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1.
Theriogenology ; 149: 139-148, 2020 Jun.
Article in English | MEDLINE | ID: mdl-32272343

ABSTRACT

The oocytes from small antral follicle have low developmental potential to reach blastocyst due to incomplete cytoplasmic maturation during in vitro maturation (IVM). Thus, we developed an in vitro culture system for porcine oocytes derived from small antral follicles with l-ascorbic acid supplement during pre-maturation (pre-IVM) to support their development to blastocyst stage. Besides that, how l-ascorbic acid effect on the developmental competence of porcine oocytes with a special focus on histone modifications will be elucidated. The in vitro culture process consisted of two steps. The first step is 22 h of pre-IVM and the second step is 42 h of IVM. We utilized dibutyryl-cyclicAMP (dbcAMP) with L-ascorbic supplement during pre-IVM. Based on the result of this procedure, we proposed that the best culture condition in which hormone human chorionic gonadotropin (hCG) be added during the last 7 h of pre-IVM and continued culture to complete IVM. We observed that, in this culture system, the meiotic competence of porcine oocytes derived from small follicles was as high as those derived from large follicles after undergoing IVM. In addition, our study suggested that l-ascorbic acid supplementation at 100 µg/mL sharply enhanced the developmental potential of porcine oocytes. Interestingly, oocytes from small antral follicles treated with l-ascorbic acid could obtain the blastocyst quantity and quality as high as that of large antral follicles. The treated groups showed a significantly higher number of blastomeres compared to those in non-treated groups in both small and large follicle groups. Besides that, = The increasing levels of acetylation of histone H3 at lysine 9 (H3K9) and methylation of histone H3 at lysine 4 (H3K4) in blastocyst derived from small and large antral follicle under the present of l-ascrobic acid lead to a significant positive effect on the developmental competence and improvement in quality of porcine embryos.


Subject(s)
In Vitro Oocyte Maturation Techniques/veterinary , Oocytes/growth & development , Ovarian Follicle/cytology , Swine , Acetylation/drug effects , Animals , Ascorbic Acid/administration & dosage , Blastocyst/physiology , Bucladesine/administration & dosage , Chorionic Gonadotropin/administration & dosage , Female , Histones/metabolism , In Vitro Oocyte Maturation Techniques/methods , Meiosis , Methylation/drug effects , Oocytes/drug effects
2.
Neurotox Res ; 38(1): 38-49, 2020 Jun.
Article in English | MEDLINE | ID: mdl-32103463

ABSTRACT

Neurotoxic effects of systemic administration of 3, 4- methylenedioxymethamphetamine (MDMA) has been attributed to MDMA and its metabolites. However, the role of the parent compound in MDMA-induced mitochondrial and memory impairment has not yet been investigated. Moreover, it is not yet studied that analogs of 3', 5'-cyclic adenosine monophosphate (cAMP) could decrease these neurotoxic effects of MDMA. We wished to investigate the effects of the central administration of MDMA on spatial memory and mitochondrial function as well as the effects of bucladesine, a membrane-permeable analog of cAMP, on these effects of MDMA. We assessed the effects of pre-training bilateral intrahippocampal infusion of MDMA (0.01, 0.1, 0.5, and 1 µg/side), bucladesine (10 and 100 µM) or combination of them on spatial memory, and different parameters of hippocampal mitochondrial function including the level of reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), mitochondrial swelling, mitochondrial outer membrane damage, the amount of cytochrome c release as well as hippocampal ADP/ATP ratio. The results showed that MDMA caused spatial memory impairments as well as mitochondrial dysfunction as evidenced by the marked increase in hippocampal ADP/ATP ratio, ROS level, the collapse of MMP, mitochondrial swelling, and mitochondrial outer membrane damage leading to cytochrome c release from the mitochondria. The current study also found that bucladesine markedly reduced the destructive effects of MDMA. These results provide evidence of the role of the parent compound (MDMA) in MDMA-induced memory impairments through mitochondrial dysfunction. This study highlights the role of cAMP/PKA signaling in MDMA-induced memory and mitochondrial defects.


Subject(s)
Bucladesine/administration & dosage , Hippocampus/drug effects , Mitochondria/drug effects , N-Methyl-3,4-methylenedioxyamphetamine/administration & dosage , Spatial Learning/drug effects , Spatial Memory/drug effects , Animals , Hippocampus/metabolism , Male , Mitochondria/metabolism , Rats, Wistar , Reactive Oxygen Species/metabolism
3.
Neuroscience ; 325: 100-10, 2016 06 14.
Article in English | MEDLINE | ID: mdl-27038748

ABSTRACT

Cellular differentiation is the process, by which a cell changes from one cell type to another, preferentially to the more specialized one. Calcium fluxes play an important role in this action. Differentiated NG108-15 or PC12 cells serve as models for studying neuronal pathways. NG108-15 cell line is a reliable model of cholinergic neuronal cells. These cells differentiate to a neuronal phenotype due to the dibutyryl cAMP (dbcAMP) treatment. We have shown that a slow sulfide donor - GYY4137 - can also act as a differentiating factor in NG108-15 cell line. Calcium is an unavoidable ion required in NG108-15 cell differentiation by both, dbcAMP and GYY4137, since cultivation in EGTA completely prevented differentiation of these cells. In this work we focused primarily on the role of reticular calcium in the process of NG108-15 cell differentiation. We have found that dbcAMP and also GYY4137 decreased reticular calcium concentration by different mechanisms. GYY4137 caused a rapid decrease in type 2 sarco/endoplasmic calcium ATPase (SERCA2) mRNA and protein, which results in lower calcium levels in the endoplasmic reticulum compared to the control, untreated group. The dbcAMP revealed rapid increase in expression of the type 3 IP3 receptor, which participates in a calcium clearance from the endoplasmic reticulum. These results point to the important role of reticular calcium in a NG108-15 cell differentiation.


