Efficacy of parthenolide on lung histopathology in a murine model of asthma.

BACKGROUND: Parthenolide is the active constituent of the plant 'Tanacetum parthenium' (Feverfew) which has been used for centuries as a folk remedy for inflammatory conditions. AIM OF THE STUDY: In this study we aimed to investigate the effects of parthenolide in a murine model of chronic asthma. MATERIALS AND METHODS: Thirty-five BALB/c mice were divided into five groups; I (control), II (placebo), III (dexamethasone), IV (parthenolide) and V (dexamethasone and parthenolide combination). Lung histology was evaluated after treatment with the study drugs. Levels of interleukin (IL)-4 and IL-5 were determined by ELISA. RESULTS: Histologic parameters except the number of mast and goblet cells improved in the parthenolide group when compared with placebo. All parameters except basal membrane thickness and number of mast cells were improved significantly better in the group receiving dexamethasone when compared with the parthenolide group. Improvement of most of the histologic parameters was similar in Groups III and V. Interleukin-4 levels were significantly reduced in the parthenolide group when compared to the placebo group. CONCLUSION: We demonstrated that parthenolide administration alleviated some of the pathological changes in asthma. But parthenolide alone is not efficient as dexamethasone therapy and the parthenolide and dexamethasone combination also did not add any beneficial effect to the dexamethasone treatment.

The protective effects of carnosine in alcohol-induced hepatic injury in rats.

Consumption of alcohol leads to oxidative stress in liver by inducing lipid peroxidation. The aim of this study was to investigate the effects of carnosine (CAR) in alcohol-induced liver injury by biochemical and histomorphological evaluations. The rats were divided into four groups, namely, control group, alcohol (AL) group, CAR group and AL + CAR group. Three doses of ethanol (5 g/kg, 25% (v/v) in distilled water) were given by nasogastric catheter for twice-a-day. CAR (100 mg/kg) was given 1 h before the administration of ethanol using the same method. Levels of alanine aminotransferase, aspartate aminotransferase, myeloperoxidase and malondialdehyde were significantly increased in the AL group compared with control, CAR and AL + CAR groups. Glutathione level was significantly decreased in the AL group, while it was increased in the AL + CAR group. Immunoreactivity of caspase-3 and bax increased in the hepatocytes of AL group when compared with control and AL + CAR groups. Expression of bcl-2 was decreased in AL group than AL + CAR group. Under electron microscopy, dense mitochondria, accumulation of lipid, sinusoidal dilatation, vacuolization and decrease in the number of microvilli were observed in AL group, while these findings were markedly less in the AL + CAR group. In conclusion, pretreatment of CAR is effective for recovering biochemical alterations and morphologic damage in the liver of rats treated with ethanol.

Topiramate and darbepoetin alpha ameliorate bilirubin-induced neuronal cell damage.

OBJECTIVE: The aim of this study was to determine whether prophylactic darbepoetin alpha and/or topiramate administration could prevent bilirubin neurotoxicity (BNTx) in experimental model of kernicterus. MATERIALS AND METHODS: A total of 60 Wistar albino rat puppies with experimental kernicterus model were included in the study. The Kernicterus was established administering a bilirubin injection via a cisterna magna puncture 30 minutes after ip drug injection. The puppies were divided into five groups with 12 in each group as shown below: a control group, bilirubin group, darbepoetin alpha group, topiramate group and darbepoetin alpha+ topiramate group. Darbepoetin alpha and/or topiramate were administered on day 5 intraperitoneally (ip). At the 6th and 24th hours, bilirubin induced neurological dysfunction (BIND) score was used to assess behavioral changes. Hearing functions were evaluated on days 10 and 28. On day 30, the Water Maze water tank test was implemented to evaluate spatial memory. The rats were sacrificed on days 6 and 34 and apoptosis in the globus pallidus and hippocampus was examined. RESULTS: The BIND score was improved following darbepoetin alpha treatment. Neither darbepoetin alpha nor topiramate therapy ameliorate spatial memory. There were no significant differences between groups in terms of the auditory brainstem response (ABR). The combined use of darbepoetin alpha and topiramate lead to slight decrease in apoptosis. CONCLUSIONS: Darbepoetin alpha or topiramate administration ameliorates bilirubin induced neurological dysfunction in experimental model of kernicterus.

