NE-100, a novel sigma receptor ligand: In vivo tests

It has been suggested that sigma receptor antagonists may be useful as antipsychotic drugs. N, N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE-100) is a novel compound with high affinity for the sigma receptor (IC50 = 4.16 nM), but low affinity (IC50 > 1000 nM) for D1, D2, 5-HT1A, 5-HT2 and phencyclidine (PCP) receptors. The head-weaving behavior induced by either (+)SKF10047 or PCP was dose-dependently antagonized by NE-100 with oral ED50 at 0.27 and 0.12 mg/kg, respectively. NE-100 did not affect dopamine agonists-induced stereotyped behavior and/or hyperactivity. NE-100 failed to induce catalepsy in rats. These findings indicate that NE-100 may have antipsychotic activity without the liability of motor side effects typical of neuroleptics.     

Increasing P(50) does not improve DO(2CRIT) or systemic VO(2) in severe anemia

Reducing the hemolobin (Hb)-O(2) binding affinity facilitates O(2) unloading from Hb, potentially increasing tissue mitochondrial O(2) availability. We hypothesized that a reduction of Hb-O(2) affinity would increase O(2) extraction when tissues are O(2) supply dependent, reducing the threshold of critical O(2) delivery (DO(2 CRIT)). We investigated the effects of increased O(2) tension at which Hb is 50% saturated (P(50)) on systemic O(2) uptake (VO(2) (SYS)), DO(2 CRIT), lactate production, and acid-base balance during isovolemic hemodilution in conscious rats. After infusion of RSR13, an allosteric modifier of Hb, P(50) increased from 36.6 +/- 0.3 to 48.3 +/- 0.6 but remained unchanged at 35.4 +/- 0.8 mmHg after saline (control, CON). Arterial O(2) saturations were equivalent between RSR13 and saline groups, but venous PO(2) was higher and venous O(2) saturation was lower after RSR13. Convective O(2) delivery progressively declined during hemodilution reaching the DO(2 CRIT) at 3.4 +/- 0.8 ml x min(-1) x 100 g(-1) (CON) and 3.6 +/- 0.6 ml x min(-1) x 100 g(-1) (RSR13). At Hb of 8.1 g/l VO(2) (SYS) started to decrease (CON: 1.9 +/- 0.1; RSR13: 1.8 +/- 0.2 ml x min(-1) x 100 g(-1)) and fell to 0.8 +/- 0.2 (CON) and 0.7 +/- 0.2 ml x min(-1). 100 g(-1) (RSR13). Arterial lactate was lower in RSR13-treated than in control animals when animals were O(2) supply dependent. The decrease in base excess, arterial pH, and bicarbonate during O(2) supply dependence was significantly less after RSR13 than after saline. These findings demonstrate that during O(2) supply dependence caused by severe anemia, reducing Hb-O(2) binding affinity does not affect VO(2) (SYS) or DO(2 CRIT) but appears to have beneficial effects on oxidative metabolism and acid base balance.     

Developmental toxicity of temafloxacin hydrochloride in the long-tailed macaque (Macaca fascicularis)

The potential developmental toxicity of temafloxacin hydrochloride was studied in the long-tailed macaque (Macaca fascicularis). Ten animals in each of the three drug-treated groups (25, 50, and 100 mg/kg) were administered temafloxacin via nasogastric intubation during gestational days (GD) 20-50. A control group of ten animals received vehicle only. The dams were monitored daily for adverse physical signs and maternal blood samples were collected for analyses of serum progesterone (P), 17 beta-estradiol (E2), and chorionic gonadotropin (CG). In addition, the conceptus was monitored periodically by ultrasound during gestation to confirm growth and viability. Increased maternal toxicity (weight loss, anorexia, emesis) and embryolethality were observed at 100 mg/kg, and a no-observable-adverse-effect-level (NOAEL) of 50 mg/kg was established. The incidence of prenatal mortality was as follows: Control = 1/10 (10%); 25 mg/kg = 1/10 (10%); 50 mg/kg = 2/10 (20%); and 100 mg/kg = 5/10 (50%). Analysis of P, E2, and CG indicated no significant effect of treatment. In addition, no significant differences were observed in embryonic/fetal growth and development when compared to historical controls. No gross structural changes were observed in fetuses exposed to 50 or 100 mg/kg, although one fetus exposed to 25 mg/kg exhibited microphthalmia. This anomaly was considered spontaneous and, therefore, unrelated to treatment.     