Subject(s)
Bucladesine/administration & dosage , Cell Differentiation/drug effects , Inositol 1,4,5-Trisphosphate Receptors/metabolism , Morpholines/administration & dosage , Neurons/drug effects , Neurons/physiology , Organothiophosphorus Compounds/administration & dosage , Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism , Animals , Calcium/metabolism , Cell Line, Tumor , Hydrogen Sulfide/administration & dosage , Mice , Mice, Inbred BALB C , RNA, Messenger/metabolism
4.
Mol Neurobiol ; 52(1): 130-41, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25128030

ABSTRACT

Multiple sclerosis (MS) is an inflammatory demyelinating disease that leads to neuronal cell loss. Cyclic AMP and its analogs are well known to decrease inflammation and apoptosis. In the present study, we examined the effects of bucladesine, a cell-permeable analogue of cyclic adenosine monophosphate (cAMP), on myelin proteins (PLP, PMP-22), inflammation, and apoptotic, as well as anti-apoptotic factors in cuprizone model of demyelination. C57BL/6J mice were fed with chow containing 0.2% copper chelator cuprizone or vehicle by daily oral gavage for 5 weeks to induce reversible demyelination predominantly of the corpus callosum. Bucladesine was administered intraperitoneally at different doses (0.24, 0.48, or 0.7 µg/kg body weight) during the last 7 days of 5-week cuprizone treatment. Bucladesine exhibited a protective effect on myelination. Furthermore, bucladesine significantly decreased the production of interleukin-6 pro-inflammatory mediator as well as nuclear factor-κB activation and reduced the mean number of apoptotic cells compared to cuprizone-treated mice. Bucladesine also decreased production of caspase-3 as well as Bax and increased Bcl-2 levels. Our data revealed that enhancement of intracellular cAMP prevents demyelination and plays anti-inflammatory and anti-apoptotic properties in mice cuprizone model of demyelination. This suggests the modulation of intracellular cAMP as a potential target for treatment of MS.


Subject(s)
Behavior, Animal/drug effects , Cyclic AMP/analogs & derivatives , Cyclic AMP/pharmacology , Demyelinating Diseases/drug therapy , Demyelinating Diseases/pathology , Neurons/pathology , Neuroprotective Agents/therapeutic use , Animals , Apoptosis/drug effects , Biomarkers/metabolism , Bucladesine/administration & dosage , Bucladesine/pharmacology , Cuprizone , Demyelinating Diseases/metabolism , Disease Models, Animal , Dose-Response Relationship, Drug , Heme Oxygenase-1/metabolism , Injections, Intraperitoneal , Interleukin-6/metabolism , Male , Mice, Inbred C57BL , Movement , Myelin Sheath/metabolism , NF-kappa B/metabolism , Neurons/drug effects , Neurons/metabolism , Neuroprotective Agents/pharmacology , Nociception/drug effects
5.
Fundam Clin Pharmacol ; 28(4): 445-54, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24033391

ABSTRACT

The present study shows interactive effects of bucladesine (db-cAMP) as a cyclic adenosine monophosphate (cAMP) agonist and H-89 as a protein kinase A (PKA) inhibitor on naloxone-induced withdrawal signs in morphine-dependent mice. Animals were treated subcutaneously with morphine thrice daily with doses progressively increased from 50 to 125 mg/kg. A last dose of morphine (50 mg/kg) was administered on the 4th day. Several withdrawal signs were precipitated by intraperitoneal (i.p.) administration of naloxone (5 mg/kg). Different doses of bucladesine (50, 100, 200 nm/mouse) and H-89 (0.05, 0.5, 1, 5 mg/kg) were administered (i.p.) 60 min before naloxone injection. In combination groups, bucladesine was injected 15 min before H-89 injection. Single administration of H-89 (0.5, 1, 5 mg/kg) and bucladesine (50, 100 nm/mouse) significantly attenuated prominent behavioral signs of morphine withdrawal. Lower doses of bucladesine (50, 100 nm/mouse) in combination with H-89 (0.05 mg/kg) increased the inhibitory effects of H-89 on withdrawal signs while in high dose (200 nm/mouse) decreased the ameliorative function of H-89 (0.05 mg/kg) in morphine-dependent animals. It is concluded that H-89 and bucladesine could affect morphine withdrawal syndrome via possible interaction with cyclic nucleotide messengering systems, protein kinase A signaling pathways, and modified related neurotransmitters.


