Age and training intensity differently affect male runners' endocrine and sexual parameters.

Physical activity is widely recognized to improve health and its inclusion in daily life at all ages is highly recommended. Gonadal hormones are known to be affected by physical activity. The exercise-induced effects on male runners of different ages were investigated by dividing 31 runners by age (Young, Y, 30-55 years; Old, O, 56-70 years) and amount of training (Light, L, <50 km/week; Heavy, H, 50 or more km/week). To test the somatic, sexual, and psychological health aspects, the Aging Male's Symptoms Scale (AMS) and the International Index of Erectile Function-6 (IIEF-6) questionnaires were administered and blood samples were drawn for adrenocorticotropic hormone, testosterone (Total-TT), free testosterone (Free-T), cortisol (C), dihydrotestosterone (DHT), estradiol, and sex hormone-binding globulin determinations. Clinical evaluations and questionnaire results showed the presence in all groups of some subclinical symptoms and "Light" dysfunctions. TT in the old-heavy (OH) group was significantly lower than in the OL group (2.38 ± 0.18 ng/mL vs. 3.36 ± 0.44 ng/ml, P = 0.05). The TT/DHT ratio was significantly higher in YH than in OH (3.64 ± 0.16 vs. 2.92 ± 0.23, P < 0.05). TT was positively correlated with AMS sexual subscale and negatively correlated with IIEF-6. Physical activity can significantly affect andrological health and testosterone levels in runners at all ages. Thus, due to the important testosterone-mediated vital functions in men, the evaluation of these parameters would be indicated in old as well as in young subjects.

Superior Properties of N-Acetylcysteine Ethyl Ester over N-Acetyl Cysteine to Prevent Retinal Pigment Epithelial Cells Oxidative Damage.

Oxidative stress plays a key role in the pathophysiology of retinal diseases, including age-related macular degeneration (AMD) and diabetic retinopathy, which are the major causes of irreversible blindness in developed countries. An excess of reactive oxygen species (ROS) can directly cause functional and morphological impairments in retinal pigment epithelium (RPE), endothelial cells, and retinal ganglion cells. Antioxidants may represent a preventive/therapeutic strategy and reduce the risk of progression of AMD. Among antioxidants, N-acetyl-L-cysteine (NAC) is widely studied and has been proposed to have therapeutic benefit in treating AMD by mitigating oxidative damage in RPE. Here, we demonstrate that N-acetyl-L-cysteine ethyl ester (NACET), a lipophilic cell-permeable cysteine derivative, increases the viability in oxidative stressed RPE cells more efficiently than NAC by reacting directly and more rapidly with oxidizing agents, and that NACET, but not NAC, pretreatment predisposes RPE cells to oxidative stress resistance and increases the intracellular reduced glutathione (GSH) pool available to act as natural antioxidant defense. Moreover, we demonstrate the ability of NACET to increase GSH levels in rats' eyes after oral administration. In conclusion, even if experiments in AMD animal models are still needed, our data suggest that NACET may play an important role in preventing and treating retinal diseases associated with oxidative stress, and may represent a valid and more efficient alternative to NAC in therapeutic protocols in which NAC has already shown promising results.

Effects of Aqueous Extract of Lycopersicum esculentum L. var. "Camone" Tomato on Blood Pressure, Behavior and Brain Susceptibility to Oxidative Stress in Spontaneously Hypertensive Rats.