Dose dependent effects of oxytocin on cognitive defects and anxiety disorders in adult rats following acute infantile maternal deprivation stress.

Maternal deprivation at an early age is a powerful stressor that causes permanent alterations in cognitive and behavioral functions during the later stages of life. We investigated the effects of oxytocin on cognitive defects and anxiety disorders caused by acute infantile maternal deprivation in adult rats. We used 18-day-old Wistar albino rats of both sexes. The experimental groups included control (C), maternally deprived (MD), maternally deprived and treated with 0.02 µg/kg oxytocin (MD-0.02 µg/kg oxy), maternally deprived and treated with 2 µg/kg oxytocin (MD-2 µg/kg oxy). When the rats were 60 days old, the open field (OF) and elevated plus maze (EPM) behavioral tests, and the Morris water maze (MWM) test for spatial learning and memory were performed. In addition, the number of neurons in the hippocampus, prefrontal cortex (PFC) and amygdala were determined using quantitative histology. We also measured vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) levels in the PFC. In both sexes, the MD group failed the learning test and the MD-2 µg/kg oxy group failed in the memory test. The MD-0.02 µg/kg oxy group spent more time in the open arm of the EPM device and their locomotor activities were greater in the OF test. The VEGF and BDNF levels in the PFC were higher in the MD-0.02 µg/kg oxy groups than the other maternally deprived groups (oxytocin ±). The number of PFC neurons was low in all male maternally deprived (oxytocin ±) groups, while the number of amygdala neurons was low in both female and male maternally deprived (oxytocin ±) groups. Male rats were more affected by maternal deprivation; administration of oxytocin had dose-dependent biphasic effects on learning, memory and anxiety.

Protective effects of taurine against renal ischemia/reperfusion injury in rats by inhibition of gelatinases, MMP-2 and MMP-9, and p38 mitogen-activated protein kinase signaling.

Dysregulated expression of matrix metalloproteinases (MMPs) is closely associated with the pathogenesis of renal ischemia/reperfusion injury (I/R). The production of excessive reactive oxygen species (ROS) causes tissue damage. Increased ROS production causes activation of p38 mitogen-activated protein kinase (MAPK) signaling, which participates in gene regulation of MMPs, especially MMP-2 and MMP-9 (gelatinases). Taurine (2-aminoethanesulfonic acid) in mammalian cells functions in bile acid conjugation, maintenance of calcium homeostasis, osmoregulation, membrane stabilization, and antioxidation, antiinflammatory, and antiapoptotic action. We investigated the effects of taurine and the possible role of p38 MAPK signaling on regulation of MMP-2 and MMP-9 in a renal I/R injury model in rats. Rats were divided into three groups: sham, I/R, and I/R + taurine treated. After a right nephrectomy, I/R was induced by clamping the left renal pedicle for 1 h followed by 6 h reperfusion. Taurine was administered 45 min prior to induction of ischemia. Renal function was assessed by serum creatinine and blood urea nitrogen (BUN) levels. Tubule injury and structural changes were evaluated by light microscopy. Malondialdehyde (MDA) levels were analyzed by high performance liquid chromatography (HPLC). Superoxide dismutase (SOD) activity levels were measured using a colorimetric kit. mRNA expression of MMP-2 and MMP-9 was determined by real-time polymerase chain reaction. MMP-2 and MMP-9 activities were measured using a fluorimetric kit. Phosphorylated p38 (p-p38) and total p38 MAPK protein expressions were evaluated by western blot. Taurine pretreatment significantly attenuated renal dysfunction and histologic damage, such as renal tubule dilation and loss of brush borders. The pretreatment also decreased the MDA level and attenuated the reduction of SOD activity in the kidney during I/R. Taurine pretreatment also decreased significantly both MMP-2 and MMP-9 mRNA expression and MMP-9 activity induced by I/R. In addition, the activity of p38 MAPK signaling was down-regulated significantly by taurine administration. Inhibition of MMP-2 and MMP-9 expression and MMP-9 activity caused by taurine may be associated with suppression of p38 MAPK activation during I/R induced renal injury in rats. Therefore, taurine administration may prove to be a strategy for attenuating renal I/R injury.

The effects of α-lipoic acid on immature rats with traumatic brain injury.

