Protective effect of misoprostol against paclitaxel-induced cardiac damage in rats.

OBJECTIVE: One of the most critical reasons for limiting cancer treatment is the toxic effects of anti-cancer drugs on healthy tissues and organs. This study aims to investigate the possible protective effects of misoprostol (MS) against the damage that arises from paclitaxel (PT), an anti-cancer pharmacological agent, in the rat heart using histopathological and biochemical analyses. METHODS: In this study, four groups, each containing seven animals, were formed by random selection from 28 Sprague Dawley female rats. Control group rats were administered 1 ml of normal saline orally and intraperitoneally (i.p.) for six days. While the PT group rats were administered PT at a dose of 2 mg/kg intraperitoneally (i.p.) on days 0, 2, 4, and 6, the MS group was administered MS at a dose of 0.2 mg/kg in 1 ml normal saline by oral gavage for six days. PT and MS were administered to the PT + MS group rats in the same dose and route as the previous groups. RESULTS: Administration of PT increased serum lactate dehydrogenase (LDH), cardiac troponin I (cTn-I), creatine kinase isoenzyme MB (CK-MB), and brain natriuretic peptide (BNP) levels. PT administration also decreased the levels of glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) in the heart tissue while increasing the level of malondialdehyde (MDA) (p < 0.05). In histopathological examinations, pathological changes, such as edema, congestion, hemorrhage, apoptosis, and degeneration, occurred in the heart tissue of PT-treated rats. The negative changes in histopathological and biochemical parameters that occurred in the PT group were almost not observed in the PT + MS group (p < 0.005). CONCLUSION: When the findings were evaluated, it was concluded that MS protects the heart tissue from the harmful effects of PT, probably due to its antioxidant, anti-apoptotic and TNF-alpha suppressive effects.

Prevention of nephrotoxicity induced by amikacin: The role of misoprostol, A prostaglandin E1 analogue.

Amikacin (AK) is an aminoglycoside that is widely used to treat life-threatening Gram-negative infections, especially in intensive care units. Despite its wide clinical indications, AK causes serious side effects such as kidney toxicity. AK was found to lead to tissue damage primarily through apoptosis and oxidative stress. Therefore, it was investigated whether misoprostol (MP), which has antioxidant and antiapoptotic properties, had a beneficial effect on kidney damage caused by AK. It was observed that kidney injury molecule-1 (KIM-1) mRNA, blood urea nitrogen (BUN), creatinine (Cr), NADPH oxidase-4 (NOX-4) and Caspase-3 (CAS-3) levels increased in the AK-treated group in comparison with the control group, while uric acid, albumin, and total protein levels were decreased. In rats that were treated with AK+MP, the levels of KIM-1 mRNA, BUN, Cr, NOX-4 and CAS-3 were significantly decreased in comparison with the AK group, while uric acid, albumin and total protein levels increased. According to the obtained results, MP was found to be quite effective in the protection of kidneys from the toxic effects of AK.

The effects of mifepristone on the structure of human decidua and chorion and Bax and Bcl-2 expression at early stage of pregnancy.

BACKGROUND: As a progesterone receptor antagonist, mifepristone combined with misoprostol is widely used to terminate early pregnancy in clinical practice. It has also been reported that mifepristone may cause cell death in decidual cells and result in hemorrhage of the decidua and insufficient blood supply. However, little is known about the histological effects of mifepristone on human decidua and chorion. METHODS: Histological and subcellular structural changes of decidua and chorionic villi from women taking mifepristone at early pregnancy times were examined by Hematoxylin and eosin (H&E) staining and transmission Electron microscope. The expression of apoptosis-related proteins Bax/Bcl-2 was examined by immunohistochemistry. RESULTS: After 48 h of mifepristone administration, the decidua tissue and chorionic villus structures were altered in women within 39-49 days of gestation and displayed varying degrees of degeneration and necrosis-like features. Apoptotic events were observed in the decidua and chorionic villi of early pregnancy, and mifepristone treatment significantly increases the number of apoptotic cells. The increased apoptotic events were concomitant with the increased expression of Bax and decreased expression of Bcl-2. CONCLUSION: This study provides evidence that mifepristone induces histological and subcellular changes in decidua and chorionic villi. Mifepristone modulates the relative ratio of Bax/Bcl-2 and the increased apoptosis contributes to the pregnancy termination at early stage of pregnancy.

Translational profiling of mouse dopaminoceptive neurons reveals region-specific gene expression, exon usage, and striatal prostaglandin E2 modulatory effects.