Behavioral disorders affect millions of people worldwide. Hypertension contributes to both the development and progression of brain damage and cognitive dysfunction and could represent the most powerful modifiable risk factor for cerebral vessel dysfunction and consequent behavioral impairment. Tomato contains antioxidants and bioactive molecules that might play an important role in the prevention of cardiovascular and brain diseases. The effects of the combined gel and serum from Lycopersicum esculentum L. var. "Camone" tomatoes and those of purified tomato glycoalkaloids (tomatine) and an antihypertensive drug (captopril) were investigated in male spontaneously hypertensive rats (SHRs) and compared with normotensive Wistar Kyoto (WKY) rats. Body weight, systolic blood pressure, behavioral parameters, as well as brain susceptibility to oxidative stress and brain cytokine contents, were assessed. Treating hypertensive rats with tomato gel/serum or captopril for four weeks caused a significant reduction in blood pressure, decreased locomotor activity and increased grooming behavior; the last two parameters were also significantly affected by tomatine treatment. Brain slices obtained from hypertensive rats treated with tomato gel/serum were more resistant to oxidative stress and contained lower levels of inflammatory cytokines than vehicle-treated ones. In contrast, tomatine treatment had no effect. In conclusion, the tomato-derived gel/serum can be considered a dietary supplement able to drive in vivo blood pressure towards healthier values and also control some central effects such as behavior and brain oxidative stress.

The CB2 Agonist ß-Caryophyllene in Male and Female Rats Exposed to a Model of Persistent Inflammatory Pain.

Cannabinoids help in pain treatment through their action on CB1 and CB2 receptors. ß-caryophyllene (BCP), an ancient remedy to treat pain, is a sesquiterpene found in large amounts in the essential oils of various spice and food plants such as oregano, cinnamon, and black pepper. It binds to the CB2 receptor, acting as a full agonist. Sex differences in the BCP-induced analgesic effect were studied by exposing male and female rats to a persistent/repeated painful stimulation. To simulate treatment of a repeated inflammatory condition, after the first formalin injection (FT1; 50 µl, 2.5%), rats received BCP per os for 7 days at two dosages: 5 and 10 mg/kg dissolved in olive oil (OIL). The control group was treated with OIL for 7 days. On day 8, the formalin test was repeated (FT2) with a lower formalin concentration (50 µl, 1%). During the first and second formalin tests, pain-induced responses (licking, flexing, and paw jerk) and spontaneous behaviors were recorded and analyzed. In the FT1 (before the beginning of treatment with BCP), females displayed higher pain responses than did males in terms of flexing duration during the first part of the test (I phase and interphase), while during the second part (II phase early and late) males showed higher levels than did females in licking duration. In the FT2, the pain responses generally decreased in the BCP groups in a dose-dependent manner (i.e., greater effect of BCP10), with a more pronounced reduction in males than in females; moreover, the pain responses remained high in the OIL groups and in the female BCP5 group. In conclusion, long-term intake of BCP appears to be able to decrease pain behaviors in a model of repeated inflammatory pain in both sexes, but to a greater degree in males.

Chemical Characterisation and Antihypertensive Effects of Locular Gel and Serum of Lycopersicum esculentum L. var. "Camone" Tomato in Spontaneously Hypertensive Rats.

Blood pressure control in hypertensive subjects calls for changes in lifestyle, especially diet. Tomato is widely consumed and rich in healthy components (i.e., carotenoids, vitamins and polyphenols). The aim of this study was to evaluate the chemical composition and antihypertensive effects of locular gel reconstituted in serum of green tomatoes of "Camone" variety. Tomato serum and locular gel were chemically characterised. The antihypertensive effects of the locular gel in serum, pure tomatine, and captopril, administered by oral gavage, were investigated for 4 weeks in male spontaneously hypertensive and normotensive rats. Systolic blood pressure and heart rate were monitored using the tail cuff method. Body and heart weight, serum glucose, triglycerides and inflammatory cytokines, aorta thickness and liver metabolising activity were also assessed. Locular gel and serum showed good tomatine and polyphenols content. Significant reductions in blood pressure and heart rate, as well as in inflammatory blood cytokines and aorta thickness, were observed in spontaneously hypertensive rats treated both with locular gel in serum and captopril. No significant effects were observed in normotensive rats. Green tomatoes locular gel and serum, usually discarded during tomato industrial processing, are rich in bioactive compounds (i.e., chlorogenic acid, caffeic acid and rutin, as well as the glycoalkaloids, α-tomatine and dehydrotomatine) that can lower in vivo blood pressure towards healthier values, as observed in spontaneously hypertensive rats.