Subject(s)
Bucladesine/pharmacology , Cyclic AMP/agonists , Isoquinolines/pharmacology , Substance Withdrawal Syndrome/prevention & control , Sulfonamides/pharmacology , Animals , Bucladesine/administration & dosage , Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors , Dose-Response Relationship, Drug , Drug Therapy, Combination , Isoquinolines/administration & dosage , Male , Mice , Morphine Dependence/physiopathology , Naloxone/pharmacology , Narcotic Antagonists/pharmacology , Substance Withdrawal Syndrome/physiopathology , Sulfonamides/administration & dosage
6.
Brain Res ; 1538: 41-50, 2013 Nov 13.
Article in English | MEDLINE | ID: mdl-24076153

ABSTRACT

This study describes the use of poly(propylene carbonate) (PPC) electrospun fibers as vehicle for the sustained delivery of dibutyryl cyclic adenosine monophosphate (dbcAMP) to the hemisected spinal cord. The dbcAMP and PPC were uniformly mixed with acetonitrile; then, electrospinning was used to generate micron fibers. The release of dbcAMP was assessed by ELISA in vitro. Our results showed that the encapsulation of dbcAMP in the fibers led to stable and prolonged release in vitro. The PPC micron fibers containing dbcAMP and the PPC micron fibers without dbcAMP were then implanted into the hemisected thoracic spinal cord, followed by testing of the functional recovery and immunohistochemistry. Compared with the control group, sustained delivery of dbcAMP promoted axonal regenerative sprouting and functional recovery and reduced glial scar formation, and the PPC micron fibers without dbcAMP did not have these effects. Our findings demonstrated the feasibility of using PPC electrospun fibers containing dbcAMP for spinal cord injury. The approach described here also will provide a platform for the potential delivery of other axon-growth-promoting or scar-inhibiting agents.


Subject(s)
Axons/drug effects , Bucladesine/administration & dosage , Spinal Cord Injuries/drug therapy , Spinal Cord Injuries/pathology , Animals , Axons/metabolism , Axons/physiology , Bucladesine/therapeutic use , Female , GAP-43 Protein/metabolism , Gliosis/drug therapy , Gliosis/pathology , Locomotion/drug effects , Nanofibers , Polypropylenes , Rats , Rats, Wistar , Recovery of Function
7.
Int Wound J ; 10(5): 542-8, 2013 Oct.
Article in English | MEDLINE | ID: mdl-22776519

ABSTRACT

Selecting an appropriate treatment for a given case of skin wound is crucial for inducing optimal healing. We used an animal model developed from normal rabbit ears in order to assess the efficacy of treatments for skin wounds with or without a wet dressing, anti microbial reagent or topical wound-stimulatory reagents. The degree of healing in each group was evaluated and compared using four histological parameters: (i) degree of reepithelialisation, (ii) amount of granulation tissue formation, and (iii) the number of capillary lumens and (iv) fibroblasts in the granulation tissue. Treatment using wet dressings resulted in an increase in capillary number compared with the open dry wound. Although the retention of povidone-iodine (PI) in wound tissue after application significantly inhibited reepithelialisation (P < 0.05), rinsing PI off with saline was comparable in effect to using only a wet dressing. The three topical reagents, namely, basic fibroblast growth factor, prostaglandin E1 and dibutyryl cyclic adenosine monophosphate, significantly improved reepithelialisation (P < 0.05). In conclusion, wounds should be kept hydrated by applying topical reagents. If there are any signs of bacterial infection, PI can be applied and rinsed later with saline in order to minimise its cytotoxic effects.


Subject(s)
Alprostadil/administration & dosage , Bucladesine/administration & dosage , Ear/injuries , Fibroblast Growth Factor 2/administration & dosage , Povidone-Iodine/administration & dosage , Wound Healing/drug effects , Wounds and Injuries/drug therapy , Animals , Anti-Infective Agents, Local/administration & dosage , Disease Models, Animal , Drug Therapy, Combination , Female , Fibroblasts/drug effects , Fibroblasts/pathology , Granulation Tissue/drug effects , Rabbits , Skin/drug effects , Skin/pathology , Vasodilator Agents/administration & dosage
8.
Exp Neurol ; 233(2): 625-44, 2012 Feb.
Article in English | MEDLINE | ID: mdl-21195070

ABSTRACT

This study was undertaken as part of the NIH "Facilities of Research-Spinal Cord Injury" project to support independent replication of published studies. Here, we repeated a study reporting that a combinatorial treatment with transplants of Schwann cells, systemic delivery of Rolipram to enhance cyclic AMP levels, and intra-spinal injections of dibutyryl cyclic AMP enhanced locomotor recovery in rats after contusion injuries at the thoracic level. We compared the following experimental groups: 1) rats that received Schwann cell transplants, systemic Rolipram, and injections of db-cyclic AMP (the combined treatment group that showed the greatest improvement in function); 2) rats that received Schwann cell transplants only and implantation of empty pumps as control; 3) rats that received Rolipram only and implantation of empty pumps as control, and 4) control rats that received no treatment other than the injection of DMEM into the spinal cord and implantation of empty pumps. The principal findings reported in Pearse et al. were not replicated in that the combined treatment group did not exhibit greater recovery on any of the measures, although the group that received Schwann cells only did exhibit enhanced recovery on several of the outcome measures. The failure of the combined treatment may be due in part to less successful engraftment of Schwann cells in our study vs. Pearse et al. Issues relating to failures to replicate, especially when effect size is small, are discussed.


