH showed a decrease of acini, ducts, and total parenchymal area. SMG exposed to EtOH showed an increase in the total stromal area. The expression of CK-19 and Vimentin were found not different between groups. CONCLUSIONS: For the first time, a three-day EtOH binge-drinking protocol during pregnancy is associated with oxidative stress and morphometric alterations in the salivary glands of offspring rats and with the functional reduction of the main salivary enzyme (amylase). CLINICAL RELEVANCE: EtOH consumption during pregnancy altered the morphology and physiology of the salivary glands of offspring rats.

Histopathological and biochemical alterations of the parotid gland induced by experimental hypothyroidism in adult male rats and the possible therapeutic effect of Nigella sativa oil.

Thyroid hormones are essential for metabolic rate regulation and play a role on the integrity of the salivary glands. Nigella sativa is a widely used plant in medicine. This study aimed to evaluate the effect of Nigella sativa oil (NSO) on the hypothyroidism-induced parotid gland pathological alterations. Rats were divided into four groups: control group, hypothyroid group: received daily oral carbimazole for 3 weeks, hypothyroid-NSO group: NSO was orally given for 4 weeks after hypothyroidism induction and NSO group: administrated NSO only for 4 weeks. After 7 weeks, all rats were sacrificed, serum thyroid hormones were estimated, and parotid glands were assessed by histopathological, immunohistochemical, ultrastructural and morphometric analyses. Hypothyroid group showed a significant decrease in thyroid hormones with increase in thyroid-stimulating hormone (TSH) levels and decrease in body and parotid weights compared to the control rats that were improved with NSO treatment. Sections of the hypothyroid group showed fibrosis, acinar cytoplasmic vacuolations, vascular congestion, ductal dilatation, wide intercellular canaliculi, nuclear pyknosis and decreased number of secretory granules. Also, there were decreased B-cell lymphoma 2 (Bcl-2) and increased p53, Bcl-2 Associated X (Bax) and alpha-smooth muscle actin (α-SMA) immune-expressions; with decreased Bax/ Bcl-2 ratio that all were attenuated by NSO. NSO ameliorates hypothyroidism-induced parotid changes by altering p53, Bax and Bcl-2 pathway.

Monosodium glutamate alters the function and morphology of the parotid gland in Sprague Dawley rats / Glutamato monosódico altera la función y morfología de la glándula parótida en ratas Sprague Dawley

Monosodium glutamate (MSG) is a flavor enhancer widely used in the food industry, with obesogenic properties, in addition to causing alterations in the oral cavity. The aim of the study was to observe the morphofunctional changes in the parotid gland after the administration of MSG in rats. 18 newborn male Sprague Dawley rats were used, divided into three groups (Control group; MSG1 group: 4 mg/g weight of monosodium glutamate, 5 doses, kept for 8 weeks, and MSG2 group: 4 mg/g weight of MSG, 5 doses, kept for 16 weeks). The body mass index (BMI) was calculated, and the salivary flow, pH, a-amylase activity, Na, Cl, K and Ca were analyzed by quantitative analysis. After euthanasia by ketamine/xylazine overdose, parotid volume was analyzed and stereology was performed. MSG administration caused an increase in BMI and a decrease in parotid volume as well as a reduction in salivary flow and pH and an increase in a-amylase activity, also increasing the salivary sodium and chlorine levels. Alterations in the normal stereological parameters of the gland were observed. Exposure to MSG caused morphofunctional alterations at parotid gland.

El glutamato monosódico (MSG), es un potenciador del sabor ampliamente utilizado en la industria alimentaria. Diversos estudios han propuesto la relación entre éste y el desarrollo de obesidad, además de provocar alteraciones en la cavidad oral. El objetivo del estudio fue observar los cambios morfofuncionales a nivel de la glándula parótida, posterior a la administración de MSG en ratas. Se utilizaron 18 ratas neonatas Sprague Dawley machos, divididas en tres grupos según su tiempo de exposición y dosis a MSG (Grupo Control, Grupo MSG1: 4 mg/g peso de glutamato monosódico, 5 dosis, mantenidas 8 semanas, Grupo MSG2: 4 mg/g peso de MSG, 5 dosis, mantenidas 16 semanas. Fue calculado el índice de masa corporal (BMI), además de ser analizado el flujo salival, pH, actividad de α-amilasa, y Na, Cl, K y Ca mediante análisis semicuantitativo. Luego de la eutanasia por sobredosis de ketamina/xilasina, las glándulas parótidas fueron extraídas y analizado su volumen y fueron procesadas para histología, y estudio estereológico. La administración de MSG causó aumento en BMI y disminución del volumen parotídeo, además de disminución del flujo y pH salival, así como aumento en actividad de la a-amilasa, aumentando además los niveles de sodio y cloro salival. Fueron observadas alteraciones a nivel de los parámetros estereológicos normales de la glándula. La exposición a MSG causó alteraciones morfofuncionales a nivel parotídeo, observándose una disminución del volumen de la glándula, acompañado de alteraciones en el adenómero y conductos estriados de la glándula, implicados en la producción, secreción y modificación de la saliva, la cual se vio alterada, en el flujo, pH, y en sus componentes.