Antihypertensive, cardio- and neuro-protective effects of Tenebrio molitor (Coleoptera: Tenebrionidae) defatted larvae in spontaneously hypertensive rats.

In pre-hypertension, moderate control of blood pressure (BP) can be obtained by a nutritional approach. The effects of a diet enriched with defatted larvae of the mealworm Tenebrio molitor (Coleoptera: Tenebrionidae) (TM) endowed with ACE inhibitory activity was studied in both spontaneously hypertensive rats (SHR) and in the age-matched normotensive Wistar Kyoto strain. These were fed for 4 weeks with standard laboratory rodent chow supplemented with or without TM or captopril. In SHR, the TM diet caused a significant reduction in BP, heart rate and coronary perfusion pressure, as well as an increase in red blood cell glutathione/glutathione disulphide ratio. Rat brain slices of SHR were more resistant to oxidative stress and contained lower levels of inflammatory cytokines, while vascular and liver enzyme-activities were not affected. These results suggest that TM can be considered a new functional food that can lower BP in vivo and thus control cardiovascular-associated risk factors such as hypertension.

Evaluation of in vitro cell and blood compatibility and in vivo analgesic activity of plant-derived dietary supplements.

OBJECTIVE: In vitro cell and blood compatibility of three dietary supplements, comprised of multiple plant extracts, Pneumo Go (PG), Green active (GA) and Equistasi (Eq), and their main component, the phytocomplex Matrix U.B.® (Union Bio S.r.l.) (M), were evaluated. Moreover, preliminary in vivo tests were performed on GA in order to assess its ability to reduce pain in an animal model. METHODS: Cell compatibility was determined using fibroblasts (NIH3T3) and primary adult human microvascular endothelial cells (HMVECad) and the neutral red uptake test. Blood compatibility was evaluated by analyzing blood parameters after incubation of the products with sodium citrate anticoagulated whole blood. Thrombin time was determined by adding thrombin to aliquots of human plasma containing the samples. Clotting time was revealed by an automatic coagulometer. The in vivo analgesic effect of GA was evaluated in Wistar rats using the formalin test. RESULTS: M and PG reduced the percentage of viable NIH3T3 cells, indicating their interference in the cell cycle. GA and Eq stimulated fibroblast proliferation and neutralized the toxic effect of M. M and PG reduced HMVECad cell viability. GA and Eq did not affect cell viability as well as negative control. The hemocompatibility tests indicated that all the samples did not interfere with fibrinogen. The in vivo test carried out in male rats showed a significant analgesic effect of GA in all formalin-induced pain behaviors. CONCLUSION: No hemotoxicity and good cell compatibility were found for all the tested samples. GA and Eq were the best candidates for further biocompatibility testing. Moreover, GA reduced pain in the animal model.

( S)-2-Amino-3-(5-methyl-3-hydroxyisoxazol-4-yl)propanoic Acid (AMPA) and Kainate Receptor Ligands: Further Exploration of Bioisosteric Replacements and Structural and Biological Investigation.

Starting from 1-4 and 7 structural templates, analogues based on bioisosteric replacements (5a-c vs 1, 2 and 6 vs 7) were synthesized for completing the SAR analysis. Interesting binding properties at GluA2, GluK1, and GluK3 receptors were discovered. The requirements for GluK3 interaction were elucidated by determining the X-ray structures of the GluK3-LBD with 2 and 5c and by computational studies. Antinociceptive potential was demonstrated for GluK1 partial agonist 3 and antagonist 7 (2 mg/kg ip).

Enrofloxacin and Toltrazuril Are Able to Reduce Toxoplasma gondii Growth in Human BeWo Trophoblastic Cells and Villous Explants from Human Third Trimester Pregnancy.