Subject(s)
Cyclic AMP/metabolism , Motor Activity/physiology , Recovery of Function/physiology , Rolipram/administration & dosage , Schwann Cells/transplantation , Spinal Cord Injuries/therapy , Animals , Bucladesine/administration & dosage , Cell Transplantation/methods , Combined Modality Therapy/methods , Injections, Spinal , Motor Activity/drug effects , Motor Skills/drug effects , Motor Skills/physiology , Rats , Rats, Inbred F344 , Recovery of Function/drug effects , Spinal Cord Injuries/metabolism , Spinal Cord Injuries/pathology , Thoracic Vertebrae/pathology
9.
Clinics (Sao Paulo) ; 66(8): 1407-12, 2011.
Article in English | MEDLINE | ID: mdl-21915492

ABSTRACT

INTRODUCTION: Results from our laboratory have demonstrated that intracerebroventricular administration of sildenafil to conscious rats promoted a noticeable increase in both lumbar sympathetic activity and heart rate, with no change in the mean arterial pressure. The intracerebroventricular administration of sildenafil may have produced the hemodynamic effects by activating sympathetic preganglionic neurons in the supraspinal regions and spinal cord. It is well documented that sildenafil increases intracellular cGMP levels by inhibiting phosphodiesterase type 5 and increases cAMP levels by inhibiting other phosphodiesterases. OBJECTIVE: To examine and compare, in conscious rats, the hemodynamic response following the intrathecal administration of sildenafil, 8-bromo-cGMP (an analog of cGMP), forskolin (an activator of adenylate cyclase), or dibutyryl-cAMP (an analog of cAMP) in order to elucidate the possible role of the sympathetic preganglionic neurons in the observed hemodynamic response. RESULTS: The hemodynamic responses observed following intrathecal administration of the studied drugs demonstrated the following: 1) sildenafil increased the mean arterial pressure and heart rate in a dose-dependent manner, 2) increasing doses of 8-bromo-cGMP did not alter the mean arterial pressure and heart rate, 3) forskolin did not affect the mean arterial pressure but did increase the heart rate and 4) dibutyryl-cAMP increased the mean arterial pressure and heart rate, similar to the effect observed following the intrathecal injection of the highest dose of sildenafil. CONCLUSION: Overall, the findings of the current study suggest that the cardiovascular response following the intrathecal administration of sildenafil to conscious rats involves the inhibition of phosphodiesterases other than phosphodiesterase type 5 that increase the cAMP level and the activation of sympathetic preganglionic neurons.


Subject(s)
Blood Pressure/drug effects , Bucladesine/pharmacology , Colforsin/administration & dosage , Cyclic GMP/analogs & derivatives , Heart Rate/drug effects , Piperazines/administration & dosage , Sulfones/administration & dosage , Vasodilator Agents/administration & dosage , Animals , Bucladesine/administration & dosage , Cyclic GMP/administration & dosage , Injections, Spinal , Male , Purines/administration & dosage , Rats , Rats, Wistar , Sildenafil Citrate
10.
Clinics ; 66(8): 1407-1412, 2011. ilus, tab
Article in English | LILACS | ID: lil-598396

ABSTRACT

INTRODUCTION: Results from our laboratory have demonstrated that intracerebroventricular administration of sildenafil to conscious rats promoted a noticeable increase in both lumbar sympathetic activity and heart rate, with no change in the mean arterial pressure. The intracerebroventricular administration of sildenafil may have produced the hemodynamic effects by activating sympathetic preganglionic neurons in the supraspinal regions and spinal cord. It is well documented that sildenafil increases intracellular cGMP levels by inhibiting phosphodiesterase type 5 and increases cAMP levels by inhibiting other phosphodiesterases. OBJECTIVE: To examine and compare, in conscious rats, the hemodynamic response following the intrathecal administration of sildenafil, 8-bromo-cGMP (an analog of cGMP), forskolin (an activator of adenylate cyclase), or dibutyryl-cAMP (an analog of cAMP) in order to elucidate the possible role of the sympathetic preganglionic neurons in the observed hemodynamic response. RESULTS: The hemodynamic responses observed following intrathecal administration of the studied drugs demonstrated the following: 1) sildenafil increased the mean arterial pressure and heart rate in a dose-dependent manner, 2) increasing doses of 8-bromo-cGMP did not alter the mean arterial pressure and heart rate, 3) forskolin did not affect the mean arterial pressure but did increase the heart rate and 4) dibutyryl-cAMP increased the mean arterial pressure and heart rate, similar to the effect observed following the intrathecal injection of the highest dose of sildenafil. CONCLUSION: Overall, the findings of the current study suggest that the cardiovascular response following the intrathecal administration of sildenafil to conscious rats involves the inhibition of phosphodiesterases other than phosphodiesterase type 5 that increase the cAMP level and the activation of sympathetic preganglionic neurons.