Evaluation of the toxic effect of silver nanoparticles and the possible protective effect of ascorbic acid on the parotid glands of albino rats: An in vivo study.

This study aimed to evaluate the toxic effect of silver nanoparticles (AgNPs) on the parotid glands (PGs) of albino rats histologically and ultrastructurally and assess the possible protective effect of ascorbic acid as an antioxidant. Thirty male albino rats weighing between 150 mg and 200 mg were divided into three groups: the control group (C1) contained 10 rats that received 2 mg/kg (body weight (bw)) of aqueous nitrate buffer by intraperitoneal (IP) injection daily for 28 days; the AgNPs group contained 10 rats that received 2 mg/kg (bw) IP AgNPs daily for 28 days; and the AgNPs-vitamin C group contained 10 albino rats that received 2 mg/kg (bw) AgNPs IP daily for 28 days with oral administration of 100 mg/kg (bw) vitamin C in drinking water daily for 28 days. The PG acinar and ductal cells of the AgNPs group showed signs of toxicity and degeneration characterized as pleomorphic nuclei, binucleation, cytoplasmic vacuolations, and stagnated secretion in the ductal lumen. In addition to degenerated mitochondria, dilated rough endoplasmic reticulum and lysosomes were filled with AgNPs (p < 0.001). The AgNPs-vitamin C group showed significantly less degenerative changes histologically and ultrastructurally compared to the AgNPs group (p = 0.002). AgNPs produced significant toxic effects on the PG of albino rats, presumably through the generation of reactive oxygen species and toxic ion release, and administration of vitamin C was shown effective in decreasing these toxic effects.

Pefloxacin induced changes in serotonergic innervation and mast cell number in rat salivary glands.

Pefloxacin is a second-generation fluoroquinolone antibiotic. Besides its advantageous characteristics, side effects including the hypofunction of salivary glands, decreased saliva production, and peripheral neuropathy were observed during the administration of pefloxacin. The aim of this study was to investigate the changes in the number of serotonergic immunoreactive fibers and mast cells after pefloxacin treatment in the parotid and sublingual glands of rats to detect the possible neurotoxic effect of pefloxacin. The adult female rats were treated with intraperitoneal (i.p.) injection of pefloxacin for three or seven days (at a concentration of 20 mg/100g body weight) and the serotonergic innervation pattern along with the change in mast cell number were evaluated by using histochemistry and immunohistochemistry in the parotid and sublingual glands. We found that a three-day treatment significantly increased the number of immunoreactive serotonergic nerve fibers, but after a seven-day treatment the number of serotonin positive nerve fibers decreased almost to values of the control group. The alteration of mast cell number was parallel with the changes of the serotonin positive fibers during the treatment. These results suggest that pefloxacin treatment can modify the finely controlled communication between the immune- and the peripheral nervous systems, resulting neurogenic inflammatory process. The background of this process is the altered serotonergic innervation and the increased number of activated mast cells releasing different mediators for example histamine, which can finally lead to reduced number of serotonin positive nerve fibers after a seven-day treatment of pefloxacin leading to atrophy and hypofunction of the salivary glands.

The Protective Impact of Black Chokeberry Fruit Extract (Aronia melanocarpa L.) on the Oxidoreductive System of the Parotid Gland of Rats Exposed to Cadmium.

