Effects of mycophenolate sodium on mucociliary clearance using a bronchial section and anastomosis rodent model

OBJECTIVE:

To study the effects of mycophenolate sodium on mucociliary clearance.

INTRODUCTION:

Mycophenolate is one of the most commonly used immunosuppressive drugs in lung transplantation. Although its pharmacokinetic properties are well defined, its side effects on mucociliary clearance have not yet been studied.

METHODS:

Sixty rats were subjected to left bronchial section and anastomosis. The right bronchus was used as a control. After surgery, the rats were assigned to two groups based on whether they received saline solution (n = 30) or mycophenolate sodium (n = 30). After 7, 15, or 30 days of treatment, 10 animals from each group were sacrificed, and in vitro mucus transportability, in situ mucociliary transport velocity and ciliary beat frequency were measured.

RESULTS:

The analysis of mucus transportability revealed that neither mycophenolate nor bronchial section altered any transportability related property for up to 30 days of treatment after surgery (p>0.05). With regard to ciliary beat frequency, the operated left bronchi from the mycophenolate group showed a significant decrease on post-surgical day 30 (p = 0.003). In addition, we found a significant reduction in the in situ mucociliary transport velocity in the mycophenolate-treated group (p = 0.0001).

DISCUSSION:

These data add important information regarding mucociliary clearance dysfunction following mycophenolate therapy and suggest that mycophenolate might contribute to the high incidence of respiratory tract infections in lung transplant patients. Further studies are needed to investigate the combined action of mycophenolate with other immunosuppressive drugs and to establish methods to protect and recover mucociliary clearance, an important airway defense mechanism.     

Protein fraction of Calotropis procera latex protects against 5-fluorouracil-induced oral mucositis associated with downregulation of pivotal pro-inflammatory mediators

Oral mucositis is an important dose-limiting and costly side effect of cancer chemotherapy. Soluble proteins obtained of the latex of Calotropis procera have been extensively characterized as anti-inflammatory in different experimentally induced inflammatory conditions, including arthritis and sepsis. In this study, the phytomodulatory laticifer proteins (LP) were challenged to regress the inflammatory events associated with 5-fluorouracil-induced oral mucositis. We also evaluated the expression of pro-inflammatory cytokines and inducible enzymes, such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Oral mucositis was induced in hamsters by two injections of 5-fluorouracil (5-FU; 60 and 40?mg/kg, i.p., on experimental days 1 and 2, respectively). LP (5?mg/kg, i.p.) was injected 24?h before and 24?h after mechanical trauma of the cheek pouches. A normal control group received only saline. On day 10, the animals were sacrificed, and the cheek pouches were excised for macroscopic and histopathological analysis, myeloperoxidase activity measurement, and immunohistochemical assessment of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), iNOS, and COX-2. LP significantly inhibited macroscopic histopathological scores and myeloperoxidase activity compared with the 5-FU control group. 5-Fluorouracil also induced marked immunostaining of TNF-α, IL-1β, iNOS, and COX-2 on inflamed conjunctive and epithelial tissue compared with the normal control group. Such damage was significantly inhibited (p?相似文献   

Feeding and reward: ontogenetic changes in an animal model of obesity

Given that food is a natural reinforcement, deficits in the reward system can lead to disordered eating behavior, inducing or worsening an already existing pre-obese phenotype. In order to evaluate developmental, food-reward-related measures we used the OLETF rat, an animal model of early-onset overeating-induced obesity, and a natural CCK-1 receptor knockout. Dopamine-like-receptor type 1 (D1R) and D2R levels were examined in a reward-related brain area (Nac shell) and sucrose preference was assessed at selected time points from weaning to adulthood (postnatal day [PND]90). In addition, a group of OLETF was pair fed (PF) to the amount of food consumed by same-age LETO controls (from weaning to PND 90) to examine the contribution of overweight to the alteration in DR expression. In addition, we examined food "craving"-like behavior by analyzing microstructural patterns of licking a palatable liquid diet. OLETF rats expressed significantly lower D2R levels than LETO controls only on PND 90. In PF OLETF, weight and D2R levels were normalized. In addition, OLETF presented exaggerated preference for the high sucrose concentration. After 30-day abstinence, OLETF rats presented significant increased initial rate of licking, suggesting food "craving". Thus, adult OLETF rats demonstrated altered D2R signaling similar to drug-induced sensitization, suggesting a link with their avidity for sucrose and their abnormal craving response. However, the current findings of a late deficit appearance and the novel PF results suggest that deficits in the motivation/regulatory systems of the OLETF rat are a developing process (at least from weaning and on) depending on the overeating and obese phenotype of the rats and not only on the CCK mutation.     