Subject(s)
Animals , Male , Rats , Blood Pressure/drug effects , Bucladesine/pharmacology , Cyclic GMP/analogs & derivatives , Colforsin/administration & dosage , Heart Rate/drug effects , Piperazines/administration & dosage , Sulfones/administration & dosage , Vasodilator Agents/administration & dosage , Bucladesine/administration & dosage , Cyclic GMP/administration & dosage , Injections, Spinal , Purines/administration & dosage , Rats, Wistar
11.
J Am Assoc Lab Anim Sci ; 49(2): 167-72, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20353690

ABSTRACT

We studied the effects of ATP, ionomycin, and dibutyryl cAMP (dbcAMP) on the motility, freezability, and oxygen consumption of rat epididymal sperm. In vitro fertilization and intrauterine insemination were performed by using frozen-thawed rat sperm. Frozen-thawed sperm diluted in raffinose-modified Krebs-Ringer bicarbonate solution-egg yolk extender containing 1.85 mM ATP and 100 microM dbcAMP exhibited considerably higher motility and viability than sperm diluted in dbcAMP-free extender. Addition of ionomycin and dbcAMP to ATP-containing extenders did not alter the oxygen consumption rate of sperm, suggesting that extracellular ionomycin and dbcAMP are not involved in the mobilization of mitochondrial energy substrates in sperm. Further, high rates of pronucleus formation and progression to the blastocyst stage were observed in embryos produced by the fertilization of oocytes with fresh sperm in an in vitro fertilization medium supplemented with ATP and dbcAMP. Oocytes were not penetrated by frozen-thawed sperm when cocultured with cumulus-oocyte complexes in a medium without ATP and dbcAMP. In contrast, cryopreserved sperm penetrated oocytes when the gametes were cultured in an ATP- and dbcAMP-containing medium, and the resultant embryos formed blastocysts. Our results show that the dilution of rat sperm in raffinose-modified Krebs-Ringer bicarbonate solution-egg yolk extender supplemented with ATP and dbcAMP prior to sperm cryopreservation enhances the freezability of the cryopreserved sperm. Furthermore, the in vitro fertilization medium we developed effectively supports the production of embryos from both fresh and cryopreserved rat sperm.


Subject(s)
Adenosine Triphosphate/administration & dosage , Bucladesine/administration & dosage , Cryopreservation/veterinary , Epididymis/cytology , Semen Preservation/veterinary , Spermatozoa/physiology , Animals , Cryopreservation/methods , Cryoprotective Agents , Embryo Culture Techniques/veterinary , Female , Fertilization in Vitro/methods , Fertilization in Vitro/veterinary , Insemination, Artificial/methods , Insemination, Artificial/veterinary , Ionomycin/pharmacology , Ionophores/pharmacology , Male , Oxygen Consumption , Pregnancy , Rats , Rats, Wistar , Semen Preservation/methods , Sperm Motility
12.
J Clin Endocrinol Metab ; 94(7): 2516-23, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19351726

ABSTRACT

CONTEXT: Decidualization of the endometrium involves the morphological and biochemical reprogramming of the estrogen-primed proliferative endometrial stromal compartment under the continuing influence of progesterone. OBJECTIVES: The aim of this study was to evaluate the involvement of the extracellular matrix contractility of eutopic and ectopic endometrial stromal cells during the tissue remodeling processes associated with decidualization. DESIGN: The effect of decidualization on the contractile profile of the endometriotic cyst stromal cells and eutopic endometrial stromal cells with or without endometriosis in the three-dimensional collagen gel culture was investigated using laser scanning microscopy, collagen gel contraction assays, and Western blot analysis. RESULTS: Decidualized ectopic and eutopic endometrial stromal cells in the three-dimensional collagen gel culture mimicked the morphology of decidual tissue in vivo. In vitro decidualization inhibited the contractility of these eutopic and ectopic endometrial stromal cells. Down-regulation of integrin alpha1beta1 and alpha2beta1 expression, suppression of Ras homology A (Rho A), Rho-associated coiled-coil-forming protein kinase (ROCK)-I and ROCK-II expression, inhibition of the differentiation into the myofibroblastic phenotype, and induction of differentiation into epithelioid decidual phenotype were observed in these cells during decidualization. CONCLUSIONS: It is suggested that the attenuation of eutopic endometrial stromal cell-mediated contractility by decidualization is a novel and integral mechanism of the physiological endometrial tissue remodeling process during menstrual cycles. Although ectopic endometrial stromal cells have enhanced contractile profile, decidualization can attenuate the contractility of these cells. These findings may be one of the action mechanisms by which oral contraceptives and progestins ameliorate endometriosis.


Subject(s)
Decidua/drug effects , Decidua/physiology , Endometriosis/physiopathology , Endometrium/physiology , Hormones/pharmacology , Stromal Cells/physiology , Uterine Diseases/physiopathology , Adult , Bucladesine/administration & dosage , Cell Movement/drug effects , Cell Movement/physiology , Cells, Cultured , Choristoma/drug therapy , Choristoma/pathology , Choristoma/physiopathology , Decidua/metabolism , Decidua/pathology , Endometriosis/drug therapy , Endometriosis/pathology , Endometrium/drug effects , Endometrium/metabolism , Endometrium/pathology , Female , Hormones/therapeutic use , Humans , Insulin-Like Growth Factor Binding Protein 1/metabolism , Progestins/administration & dosage , Progestins/pharmacology , Progestins/therapeutic use , Prolactin/metabolism , Stromal Cells/drug effects , Stromal Cells/metabolism , Uterine Diseases/drug therapy , Uterine Diseases/pathology , Young Adult
13.
J Neurotrauma ; 26(5): 733-40, 2009 May.
Article in English | MEDLINE | ID: mdl-19397425