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality during childhood. TBI enhances formation of reactive oxygen species that cause neuron damage and apoptosis. α-Lipoic acid (LA) is a free radical scavenger and biological antioxidant. We investigated the effects of LA treatment on the parietal and prefrontal cortex, and on the hippocampal regions of the brain in 7-day-old rat pups that had been subjected to contusion injury. Forty-two male rats were divided randomly into a control group, a TBI group and a TBI + LA treated group. LA was administered 30 min after TBI through an intragastric tube once daily for 2 days. Forty-eight hours after TBI, the animals were sacrificed and tissues were examined for apoptosis and density of neurons. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) and active caspase-3 immunostaining were used to detect apoptosis. Glutathione peroxidase (GPx), superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels also were measured. Histological evaluation showed that LA treatment significantly reduced TBI-induced neuronal death in the hippocampus, prefrontal and parietal cortex; TUNEL- and caspase-3-positive cells also were decreased in the same regions. In addition, LA administration increased GPx and SOD activity in the prefrontal cortex. It appears that LA may be beneficial for TBI in rats.

The effects of alpha-lipoic acid on MMP-2 and MMP-9 activities in a rat renal ischemia and re-perfusion model.

Matrix metalloproteinases (MMPs) are enzymes that are responsible for degradation of extracellular matrix (ECM); they are involved in the pathogenesis of ischemia-re-perfusion (I-R) injury. We investigated the possible preventive effect of alpha-lipoic acid (LA) in a renal I-R injury model in rats by assessing its reducing effect on the expression and activation of MMP-2 and MMP-9 induced by I-R. Rats were assigned to four groups: control, sham-operated, I-R (saline, i.p.) and I-R+ LA (100 mg/kg, i.p.). After a right nephrectomy, I-R was induced by clamping the left renal pedicle for 1 h, followed by 6 h re-perfusion. In the sham group, a right nephrectomy was performed and left renal pedicles were dissected without clamping and the entire left kidney was excised after 6 h. LA pretreatment was started 30 min prior to induction of ischemia. Injury to tubules was evaluated using light and electron microscopy. The expressions of MMP-2 and MMP-9 were determined by immunohistochemistry and their activities were analyzed by gelatin zymography. Serum creatinine was measured using a quantitative kit based on the Jaffe colorimetric technique. Malondialdehyde (MDA) and glutathione (GSH) were analyzed using high performance liquid chromatography. Tissue inhibitor of metalloproteinase (TIMP)-2 and TIMP-1 were assessed using enzyme-linked immunosorbent assay (ELISA). I-R caused tubular dilatation and brush border loss. LA decreased both renal dysfunction and abnormal levels of MDA and GSH during I-R. Moreover, LA decreased significantly both MMP-2 and MMP-9 expressions and activations during I-R. TIMP-1 and TIMP-2 levels were increased significantly by LA administration. LA modulated increased MMP-2 and MMP-9 activities and decreased TIMP-1 and TIMP-2 levels during renal I-R.

Age-related changes in apoptosis in rat hippocampus induced by oxidative stress.

Also known as programmed cell death, apoptosis is a sequence of events that leads to elimination of cells without releasing harmful substances into the surrounding area. Apoptosis may be induced by intracellular or extracellular signals. Certain apoptotic signals activate mitochondrial pro-apoptotic events and increase reactive oxygen species (ROS). Increased ROS production may lead to oxidative stress. The goal of our study was to characterize age-related changes in apoptosis induced by oxidative stress in the hippocampus. Rats 2, 7, 21 and 38 days old, and adult rats were used for our study. Hippocampal CA1, CA2, CA3 and dentate gyrus apoptosis, and hippocampal superoxide dismutase (SOD), glutathione peroxidase (GPx) enzyme activities and thiobarbituric acid reactive substances (TBARS) levels were measured. We found that numbers of hippocampal neurons were low in rats 2, 7 and 21 days old (CA1, p < 0.001; CA3, p < 0.05; gyrus dentatus, p < 0.001). The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) positive cell count was highest in the CA1 and dentate gyrus of 21-day-old rats. Among 21-day-old rats, the hippocampal TBARS levels and SOD enzyme activity were high, whereas GPx activity was low. These results demonstrate that the hippocampal CA1 and dentate gyrus of 21-day-old rats are more prone to damage by oxidative stress.