Cadmium (Cd) is a strongly toxic heavy metal with prooxidative properties. Since the exposure of the general population to this metal is predicted to increase, effective methods are being sought to prevent its negative actions. One of them involves the use of the antioxidant potential of polyphenol compounds contained in black chokeberry fruit extract and their capability of complex formation with Cd2+. The study objective was to investigate whether the administration of A. melanocarpa fruit extract rich in polyphenol compounds during low and moderate exposures to cadmium can protect the parotid gland against oxidative damage. The study was conducted using the experimental model on female Wistar rats which were given 0.1% aqueous extract of Aronia melanocarpa fruit (AE) and/or cadmium at a concentration of 1 (Cd1) or 5 (Cd5) mg Cd/kg feed for 3 and 10 months, and on control animals. The exposure to Cd attenuated the enzymatic antioxidant barrier (catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx)) and increased the concentration of hydrogen peroxide (H2O2), protein carbonyl (PC) groups, and oxidized lipids (LPO) in parotid gland. These disorders led to a reduction in the total antioxidative status (TAS), an increase in the total oxidative state (TOS), and development of stress. The administration of AE at both levels of exposure to cadmium substantially improved the enzymatic antioxidant barrier (CAT, SOD, GPx) and prevented oxidative damage to cellular macromolecules (PC, LPO) and the increase in the level of H2O2, MPO, TOS, and stress indicator (OSI = TOS/TAS) in the parotid gland. Concluding, it should be stated that the consumption of aronia products may prevent oxidative/antioxidative imbalance induced by Cd and oxidative stress development in the parotid gland, thus protecting the gland from damage.

Anaesthesia mumps: much to do about nothing.

Anaesthesia mumps is an uncommon postoperative complication resulting in unilateral or bilateral swelling of the parotid glands following surgical and endoscopic procedures. Our case illustrates the benign course of anaesthesia mumps in a postoperative vaginal hysterectomy patient with no underlying illness and also discusses previous cases in the literature and management strategies.

Fístula parotídea tras biopsia cutánea: tratamiento con toxina botulínica / Parotid Fistula After Skin Biopsy: Treatment With Botulinum Toxin

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P2X7 receptor deletion suppresses γ-radiation-induced hyposalivation.

Head and neck cancer treatments typically involve a combination of surgery and radiotherapy, often leading to collateral damage to nearby tissues causing unwanted side effects. Radiation damage to salivary glands frequently leads to irreversible dysfunction by poorly understood mechanisms. The P2X7 receptor (P2X7R) is a ligand-gated ion channel activated by extracellular ATP released from damaged cells as "danger signals." P2X7R activation initiates apoptosis and is involved in numerous inflammatory disorders. In this study, we utilized P2X7R knockout (P2X7R-/-) mice to determine the role of the receptor in radiation-induced salivary gland damage. Results indicate a dose-dependent increase in γ-radiation-induced ATP release from primary parotid gland cells of wild-type but not P2X7R-/- mice. Despite these differences, apoptosis levels are similar in parotid glands of wild-type and P2X7R-/- mice 24-72 h after radiation. However, γ-radiation caused elevated prostaglandin E2 (PGE2) release from primary parotid cells of wild-type but not P2X7R-/- mice. To attempt to uncover the mechanism underlying differential PGE2 release, we evaluated the expression and activities of cyclooxygenase and PGE synthase isoforms. There were no consistent trends in these mediators following radiation that could explain the reduction in PGE2 release in P2X7R-/- mice. Irradiated P2X7R-/- mice have stimulated salivary flow rates similar to unirradiated controls, whereas irradiated wild-type mice have significantly decreased salivary flow rates compared with unirradiated controls. Notably, treatment with the P2X7R antagonist A438079 preserves stimulated salivary flow rates in wild-type mice following γ-radiation. These data suggest that P2X7R antagonism is a promising approach for preventing γ-radiation-induced hyposalivation.

Submandibular gland-specific inflammaging-induced hyposalivation in the male senescence-accelerated mouse prone -1 line (SAM-P1).

Aging has pronounced effects on mammalian tissues and cells, but the impacts of aging on salivary gland function are relatively unknown. This study aims to evaluate the effects of aging on submandibular gland (SMG) and parotid gland (PG) functions in the male senescence-accelerated mouse. In vivo analysis at the systemic level revealed that salivary secretion induced by pilocarpine, a muscarinic agonist, from the SMG was significantly decreased in aged mice, whereas salivary secretion from the PG was not affected. To evaluate organ-level function, the SMG was perfused with the muscarinic agonists carbachol and calcium ionophore A23187 ex vivo to induce salivary secretion, and decreased saliva production was also observed in the aged SMG. Histological analysis revealed the presence of CD4-positive lymphocytes infiltrating the aged SMG. Furthermore, real-time PCR revealed that the aged SMG exhibited accelerated cell aging, increased levels of the inflammatory cytokine interleukin-6, and decreased mRNA levels of the water channel protein aquaporin-5 (AQP5). In summary, these results demonstrate that SMG function in aged mice was diminished, and that cell senescence, chronic inflammation, and the decreased gene expression of AQP5 are the likely causes of hyposalivation in the SMG of aged mice.