Classical treatment for congenital toxoplasmosis is based on combination of sulfadiazine and pyrimethamine plus folinic acid. Due to teratogenic effects and bone marrow suppression caused by pyrimethamine, the establishment of new therapeutic strategies is indispensable to minimize the side effects and improve the control of infection. Previous studies demonstrated that enrofloxacin and toltrazuril reduced the incidence of Neospora caninum and Toxoplasma gondii infection. The aim of the present study was to evaluate the efficacy of enrofloxacin and toltrazuril in the control of T. gondii infection in human trophoblast cells (BeWo line) and in human villous explants from the third trimester. BeWo cells and villous were treated with several concentrations of enrofloxacin, toltrazuril, sulfadiazine, pyrimethamine, or combination of sulfadiazine+pyrimethamine, and the cellular or tissue viability was verified. Next, BeWo cells were infected by T. gondii (2F1 clone or the ME49 strain), whereas villous samples were only infected by the 2F1 clone. Then, infected cells and villous were treated with all antibiotics and the T. gondii intracellular proliferation as well as the cytokine production were analyzed. Finally, we evaluated the direct effect of enrofloxacin and toltrazuril in tachyzoites to verify possible changes in parasite structure. Enrofloxacin and toltrazuril did not decrease the viability of cells and villous in lower concentrations. Both drugs were able to significantly reduce the parasite intracellular proliferation in BeWo cells and villous explants when compared to untreated conditions. Regardless of the T. gondii strain, BeWo cells infected and treated with enrofloxacin or toltrazuril induced high levels of IL-6 and MIF. In villous explants, enrofloxacin induced high MIF production. Finally, the drugs increased the number of unviable parasites and triggered damage to tachyzoite structure. Taken together, it can be concluded that enrofloxacin and toltrazuril are able to control T. gondii infection in BeWo cells and villous explants, probably by a direct action on the host cells and parasites, which leads to modifications of cytokine release and tachyzoite structure.

Perinatal 17α-ethinylestradiol exposure affects formalin-induced responses in middle-aged male (but not female) rats.

17α-Ethinylestradiol (EE), the main component of the contraceptive pill, is a synthetic estrogen found in rivers of the United States and Europe as an environmental contaminant. It is one of the most studied xenoestrogens due to its possible effect on the reproductive system. In the present study we evaluated the modulation of pain responses induced by formalin injection (licking, flexing, paw-jerk) in 8-month-old male and female offspring of female rats treated with two different doses of EE (4ng/kg/day or 400ng/kg/day) during pregnancy and lactation. Spontaneous behaviors and gonadal hormone levels were also determined. Both concentrations of EE induced an increase of pain behaviors in males only, i.e. higher flexing and licking of the formalin-injected paw than in OIL-exposed rats, during the second, inflammatory, phase of the formalin test. Grooming duration was increased by EE exposure in both males and females. Prenatal EE exposure (both concentrations) decreased estradiol plasma levels in the formalin-injected females but not in the males. These results underline the possibility that exposure to an environmental contaminant during the critical period of development can affect neural processes (such as those involved in pain modulation) during adulthood, indicating long-term changes in brain circuitry. However, such changes may be different in males and females.

Protective effect of palmitoylethanolamide in a rat model of cystitis.

PURPOSE: PEA is an endogenous mediator released together with the endocannabinoid anandamide from membrane phospholipids. It is a plant derived compound with analgesic and anti-inflammatory properties. We verified whether the pathophysiology of experimental cystitis involves changes in the levels of PEA and of some of its targets, ie CB1 and CB2 receptors, and PPARα. We also determined whether exogenously administered PEA could be proposed as a preventive measure for cystitis. MATERIALS AND METHODS: Cystitis was induced by cyclophosphamide in female rats. Nociceptive responses, voiding episodes, gross damage, myeloperoxidase activity, bladder weight, bladder PEA and endocannabinoid levels (measured by liquid chromatography-mass spectrometry) and the expression of PEA targets (measured by quantitative reverse transcriptase-polymerase chain reaction) were recorded. RESULTS: Cyclophosphamide induced pain behavior, bladder inflammation and voiding dysfunction associated with increased bladder levels of PEA, up-regulation of CB1 receptor mRNA expression, down-regulation of PPARα mRNA and no change in CB2 receptor mRNA expression. Exogenously administered, ultramicronized PEA attenuated pain behavior, voids and bladder gross damage. The CB1 antagonist rimonabant and the PPARα antagonist GW6471 counteracted the beneficial effect of PEA on gross damage. Also, GW6471 further decreased voiding episodes in rats treated with PEA. CONCLUSIONS: The current study provides strong evidence for a protective role of PEA as well as an alteration in bladder levels of PEA and of some of its targets in cyclophosphamide induced cystitis.