Forebrain dopamine-sensitive (dopaminoceptive) neurons play a key role in movement, action selection, motivation, and working memory. Their activity is altered in Parkinson's disease, addiction, schizophrenia, and other conditions, and drugs that stimulate or antagonize dopamine receptors have major therapeutic applications. Yet, similarities and differences between the various neuronal populations sensitive to dopamine have not been systematically explored. To characterize them, we compared translating mRNAs in the dorsal striatum and nucleus accumbens neurons expressing D1 or D2 dopamine receptor and prefrontal cortex neurons expressing D1 receptor. We identified genome-wide cortico-striatal, striatal D1/D2 and dorso/ventral differences in the translating mRNA and isoform landscapes, which characterize dopaminoceptive neuronal populations. Expression patterns and network analyses identified novel transcription factors with presumptive roles in these differences. Prostaglandin E2 (PGE2) was a candidate upstream regulator in the dorsal striatum. We pharmacologically explored this hypothesis and showed that misoprostol, a PGE2 receptor agonist, decreased the excitability of D2 striatal projection neurons in slices, and diminished their activity in vivo during novel environment exploration. We found that misoprostol also modulates mouse behavior including by facilitating reversal learning. Our study provides powerful resources for characterizing dopamine target neurons, new information about striatal gene expression patterns and regulation. It also reveals the unforeseen role of PGE2 in the striatum as a potential neuromodulator and an attractive therapeutic target.

Crystal structure of misoprostol bound to the labor inducer prostaglandin E2 receptor.

Misoprostol is a life-saving drug in many developing countries for women at risk of post-partum hemorrhaging owing to its affordability, stability, ease of administration and clinical efficacy. However, misoprostol lacks receptor and tissue selectivities, and thus its use is accompanied by a number of serious side effects. The development of pharmacological agents combining the advantages of misoprostol with improved selectivity is hindered by the absence of atomic details of misoprostol action in labor induction. Here, we present the 2.5 Å resolution crystal structure of misoprostol free-acid form bound to the myometrium labor-inducing prostaglandin E2 receptor 3 (EP3). The active state structure reveals a completely enclosed binding pocket containing a structured water molecule that coordinates misoprostol's ring structure. Modeling of selective agonists in the EP3 structure reveals rationales for selectivity. These findings will provide the basis for the next generation of uterotonic drugs that will be suitable for administration in low resource settings.

Misoprostol-induced fever and genetic polymorphisms in drug transporters SLCO1B1 and ABCC4 in women of Latin American and European ancestry.

AIM: Misoprostol, a prostaglandin analogue used for the treatment of postpartum hemorrhage and termination of pregnancy, can cause high fevers. Genetic susceptibility may play a role in misoprostol-induced fever. SUBJECTS & METHODS: Body temperature of women treated with misoprostol for termination of pregnancy in the UK (n = 107) and for postpartum hemorrhage in Ecuador (n = 50) was measured. Genotyping for 33 single nucleotide polymorphisms in 15 candidate genes was performed. Additionally, we investigated the transport of radiolabeled misoprostol acid across biological membranes in vitro. RESULTS: The ABCC4 single nucleotide polymorphism rs11568658 was associated with misoprostol-induced fever. Misoprostol acid was transported across a blood-brain barrier model by MRP4 and SLCO1B1. CONCLUSION: Genetic variability in ABCC4 may contribute to misoprostol-induced fever in pregnant women. Original submitted 21 January 2015; Revision submitted 24 April 2015.

Manejo activo de la tercera fase del parto más 400 mg de misoprostol sublingual y 200 mg de misoprostol rectal frente a manejo activo solo en la prevención de la hemorragia posparto. Ensayo clínico aleatorizado / Active management of the third phase of labour plus 400 mg of sublingual misoprostol and 200 mg of rectal misoprostol versus active management only in the prevention of post-partum haemorrhage. A randomised clinical trial

Objetivos: Evaluar la eficacia y la seguridad de 400 mg de misoprostol por vía sublingual y 200 mg rectal más manejo activo de la tercera fase del parto frente a manejo activo para prevenir la hemorragia posparto. Sujetos y métodos: Se sometió a 1.400 mujeres a recibir el misoprostol más manejo activo (grupo I) o manejo activo (grupo II). Las variables medidas fueron la incidencia de hemorragia posparto, el volumen de sangre perdido y el uso de uterotónicos adicionales. Resultados: En el grupo I hubo 28/702 (4,0%) hemorragias y en el grupo II 50/698 (7,2%), p = 0,005; riesgo relativo (RR) = 0,538; intervalo de confianza (IC) del 95% para RR (0,335-0,866). En mujeres con hemorragia posparto, el volumen de sangre perdida fue 981 ± 309 cc y 888 ± 326 cc, p = 0,225 en los grupos I y II, respectivamente. Necesitaron uterotónicos adicionales 33 (4,7%) frente a 54 (7,7% mujeres, p = 0,025 en los grupos I y II, respectivamente). Conclusiones: Se podría recomendar la administración de misoprostol por vía sublingual/rectal junto al manejo activo para prevenir la hemorragia posparto (AU)