ABSTRACT

In this investigation, two cell-permeable synthetic analogs of cAMP, dibutyryl-cAMP (db-cAMP) and 8-bromo-cAMP, which are widely used to elevate intracellular cAMP levels under experimental conditions, were investigated for their ability to dose-dependently improve histological and functional outcomes following continuous delivery in two models of incomplete spinal cord injury (SCI). The cAMP analogs were delivered via osmotic minipumps at 1-250 mM through an indwelling cortical cannula or by intrathecal infusion for up to 4 weeks after either a T8 unilateral over-hemisection or a C2-3 dorsolateral quadrant lesion, respectively. In both SCI models, continuous db-cAMP delivery was associated with histopathological changes that included sporadic micro-hemorrhage formation and cavitation, enhanced macrophage infiltration and tissue damage at regions beyond the immediate application site; no deleterious or beneficial effect of agent delivery was observed at the spinal injury site. Furthermore, these changes were accompanied by pronounced behavioral deficits that included an absence of progressive locomotor recovery, increased extensor tone, paralysis, and sensory abnormalities. These deleterious effects were not observed in saline-treated animals, in animals in which the db-cAMP dose did not exceed 1 mM, or in those animals that received a high dose (250 mM) of the alternative cAMP analog, 8-bromo-cAMP. These results demonstrate that, for continuous intraparenchymal or intrathecal administration of cAMP analogs for the study of biological or therapeutic effects within the central nervous system (CNS), consideration of the effective concentration applied as well as the potential toxicity of chemical moieties on the parent molecule and/or their activity needs to be taken into account.


Subject(s)
8-Bromo Cyclic Adenosine Monophosphate/administration & dosage , 8-Bromo Cyclic Adenosine Monophosphate/therapeutic use , Bucladesine/administration & dosage , Bucladesine/therapeutic use , Spinal Cord Injuries/drug therapy , Animals , Axons/pathology , Behavior, Animal/physiology , Cerebral Cortex/metabolism , Contusions/drug therapy , Dose-Response Relationship, Drug , Female , Immunohistochemistry , Infusion Pumps, Implantable , Injections, Spinal , Locomotion/physiology , Macrophages/pathology , Rats , Rats, Inbred Lew , Spinal Cord/pathology , Spinal Cord Injuries/pathology , Spinal Cord Injuries/psychology
14.
Biotech Histochem ; 84(2): 47-54, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19229699

ABSTRACT

Dibutryl (DB) adenosine 3',5'-cyclic monophosphate (cAMP) is an important modulator of physiological functions. To determine the protective effects of DBcAMP on heart tissue, we evaluated changes in immunoreactivity of endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS) and transforming growth factor-beta (TGF-beta) in left cervical vagotomized rats treated with DBcAMP. Male rats were divided into four groups. In Group 1, animals were subjected to a left cervical vagotomy. Group 2 received a 1 ml bolus injection of 15 ml/kg DBcAMP in addition to the left vagotomy. DBcAMP alone was given to Group 3 and Group 4 was the control group. For each animal, mean arterial pressure (MAP) and heart rate (HR) were measured. For indirect immunohistochemistry, anti-eNOS, anti-iNOS, and anti-TGF-beta primary antibodies were used. In Group 1, MAP and HR values decreased slightly. In Groups 2 and 3, DBcAMP induced a statistically significant drop in HR and MAP. In Group 1, strong eNOS, iNOS, and TGF-beta immunoreactivities were observed. Immunostaining intensities decreased in Groups 2 and 3. The results of the study reported here suggest that increased immunoreactivities of eNOS, iNOS, and TGF-beta might contribute to the effects on the heart tissue after left vagotomy and imply that DBcAMP acts on heart tissue via nitric oxide.


Subject(s)
Bucladesine/administration & dosage , Myocardium/metabolism , Nitric Oxide Synthase Type III/metabolism , Signal Transduction/physiology , Transforming Growth Factor beta/metabolism , Animals , Dose-Response Relationship, Drug , Gene Expression/drug effects , Male , Rats , Rats, Sprague-Dawley , Signal Transduction/drug effects
15.
Arch. venez. farmacol. ter ; 27(2): 129-131, 2008. graf
Article in Spanish | LILACS | ID: lil-517104

ABSTRACT

El extracto acuoso de las hojas de Bauhinia megalandra ha sido muy empleado en Venezuela en el tratamiento empírico de la diabetes mellitus. En el presente trabajo se estudió el efecto del extracto acuoso de B. megalandra sobre la glucogenolísis hepática estimulada por adrenalina o dibutiril AMPc. La administración oral del extracto de la planta, a ratas alimentadas, disminuyó de una manera estadísticamente significativa el incremento de la glicemia promovido por la adrenalina. De igual manera, rebanadas de hígado de ratas alimentadas incubadas en presencia del extracto de B. megalandra produjeron menos glucosa en respuesta a la adrenalina o al dibutiril AMPc que los controles. Estos resultados indican una disminución de la glucogenolísis hepática por efecto del extracto acuoso de hojas de B. megalandra, probablemente por inhibición de la enzima glucosa-6-fosfatasa.