Modulation of fear/anxiety responses, but not food intake, following α-adrenoceptor agonist microinjections in the nucleus accumbens shell of free-feeding rats

This study investigated the effect of α-adrenoceptor agonists microinjected into the shell region of the accumbens nucleus (AcbSh) on feeding and anxiety-related behaviors in free-feeding rats. Male Wistar rats with a chronically implanted cannula into the AcbSh were unilaterally microinjected with either clonidine (CLON, α(2)-adrenoceptor agonist) or phenylephrine (PHEN, α(1)-adrenoceptor agonist) at the doses of 6 and 20 nmol and submitted to the elevated plus-maze (EPM), a pre-clinical test of anxiety. Immediately after the EPM test, the animals underwent food intake evaluation for 30 min. The data showed that rats microinjected with CLON (20 nmol/0.2 μl) into the AcbSh exhibited increased %Open arm time, which is compatible with an anxiolytic-like effect. The CLON-induced anxiolysis was corroborated by increased head-dipping and decreased stretched-attend posture, two ethologically derived behaviors which are fear/anxiety-motivated. The animal's locomotor activity was not changed by 20 nmol CLON microinjection into the AcbSh. However, neither dose of PHEN microinjected into the AcbSh was able to alter either the spatial-temporal or ethological variables representative of fear/anxiety and locomotion. Food intake was not altered by any dose of CLON and PHEN microinjected into the AcbSh, but the 20 nmol CLON microinjection induced increased motor activity in the feeding test. The data suggests that noradrenergic projections to the AcbSh may underlie fear/anxiety modulation through α(2)-adrenoceptor in the AcbSh, while feeding behavior was unaffected by noradrenergic modulation in the AcbSh of free-feeding rats. This article is part of a Special Issue entitled 'Anxiety and Depression'.     

Role of peripheral and spinal 5-HT2B receptors in formalin-induced nociception

In this study we assessed the role of local peripheral and spinal serotonin 2B (5-HT_2B) receptors in rats submitted to the formalin test. For this, local peripheral ipsilateral, but not contralateral, administration of the highly selective 5-HT_2B receptor antagonist 2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyridine (RS-127445, 0.01-1 nmol/paw) significantly prevented 1% formalin-induced flinching behavior. Moreover, local peripheral ipsilateral, but not contralateral, of the selective 5-HT₂ receptor agonist (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI, 1-10 nmol/paw) augmented 0.5% formalin-induced nociceptive behavior. The local pronociceptive effect of the 5-HT₂ receptor agonist DOI (10 nmol/paw) was significantly prevented by the local injection of RS-127445 (0.01 nmol/paw). Moreover, intrathecal injection of the selective 5-HT_2B receptor antagonist RS-127445 (0.1-10 nmol/rat) also prevented 1% formalin-induced nociceptive behavior. In contrast, spinal injection of the 5-HT₂ receptor agonist DOI (1-10 nmol/rat) significantly increased flinching behavior induced by 0.5% formalin. The spinal pronociceptive effect of the 5-HT₂ receptor agonist DOI (10 nmol/rat) was prevented by the intrathecal injection of the 5-HT_2B receptor antagonist RS-127445 (0.1 nmol/rat). Our results suggest that the 5-HT_2B receptors play a pronociceptive role in peripheral as well as spinal sites in the rat formalin test. 5-HT_2B receptors could be a target to develop analgesic drugs.     

In vitro antioxidant activity and in vivo antidepressant-like effect of α-(phenylselanyl) acetophenone in mice

In this study, the antioxidant and antidepressant-like effects of α-(phenylselanyl) acetophenone (PSAP), an organoselenium compound, were investigated. To assess the in vitro antioxidant properties, PSAP was evaluated in four test systems (DPPH, ABTS, FRAP and inhibition of lipid peroxidation). PSAP (100-500 μM) showed potent antioxidant activity and protected against lipid peroxidation. Additionally, we investigated whether PSAP, when administered in mice (100, 200 and 400 mg/kg, per oral, p.o.), could cause acute toxicity. Our results demonstrated that PSAP did not cause the death of any animal, significantly reduce body weight or cause any oxidative tissue stress following treatment. This study also evaluated the effect of PSAP (0.1-10 mg/kg, p.o) on mice in a forced swim test (FST) and tail suspension test (TST), assays that are predictive of depressant activity and motor activity in the open-field. PSAP (5-10 mg/kg) significantly reduced immobility time in the FST and TST without affecting motor activity. In addition, the antidepressant-like effect caused by PSAP (5 m/kg, p.o) in mice during the TST was dependent on an interaction with the serotonergic system (5-HT_1A receptors), but not with the noradrenergic, dopaminergic or adenosinergic system. Together, these results suggest that PSAP possesses antioxidant and antidepressant-like properties and may be of interest as a therapeutic agent for the treatment of depressive disorders.     