Objectives: To evaluate the efficacy and safety of 400 mg sublingual misoprostol and 200 mg rectal misoprostol plus active management of the third stage of labour versus active management only to prevent postpartum haemorrhage. Subjects and methods: A total of 1400 women were randomly assigned to receive misoprostol plus active management (group I) or active management only (group II). The variables studied were incidence of postpartum haemorrhage, blood volume lost and need of additional uterotonics. Results: In group I there were 28/702 (4.0%) haemorrhages and in group II 50/698 (7.2%), P=.005; RR =.538; 95% CI for RR (0.335-0.866). In women having postpartum haemorrhage the lost blood volume was 981 ± 309 cc and 888 ± 326 cc. P=.225 in groups I and II, respectively. Additional uterotonics were needed in 33 women in group I (4.7%) vs. 54(7.7%) women in group II (P=.025). Conclusions: The use of sublingual/rectal misoprostol plus active management appears to be useful for the prevention of postpartum haemorrhage (AU)

Effect of misoprostol on bone mineral density in women with postmenopausal osteoporosis.

OBJECTIVE: To evaluate the effect of misoprostol on bone mineral density in postmenopausal women. MATERIALS AND METHODS: The study was performed in a randomized controlled prospective manner in 90 women with menopause at Süleymaniye Maternity and Women's Diseases Teaching and Research Hospital between January and December 2003. Cases were divided into three groups each consisting of 30 women who were in menopause for at least 1 year and had t-scores less than -1 by dual energy X-ray densitometry (DEXA). Group I was treated with misoprostol and calcium, Group II received tibolone and calcium and Group III was given calcium only and considered as control group. In all patients, bone mineral density in L1-L4 vertebrae, femur neck and Ward triangle were measured by DEXA and t and z scores were calculated. RESULTS: All groups were similar demographically. Bone mineral density in L1-L4 vertebrae, femur neck and Ward triangle in the group treated with misoprostol, increased by 5, 8.1 and 3.6%, respectively. In the tibolone group, bone mineral density in L1-L4 vertebrae, femur neck and Ward triangle increased by 8.3, 5.3 and 7.8%, respectively. There was not a significant difference in t and z-scores and bone mineral density measurements between misoprostol and tibolon groups. CONCLUSION: Misoprostol may be an alternative treatment for patients with osteopenia and osteoporosis who are not suitable for hormone replacement therapy.

Somatostatin, misoprostol and galanin inhibit gastrin- and PACAP-stimulated secretion of histamine and pancreastatin from ECL cells by blocking specific Ca2+ channels.

The oxyntic mucosa is rich in ECL cells. They secrete histamine and chromogranin A-derived peptides, such as pancreastatin, in response to gastrin and pituitary adenylate cyclase-activating peptide (PACAP). Secretion is initiated by Ca2+ entry. While gastrin stimulates secretion by opening L-type and N-type Ca2+ channels, PACAP stimulates secretion by activating L-type and receptor-operated Ca2+ channels. Somatostatin, galanin and prostaglandin E2 (PGE2) inhibit gastrin- and PACAP-stimulated secretion from the ECL cells. In the present study, somatostatin and the PGE2 congener misoprostol inhibited gastrin- and PACAP-stimulated secretion 100%, while galanin inhibited at most 60-65%. Bay K 8644, a specific activator of L-type Ca2+ channels, stimulated ECL-cell secretion, an effect that was inhibited equally effectively by somatostatin, misoprostol and galanin (75-80% inhibition). Pretreatment with pertussis toxin, that inactivates inhibitory G-proteins, prevented all three agents from inhibiting stimulated secretion (regardless of the stimulus). Pretreatment with nifedipine (10 microM), an L-type Ca2+ channel blocker, reduced PACAP-evoked pancreastatin secretion by 50-60%, gastrin-evoked secretion by approximately 80% and abolished the response to Bay K 8644. The nifedipine-resistant response to PACAP was abolished by somatostatin and misoprostol but not by galanin. Gastrin and PACAP raised the intracellular Ca2+ concentration in a biphasic manner, believed to reflect mobilization of internal Ca2+ followed by Ca2+ entry. Somatostatin and misoprostol blocked Ca2+ entry (and histamine and pancreastatin secretion) but not mobilization of internal Ca2+. The present observations on isolated ECL cells suggest that Ca2+ entry rather than mobilization of internal Ca2+ triggers exocytosis, that gastrin and PACAP activate different (but over-lapping) Ca2+ channels, that somatostatin, misoprostol and galanin interact with inhibitory G-proteins to block Ca2+ entry via L-type Ca2+ channels, and that somatostatin and misoprostol (but not galanin) in addition block N-type and/or receptor-operated Ca2+ channels.