Subject(s)
Animals , Rats , Bucladesine/administration & dosage , Bucladesine/therapeutic use , Diabetes Mellitus , Epinephrine/adverse effects , /adverse effects
16.
Eur J Pharmacol ; 562(3): 212-20, 2007 May 21.
Article in English | MEDLINE | ID: mdl-17379207

ABSTRACT

We previously had shown that bilateral intrahippocampal infusion of 1 microg nicotine (but not 0.5 microg dose) led to an improvement in spatial memory retention in the Morris water maze task in male rats. We also reported that a similar type of bilateral infusion of H89, a protein kinase AII (PKA II) inhibitor, caused a deficit in spatial memory retention. In the present study, we wished to test the hypothesis that intrahippocampal infusion of dibutyryl cyclic AMP (DB-cAMP also called bucladesine), a membrane permeable selective activator of PKA, into the CA1 region can cause an improvement in spatial memory in this maze task. Indeed, bilateral infusion of 10 and 100 microM bucladesine (but not 1 and 5 microM doses) led to a significant reduction in escape latency and travel distance (showing an improvement in spatial memory) compared to the control. Also, bilateral infusion of 0.5 microg nicotine or 1 microM bucladesine alone did not lead to an improvement in spatial memory. However, such bilateral infusion of bucladesine at 1 and 5 microM concentrations infused within minutes after 0.5 microg nicotine infusion improved spatial memory retention. Taken together, our data suggest that intrahippocampal bucladesine infusions improve spatial memory retention in male rats and that bucladesine can interact synergistically with nicotine to improve spatial memory.


Subject(s)
Bucladesine/pharmacology , Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors , Nicotine/pharmacology , Nicotinic Agonists/pharmacology , Retention, Psychology/drug effects , Animals , Behavior, Animal/drug effects , Bucladesine/administration & dosage , Cyclic AMP-Dependent Protein Kinases/metabolism , Dose-Response Relationship, Drug , Drug Synergism , Drug Therapy, Combination , Hippocampus , Male , Maze Learning/drug effects , Nicotine/administration & dosage , Nicotinic Agonists/administration & dosage , Rats , Rats, Wistar , Signal Transduction/drug effects , Space Perception/drug effects
17.
J Neurosci ; 24(28): 6402-9, 2004 Jul 14.
Article in English | MEDLINE | ID: mdl-15254096

ABSTRACT

Previous attempts to promote regeneration after spinal cord injury have succeeded in stimulating axonal growth into or around lesion sites but rarely beyond them. We tested whether a combinatorial approach of stimulating the neuronal cell body with cAMP and the injured axon with neurotrophins would propel axonal growth into and beyond sites of spinal cord injury. A preconditioning stimulus to sensory neuronal cell bodies was delivered by injecting cAMP into the L4 dorsal root ganglion, and a postinjury stimulus to the injured axon was administered by injecting neurotrophin-3 (NT-3) within and beyond a cervical spinal cord lesion site grafted with autologous bone marrow stromal cells. One to 3 months later, long-projecting dorsal-column sensory axons regenerated into and beyond the lesion. Regeneration beyond the lesion did not occur after treatment with cAMP or NT-3 alone. Thus, clear axonal regeneration beyond spinal cord injury sites can be achieved by combinatorial approaches that stimulate both the neuronal soma and the axon, representing a major advance in strategies to enhance spinal cord repair.


Subject(s)
Axons/drug effects , Bucladesine/therapeutic use , Nerve Regeneration/drug effects , Neurotrophin 3/therapeutic use , Spinal Cord Injuries/drug therapy , Animals , Axons/physiology , Bone Marrow Transplantation , Bucladesine/administration & dosage , Combined Modality Therapy , Drug Evaluation , Drug Evaluation, Preclinical , Drug Therapy, Combination , Female , Ganglia, Spinal , Injections, Intralesional , Neurons, Afferent/drug effects , Neurons, Afferent/physiology , Neurotrophin 3/administration & dosage , Rats , Rats, Inbred F344 , Stromal Cells/transplantation , Transplantation, Autologous
18.
Ann Pharmacother ; 38(1): 70-2, 2004 Jan.
Article in English | MEDLINE | ID: mdl-14742798

ABSTRACT

OBJECTIVE: To report a case illustrating therapeutic success with long-term topical application of aseptic vancomycin ointment to treat methicillin-resistant Staphylococcus aureus (MRSA) infection at a cranioplasty site. CASE SUMMARY: A 63-year-old Japanese woman underwent evacuation of a subdural hematoma complicated by subarachnoid hemorrhage. Subsequent craniotomy for clipping and external decompression of an aneurysm of the neck was followed by cranioplasty using an autologous bone graft. The graft became infected with MRSA, which responded to intravenously infused vancomycin. The graft was then replaced with a ceramic implant. The implant site became reinfected with MRSA. Vancomycin infusion failed on this occasion, despite a favorable in vitro sensitivity test. After obtaining patient consent, investigative treatment was begun using long-term aseptic application of vancomycin 2.5% ointment, resulting in control of the infection and negative cultures. DISCUSSION: The care of an infection at the site of cranioplasty with a ceramic artificial bone implant is difficult. Our patient's infection resolved with the use of vancomycin ointment. In this case, blood concentrations of vancomycin remained below detectable levels, and no adverse effects resulted from application of vancomycin ointment. CONCLUSIONS: Topical administration of vancomycin was more effective than systemic administration in the treatment of our patient's MRSA skull implant infection. No adverse effects from topical treatment were encountered over 3 years.