Toluene impairs learning and memory, has antinociceptive effects, and modifies histone acetylation in the dentate gyrus of adolescent and adult rats

Toluene misuse usually initiates at an early age when the central nervous system is still immature, causing deleterious effects such as cognitive impairment. Epigenetic regulatory mechanisms have been proposed to explain long-term changes involved not only in memory, but also in toluene's actions. The aim of this study was to evaluate the effects of acute and chronic toluene exposure on learning, memory and histone acetylation in the rat hippocampus during two stages of life: adolescence and young adulthood. Because the memory tests used in this work involved object exploration and the perception of a noxious stimulus, general activity and nociception tests were also conducted. Acute and chronic toluene inhalation impaired learning, short-term and long-term memory in an object-recognition test and in an inhibitory avoidance task in both groups of age. This effect was concentration-dependent and occurred even at low toluene concentrations (1000, 2000 ppm) that were otherwise non-effective. Acute toluene inhalation produced antinociception, and tolerance to this effect developed after chronic exposure. Histone acetylation in the dentate gyrus showed differences depending on the histone, treatment and age: a single toluene exposure increased H4 acetylation in adolescents and young adult rats, whereas chronic exposure decreased H3 acetylation, but only in adults. In conclusion, this work provides evidence of toluene-induced impairment on learning, short- and long-term memory in adolescent and young adult rats, and shows that even a single toluene exposure can induce epigenetic modifications in the rat hippocampus.     

Role of peripheral and spinal 5-HT(3) receptors in development and maintenance of formalin-induced long-term secondary allodynia and hyperalgesia

The role of peripheral and spinal 5-HT₃ receptors in formalin-induced secondary allodynia and hyperalgesia in rats was assessed. Formalin produced acute nociceptive behaviors (flinching and licking/lifting) followed by long-term secondary mechanical allodynia and hyperalgesia in both paws. In experiments where the test drug was anticipated to augment or antagonize the response, 0.5 or 1% formalin, respectively, was used for injection. Peripheral ipsilateral, but not contralateral, pre-treatment (− 10 min) with serotonin (5-HT, 10-100 nmol/paw) and the selective 5-HT₃ receptor agonist 1-(m-chlorophenyl)-biguanide (m-CPBG, 10-300 nmol/paw) increased 0.5% formalin-induced secondary allodynia and hyperalgesia in both paws. Moreover, spinal pre-treatment with m-CPBG (10-300 nmol/rat) increased 0.5% formalin-induced secondary hyperalgesia but not allodynia in both paws. Accordingly, peripheral ipsilateral (30-300 nmol/paw), but not contralateral (300 nmol/paw), and spinal (10-100 nmol) pre-treatment with the selective 5-HT₃ receptor antagonist ondansetron prevented 1% formalin-induced secondary mechanical allodynia and hyperalgesia in both paws. The peripheral pronociceptive effects of 5-HT (100 nmol/paw) and m-CPBG (300 nmol/paw) as well as the spinal effect of m-CPBG (300 nmol/rat) were completely prevented by the peripheral (10 nmol/paw) and spinal (1 nmol/rat) injection, respectively, of ondansetron. At these doses, ondansetron did not modify per se formalin-induced nociceptive behaviors. Spinal (30-300 nmol/rat), but not peripheral (300 nmol/paw), post-treatment (on day 6) with ondansetron reversed established formalin-induced secondary mechanical allodynia and hyperalgesia in both paws. Results suggest that a barrage of afferent input induced by 5-HT at peripheral 5-HT₃ receptors participates in the development of formalin-induced long-term secondary allodynia and hyperalgesia in the rat. In addition, our data suggest that spinal 5-HT₃ receptors play an important role during development and maintenance of these evoked long-term behaviors.     

Sarin causes autonomic imbalance and cardiomyopathy: an important issue for military and civilian health

Sarin, a lethal chemical nerve agent, may be a causative factor in multifactorial syndrome implicated in the Gulf War and Tokyo terrorist attacks. Although a high dose results in seizure and death, low-dose exposure may lead to autonomic imbalance and chronic cardiac pathologies. In this study, echocardiography and electrocardiography were used to examine the late-onset effects of a low-dose sarin on cardiac structure and function in mice. Adrenal corticosterone and tyrosine hydroxylase mRNA levels were measured. Stress responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis was also tested. Findings demonstrate changes consistent with a dilated cardiomyopathy, including left ventricular dilatation, reduced contractility, and altered electrophysiological and inotropic responses to β-adrenergic stimulation. Results also indicate reduced adrenal tyrosine hydroxylase mRNA, corticosterone and altered stress responsiveness of HPA indicating autonomic imbalance. The role of low-dose sarin/organophosphate exposure needs to be considered in the military and civilian populations that suffer from autonomic imbalance and/or cardiomyopathies of indeterminate origin.     

Anti-inflammatory effect of α,β-amyrin, a triterpene from Protium heptaphyllum, on cerulein-induced acute pancreatitis in mice

Objective  

To evaluate the anti-inflammatory effect of α,β-amyrin, a pentacyclic triterpenoid from Protium heptaphyllum, on cerulein-induced acute pancreatitis in mice.