Pharmacology of functional endogenous IP prostanoid receptors in NCB-20 cells: comparison with binding data from human platelets.

The objective of these studies was to characterize the effects of a broad range of prostanoid agonists upon the stimulation of cAMP production in National Cancer Bank (NCB-20; mouse neuroblastoma/hamster brain hybridoma) cells. The pharmacology of these functional responses in NCB-20 cells was compared with that of the classic endogenous IP receptor present on human platelets using [3H]-iloprost binding techniques. In both assay systems, agonists from the IP prostanoid class exhibited the highest affinities and functional potencies. Specific prostanoids exhibited the following rank order of potency (EC50 +/- SEM) in stimulating cAMP production in the NCB-20 cells: carbaprostacyclin (4.3 +/- 0.9 nM) = PGI2 (6.6 +/-1.5 nM) > iloprost (75+/-13 nM) > 11-deoxy PGE, (378+/-138 nM) > misoprostol (1,243+/-48) > PGE2 (3020+/-700 nM) > ZK-118182 (7265+/-455 nM). Iloprost wasthe most potent compound in the human platelet binding assay while prostanoidsfromthe DPand EP receptor classes showed modest affinity. These studies provide functional and binding information for a broad range of both natural and synthetic prostanoid receptor ligands at the endogenous IP receptor in two different cell types.

Prostaglandin E2 enhancement of interferon-gamma production by antigen-stimulated type 1 helper T cells.

Prostaglandin E2 (PGE2) is a potent mediator generated in immune tissues by cyclooxygenation of arachidonic acid. PGE2 affects T cell functions through four homologous G protein-coupled receptors termed EP1R, EP2R, EP3R, and EP4R that differ in tissue distribution and signaling. Antigen-evoked secretion of interferon-gamma (IFN-gamma) by sperm whale myoglobin-specific Th1 cells of DBA/2 mouse I-Ed-restricted clones, that express EP3Rs and EP4Rs, was enhanced a maximum of 3-fold by 10(-10) to 10(-8) M PGE2 and 2.5-fold each for the EP1R/EP3R-directed agonist sulprostone (10(-8) and 10(-7) M) and for the EP4R/EP3R/EP2R agonist misoprostol (10(-9) M). Neither PGE2 nor the synthetic analogs affected secretion of IFN-gamma by PMA plus ionomycin-stimulated clones of Th1 cells. Antigen-evoked secretion of IFN-gamma by influenza hemagglutinin-specific mouse lymph node Th1 cells, that also express EP3Rs and EP4Rs, was increased a maximum of 12-fold by 10(-9) to 10(-8) M PGE2, 14-fold by 10(-9) M sulprostone, and 10-fold by 10(-9) M misoprostol. Production of IFN-gamma by either type of Th1 cell was not affected significantly by 10(-6) M PGE2 alone. The generation of IFN-gamma by antigen-stimulated Th1 cells thus is significantly enhanced by physiologically relevant concentrations of PGE2.

Effects of misoprostol and prostaglandin E2 on proteoglycan biosynthesis and loss in unloaded and loaded articular cartilage explants.