In vitro and in vivo characterization of the new analgesic combination Beta-caryophyllene and docosahexaenoic Acid.

Beta-caryophyllene (BCP) and docosahexaenoic acid (DHA) are components of several plants with documented anti-inflammatory and analgesic effects in animal pain models. In the present study, in vitro and in vivo tests were carried out to evaluate their effects, alone or in combination, during long-lasting administration in a model of persistent pain. IR spectra of the two compounds were obtained to determine their chemical stability and then in vitro toxicity was evaluated in fibroblasts and astrocytes. In the in vivo tests, the analgesic effects of BCP and BCP+DHA were determined in male rats subjected to a model of persistent recurrent pain (three repetitions of the formalin test once a week) to mimic recurrent pain. Both substances were administered per os in almond oil for 2 weeks. Gonadal hormones were determined at the end of the tests to evaluate treatment-induced effects on their levels. BCP changed fibroblast and astrocyte survival in a dose-dependent manner and the effect was counteracted by DHA coadministration. In the in vivo tests, pain responses were significantly decreased in the BCP and BCP+DHA groups with respect to OIL after 1 and 2 weeks of treatment. Estradiol and testosterone levels were increased only in the BCP group. In conclusion, BCP alone or at lower concentration in combination with DHA was efficacious in modulating pain, showing a clear analgesic activity.

Gonadal ERα/ß, AR and TRPV1 gene expression: modulation by pain and morphine treatment in male and female rats.

The results of several studies strongly indicate a bidirectional relationship among gonadal hormones and pain. While gonadal hormones play a key role in pain modulation, they have been found to be affected by pain therapies in different experimental and clinical conditions. However, the effects of pain and pain therapy on the gonads are still not clear. In this study, we determined the long-lasting (72 h) effects of inflammatory pain (formalin test) and/or morphine on estrogen receptor (ER), androgen receptor (AR) and TRPV1 gene expression in the rat testis and ovary. The animals were divided into groups: animals receiving no treatment, animals exposed only to the experimental procedure (control group), animals receiving no pain but morphine (sham/morphine), animals receiving pain and morphine (formalin/morphine), and animals receiving only formalin (formalin/saline). Testosterone (T) and estradiol (E) were determined in the plasma at the end of the testing. In the sham/morphine rats, there were increases of ERα, ERß, AR and TRPV1 mRNA expression in the ovary; in the testis, ERα and ERß mRNA expression were reduced while AR and TRPV1 expression were unaffected by treatment. T and E plasma levels were increased in morphine-treated female rats, while T levels were greatly reduced in morphine-treated and formalin-treated males. In conclusion, both testicular and ovarian ER (ERα and ERß) and ovarian AR and TRPV1 gene expression appear to be affected by morphine treatment, suggesting long-lasting interactions among opioids and gonads.

Central CRH administration changes formalin pain responses in male and female rats.