Subject(s)
Craniotomy , Methicillin Resistance/drug effects , Ointments/administration & dosage , Staphylococcal Infections/drug therapy , Surgical Wound Infection/drug therapy , Vancomycin/administration & dosage , Administration, Topical , Brain Diseases/complications , Brain Diseases/surgery , Bucladesine/administration & dosage , Bucladesine/therapeutic use , Drug Administration Schedule , Female , Humans , Injections, Intravenous , Middle Aged , Postoperative Care , Postoperative Complications/drug therapy , Prosthesis-Related Infections/drug therapy , Prosthesis-Related Infections/etiology , Prosthesis-Related Infections/surgery , Time Factors , Transplantation, Autologous , Treatment Outcome , Vancomycin/pharmacokinetics , Vancomycin/therapeutic use
19.
Asian J Androl ; 5(2): 113-5, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12778321

ABSTRACT

AIM: To study the influences of dibutyryl cyclic adenosine monophosphate (dbcAMP) and forskolin on human sperm motility in vitro. METHODS: Semen samples, aseptically obtained by masturbation and prepared by swim-up technique from 20 fertile men, were incubated with different concentrations of dbcAMP and forskolin at 37 deg. Measurements were carried out after 10 min, 20 min, 30 min and 60 min incubation. Motility parameters were estimated by using an automatic analyzing system. RESULTS: Treatment with dbcAMP or forskolin resulted in a significant increase in sperm motility and progressive motility. The larger the concentrations of dbcAMP or forskolin, the greater the effect appeared. The straight linear velocity and curvilinear velocity were not affected by both agents. CONCLUSION: dbcAMP and forskolin increase the motility and progressive motility of human sperm in vitro.


Subject(s)
Bucladesine/pharmacology , Colforsin/pharmacology , Sperm Motility/drug effects , Adult , Bucladesine/administration & dosage , Colforsin/administration & dosage , Dose-Response Relationship, Drug , Humans , In Vitro Techniques , Male , Osmolar Concentration
20.
Br J Pharmacol ; 138(7): 1351-7, 2003 Apr.
Article in English | MEDLINE | ID: mdl-12711636

ABSTRACT

1. Nitric oxide has been described either as pronociceptive or antinociceptive. In this investigation, using an electronic pressure-metre, the intradermal and the subcutaneous effects of prostaglandin E(2) (PGE(2)) and agents that mimic or inhibit the arginine/NO/cGMP pathway were compared. 2. The hypernociceptive effect of the intradermal injection of PGE(2) (100 ng) was immediate, peaking within 15-30 min and returning to basal values in 45-60 min. The subcutaneous injection of PGE(2) induced a hypernociception with a delayed peak (3 h) plateauing for 4-6 h. 3. Intradermal administration of 3-morpholino-sydnonimine-hydrochloride (SIN-1) enhanced, while its subcutaneous administration inhibited, subcutaneous hypernociception induced by PGE(2). This inhibition was prevented by ODQ (8 micro g) but not by NG-monomethyl-L-arginine (L-NMMA) (50 micro g). 4. Intradermal but not subcutaneous administration of L-arginine (1-100 micro g), SIN-1 (1-100 micro g) and dibutyrylguanosine 3':5'-cyclic monophosphate (db cGMP) (0.1-100 micro g) induced an early (15-30 min) dose-dependent hypernociceptive effect. Intradermal pretreatment with NG-monomethyl-L-arginine (L-NMMA; 50 micro g) inhibited the hypernociception induced by L-Arg (10 micro g), but not that induced by SIN-1 (10 micro g) or db cGMP (10 micro g). 5. Intradermal injection of ODQ (8 micro g) antagonized the hypernociception induced by L-arginine and SIN-1, but not that induced by db cGMP. 6. Considering (a) the different time course of intradermal and subcutaneous PGE(2)-induced hypernociception, (b) the opposite nociceptive effect of intradermal and subcutaneous administration of SIN-1 (db cGMP) as well as the arginine/NO/cGMP pathway, the existence of different subsets of nociceptive primary sensory neurons in which the arginine/NO/cGMP pathway plays opposing roles is suggested. This hypothesis would explain the apparent contradictory observations described in the literature.


Subject(s)
Arginine/antagonists & inhibitors , Arginine/pharmacology , Cyclic GMP/administration & dosage , Dermis/physiopathology , Dinoprostone/administration & dosage , Hyperalgesia/chemically induced , Molsidomine/analogs & derivatives , Nociceptors/drug effects , Nociceptors/physiopathology , Pain Measurement/drug effects , Subcutaneous Tissue/physiopathology , Animals , Bucladesine/administration & dosage , Bucladesine/antagonists & inhibitors , Cyclic GMP/physiology , Dose-Response Relationship, Drug , Injections, Subcutaneous , Male , Molsidomine/administration & dosage , Molsidomine/antagonists & inhibitors , Nitric Oxide/physiology , Oxadiazoles/administration & dosage , Quinoxalines/administration & dosage , Rats , Rats, Wistar , Time Factors , omega-N-Methylarginine/administration & dosage
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