The effects of misoprostol, a prostaglandin E1 analog, and prostaglandin E2 on proteoglycan biosynthesis and loss were studied in unloaded and mechanically loaded mature bovine articular cartilage explants. The prostaglandins were administered daily at dosages of 0, 10, 100 and 1000 eta g/ml for up to seven days, and proteoglycan biosynthesis determined by measurement of radiolabelled sulfate incorporation. The presence of misoprostol lead to a significant (p < 0.001) dose-dependent inhibition (30%-50%) in proteoglycan biosynthesis which was also dependent on exposure time (p < 0.05). A significant decrease in biosynthesis (34%) was also found for prostaglandin E2, but only at the highest dose (1000 eta g/ml). Proteoglycan catabolism rates were not affected by either substance as assessed by loss of newly synthesized proteoglycan. The application of a continuous cyclic mechanical compressive load (stress of 1.0 MPa at 1 hertz for 24 hours) resulted in a significant inhibition of proteoglycan biosynthesis (up to 50%) as compared to unloaded explants. However, there was no additive effect when mechanical load and misoprostol or prostaglandin E2 were combined. These results suggest that prostaglandins may have a role in the degenerative and repair process in various forms of arthritis where elevated intra-articular levels of prostaglandin E2 are present.

Preferential binding of the novel prostaglandin SC-46275 to canine gastric versus intestinal receptors.

Prostaglandins (PGs) in the E-series exhibit potent gastric antisecretory activity, but can also cause diarrhea, which is mediated via PGE receptors. SC-46275, an omega-chain cyclopentenyl analog of the E-type PG enisoprost, was evaluated with other E-PGs for PGE receptor binding activity in gastric and intestinal tissues. SC-46275, enisoprost, misoprostol and PGE1 were first evaluated in enriched canine gastric parietal cells with [3H]misoprostol free acid binding and subsequently with [3H]PGE1 binding in canine intestinal tissues where misoprostol free acid had weak receptor binding activity. The receptor binding potency of SC-46275 (IC50, 0.013 mM) in enriched canine parietal cell preparations was found to be much greater than misoprostol and enisoprost (IC50, 10 and 8 nM), whereas PGE1 had the least potency (IC50, 37 nM). Similar relative potencies for these PGs were also obtained in the inhibition of histamine-stimulated acid secretion in enriched parietal cell preparations. In small intestinal mucosal and muscle membranes, the receptor binding potency of SC-46275 (IC50, 13 and 20 microM) was much less than misoprostol or enisoprost (IC50, 0.39-1.2 microM) and substantially less than PGE1 (IC50, 0.017 and 0.066 microM). This weak binding activity of SC-46275 in intestinal tissues is consistent with its reported weak diarrheagenic activity in the rat. These results suggest that SC-46275 binds preferentially to gastric vs. intestinal PGE receptors and is specific for the EP3 receptors.

TEI-3356, a highly selective agonist for the prostaglandin EP3 receptor.

Recently, we cloned cDNAs for the three mouse PGE receptor subtypes, EP1, EP2 and EP3, and the prostacyclin receptor, and established cells that stably express each receptor. We examined the selectivity of TEI-3356, an isocarbacyclin analogue, compared with other EP agonists, sulprostone and misoprostol, using Chinese hamster ovary cells expressing each cloned receptor. TEI-3356 selectively displaced the [3H]PGE2 binding to EP3-expressing cell membranes, but showed very low affinity for both EP1 and EP2. Although TEI-3356 is an isocarbacyclin analogue, it showed low affinity for the prostacyclin receptor. On the other hand, sulprostone strongly displaced the [3H]PGE2 binding to EP1 and EP3, but not to EP2. Misoprostol weakly bound to the three subtypes without selectivity. TEI-3356 decreased the forskolin-induced cAMP formation in a concentration-dependent manner in the EP3-expressing cells, the half-maximal concentration for the inhibition being similar to that of sulprostone but lower than that of PGE2. These results demonstrate that TEI-3356 is a potent and highly selective agonist for the EP3 receptor.

Influence of misoprostol, a synthetic prostaglandin E1 analog, on the healing of colonic anastomoses in rats.

PURPOSE: This study was designed to examine the influence of misoprostol, a synthetic prostaglandin E1 analog, on the healing of colonic anastomoses in rats, with particular regard to changes in collagen levels at the site of the anastomoses and their histopathologic aspects. METHODS: Sixty rats were submitted to resection and anastomosis of the colon, and divided at random into two groups. The test group received misoprostol intragastrically (200 micrograms/kg body weight), twice daily, from the day of operation until sacrifice. Controls received 0.9 percent NaCl. The animals were sacrificed on the third, seventh, or fourteenth postoperative day, and the results of the histopathologic analyses and hydroxyproline concentrations were compared. RESULTS: Our results show that misoprostol administration increased the hydroxyproline concentration on the fourteenth postoperative day without interfering in the inflammatory response (P < 0.05). CONCLUSION: Misoprostol interferes with the balance between the synthesis and degradation of collagen, resulting in an elevation of collagen levels by the fourteenth postoperative day without influencing the inflammatory response.