Corticotropin-releasing hormone (CRH) is suggested to be involved in the regulation of pain. To better evaluate the CRH-mediated behavioral alterations in the formalin inflammatory pain test, we administered CRH or the CRH receptor antagonist α-helical CRH(9-41) (ahCRH) intracerebroventricularly to male and female rats and compared the effects with those of saline control. Nociceptive stimulation was carried out through a subcutaneous injection of dilute formalin (50µL, 10%) in the plantar surface of the hind paw. In both sexes, formalin-induced responses, recorded for 60min, were affected by CRH but not by ahCRH treatment. Paw flexing duration was decreased in both sexes during the formalin interphase period in the CRH-treated group compared to saline control groups; however, licking of the injected paw was markedly increased by the same treatment at other time periods. Treatments induced only a few changes in spontaneous non-pain behaviors, which do not account for the effects on pain response. In conclusion, these data demonstrate the ability of CRH to affect the behavioral responses to an inflammatory nociceptive stimulus, and that the effects can be in opposite directions depending on the behavioral response considered.

Sex differences in the analgesic effects of ICI 182,780 and Flutamide on ureteral calculosis in rats.

To better define the involvement of gonadal hormones in the sex differences observed in experimental visceral pain, we administered antagonists of estrogen receptors (ICI 182,780 [ICI]) or androgen receptors (Flutamide [FLU]) to adult male and female rats suffering from artificial ureteral calculosis. Subjects were divided into groups and treated with one of the substances (ICI, FLU) or sweet almond oil (OIL, vehicle) for 5 days, starting 2 days before surgery. On day 3, animals underwent surgery, with half receiving an artificial calculosis (Stone) and half only a sham procedure. The animals' behavior (number and duration of ureteral crises) and blood hormone levels (estradiol and testosterone) were determined in all groups. In OIL-treated rats the number and duration of crises were higher in females than in males. The administration of ICI or FLU resulted in hormonal effects in males and behavioral effects in females. In males ICI treatment increased estradiol plasma levels and FLU increased testosterone plasma levels; in females ICI and FLU treatments both decreased the number and duration of the ureteral crises. These results, confirming previous findings of higher sensitivity of females than males to urinary tract pain, showed the modulatory effects of estrogen and androgen antagonists on the behavioral responses induced by pain but only in females.

Aromatase and 5-alpha reductase gene expression: modulation by pain and morphine treatment in male rats.

BACKGROUND: The steroid hormone testosterone has been found to be greatly reduced by opioids in different experimental and clinical conditions. The purpose of this study on male rats was to determine the effects of a single injection of morphine (5 mg/Kg) on persistent pain (formalin test) and the single or combined effects on p450-aromatase and 5-alpha reductase type 1 mRNA expression in the brain, liver and testis. Testosterone was determined in the plasma and in the brain, morphine was assayed in the plasma. RESULTS: In the morphine-treated rats, there were increases of 5-alpha reductase mRNA expression in the liver and aromatase mRNA expression in the brain and gonads. Morphine was detected in the blood of all morphine-treated rats even though there were no clear analgesic affects in the formalin-treated animals three hours after treatment. Testosterone was greatly reduced in the plasma and brain in morphine-treated subjects. CONCLUSIONS: It appears that morphine administration can induce long-lasting genomic effects in different body areas which contribute to the strong central and peripheral testosterone levels. These changes were not always accompanied by behavioral modifications.

Estradiol and testosterone differently affect visceral pain-related behavioural responses in male and female rats.

In the study of pain, the presence of sex differences is well known, with female subjects being more affected in a number of chronic painful conditions; however, the underlying mechanisms and the involvement of gonadal hormones, are still controversial. This study evaluated visceral pain in a validated rat model of artificial calculosis and the effects of estradiol and testosterone administration. Adult male and female rats were divided into groups and treated with one of the substances or Oil (vehicle) for 5 days, starting 2 days before surgery, with half receiving an artificial calculosis (Stone) and half only a sham (Sham) procedure. The animals' behaviour (ureteral crises, frequency and duration) were recorded for 72 h; estradiol and testosterone plasma levels were determined in all groups at the end of the observation period. After surgery, only Stone rats showed ureteral pain crises, with a significant sex difference in the Oil-treated groups in which the number and duration of crises were higher in females than in males. This difference was not present in the estradiol-treated groups in which ureteral crises were decreased only in females while testosterone treatment had no effect in either sex. Estradiol and testosterone plasma levels were affected by treatments in both sexes. These results confirm that, also in this model of visceral pain, females experience more pain than males; moreover, they show that supraphysiological levels of estradiol, but not of testosterone, are analgesic only in females. A dose and sex-dependent efficacy of gonadal hormones is suggested and discussed.

Endocrine consequences of opioid therapy.

Gonadal hormones are known to be affected by morphine and other opioids. In this paper, we summarize data collected in recent years which clearly indicate that the opioid-induced effects on steroid hormones depend on the opioid used and in some cases on the sex of the subject. Indeed morphine is able to reduce hormones like testosterone and cortisol in both male and female subjects in just a few hours, probably acting directly on peripheral glands. These depressant effects of morphine on hormones are also present in the treatment of surgical pain and are quickly reversible once opioid administration is suspended. Similar actions were also found to occur in experimental animals and in vitro in glial cells, further confirming the morphine-induced reduction of testosterone cell content. Testosterone and its metabolites are well known substances involved in the development and maintenance of the brain and all body structures. Thus when treating pain with opioids, their effects on hypothalamo-pituitary-gonadal and hypothalamo-pituitary-adrenal-related hormones must be considered and, where possible, hormone replacement therapy should be started.

Perinatal exposure to xenoestrogens affects pain in adult female rats.

Estrogens have a variety of effects in addition to their action on reproductive structures, including permanent effects on the Central Nervous System (CNS). Therefore environmental chemicals with estrogenic activity (xenoestrogens) can potentially affect a number of CNS functions. In the present experiment, female rats receiving ethynylestradiol (EE) or methoxychlor (MXC) via the mothers during pregnancy (pre) or lactation (post) were tested in comparison with females born from mothers treated with OIL. The Object Recognition, Plantar and Formalin tests were carried out to evaluate the effects of these compounds on integrated functions such as memory and pain. Testosterone and estradiol plasma levels were determined by RIA. The results of the Object Recognition and Plantar tests did not differ among groups. However the groups differed in the Formalin test since flexing duration was higher in the EE- and MXC-pre groups than in the EE- and MXC-post and OIL groups. Estradiol plasma levels were higher in EE-pre than in the other groups. These results confirm the possibility that estrogen-like compounds (EE and MXC) can affect complex neural processes like pain when taken during critical stages of CNS development.

Effects of 17beta-estradiol on rat urinary bladder: gender differences in anoxia-glucopenia and reperfusion damage.

AIM: To study the effect of 17beta-estradiol (E(2)) as a neuroprotective agent in male and female rat urinary bladders subjected to anoxia-glucopenia and reperfusion (A/G-R) damage. METHODS: Rat urinary bladders were exposed to 1 hour of A-G and 2 hours of reperfusion (R). Intrinsic nerves underwent electrical field stimulation. The effect of E(2) on the contractile response and its recovery in R phase, was monitored by adding it to the bath medium, at different concentrations, 60 min before A-G, during the A-G and the first 30 min of R. Furthermore, on both genders, in vivo treatments with E(2), testosterone, IC1 182,780 and anastrozole were performed. RESULTS: After A-G the recovery of the nerve function in female bladders were significantly higher than in male. E(2) given both in vivo (increased of E(2) plasma levels were monitored) and in vitro, resulted to be neuroprotective in male bladder subjected to A-G/R damage. When rats were treated with anastrozole, a lower recovery of nerve responses both in male and female bladders was observed. Finally, treatments with E2 receptor antagonist ICI 182,780 increased E(2) plasma levels and showed to abolished E(2) neuroprotection, thus suggesting that E2 promotes neuronal survival likely through a rapid estrogen receptor mediated response. CONCLUSIONS: Male rat urinary bladder serves are more susceptible to A-G/R damage than female. E(2) exhibits neuroprotective properties and could be a lead for novel agents capable to protect the urinary bladder from ischaemia/reperfusion damage associated with urinary bladder disorders.