Regulation of the mouse aggressive behavior (pharmacologic analysis of the GABAergic mechanism)

Ethological procedures were used to study the effects of GABA-positive drugs on aggression in male albino mice kept in isolation (opponent test). The results revealed several variants of antiaggressive effects of the tested GAB Aergic drugs: 1) antiaggressive, re-socializing of GABAA agonists muscimol (0.125 and 0.5 mg/kg) and THIP (2.0 mg/kg), and GABAB agonist baclofen (2.5-10 mg/kg); 2) antiaggressive, sedative of GABAB agonists baclofen (12.5 mg/kg), phenibut (50-100 mg/kg), and inhibitor of GABA transamininase sodium valproate (100 mg/kg); 3) antiaggressive, anxiogenic for muscimol (1 mg/kg), THIP (5 mg/kg), and sodium valproate (25-50 mg/kg).     

VE和L-肌肽对大菱鲆幼鱼生长、抗氧化、非特异性免疫及血清生化指标的影响

实验以大菱鲆（Scophthalmus maximus）幼鱼[（14.00±0.02）g]为研究对象,采用2×4双因素设计,设2个VE水平（0和75 mg/kg）和4个L-肌肽水平（0、50、100和200 mg/kg）,研究VE和L-肌肽对其生长、抗氧化、非特异性免疫及血清生化指标的影响。实验共分8组,每组3个重复,每个重复46尾鱼,实验周期为8周。结果显示:（1）在饲料中添加75 mg/kg VE显著提高了大菱鲆幼鱼增重率（WGR）和特定生长率（SGR）（P < 0.05）,L-肌肽添加量≤100 mg/kg对实验鱼生长性能无显著影响（P>0.05）,添加量为200 mg/kg时鱼体WGR、SGR和蛋白质效率（PER）显著降低,饲料系数（FCR）显著升高（P < 0.05）;（2）VE和L-肌肽对血清谷胱甘肽过氧化物酶（GSH-PX）、过氧化氢酶（CAT）活性和丙二醛（MDA）含量及肝脏总抗氧化能力（T-AOC）、超氧化物歧化酶（SOD）活性和MDA含量均具有显著的交互作用（P < 0.05）,在VE 75 mg/kg水平下,L-肌肽添加量为50和100 mg/kg时血清GSH-PX活性最高,L-肌肽添加量为100和200 mg/kg时血清CAT活性最高且与添加量为50 mg/kg差异不显著（P>0.05）,添加100 mg/kg肝脏T-AOC和SOD活性达到最高且50 mg/kg组的SOD与100 mg/kg组差异不显著（P>0.05）,主效应结果显示,VE显著提高了血清T-AOC、SOD及肝脏CAT活性（P < 0.05）,L-肌肽显著提高了血清T-AOC（P < 0.05）;（3）VE和L-肌肽对血清补体C3和LZM活性交互作用显著,在75 mg/kg VE水平下,L-肌肽添加量为50 mg/kg时,补体C3水平最高（P < 0.05）,主效应显示,VE和L-肌肽对血清总蛋白（TP）影响均不显著（P>0.05）;（4）添加VE显著降低了血清总胆固醇（TCHO）和甘油三酯（TG）含量（P < 0.05）,添加L-肌肽显著降低了血清TG含量,且在L-肌肽50 mg/kg时达到最低。综合考虑大菱鲆幼鱼[（14.00-39.43）g]的生长性能、抗氧化性能、非特异性免疫及血清生化指标得出,在实验配方条件下（鱼油70 g/kg,大豆卵磷脂10 g/kg）,添加VE 75 mg/kg时,L-肌肽的适宜添加量为50 mg/kg。     

Effect of recombinant SP-C surfactant in a porcine lavage model of acute lung injury.

Synthetic surfactants allow examination of the effects of specific components of natural surfactant. To determine whether surfactant containing apoprotein C, dipalmitoyl-phosphatidylcholine, phosphatidylglycerol, and palmitic acid restores gas-exchanging function in acute lung injury (ALI), we administered such surfactant (in doses of 50 or 100 mg/kg and in volumes from 1 to 6 ml/kg) or phospholipid (PL) alone, by intratracheal instillation, to pigs with ALI induced by massive saline lavage. Animals ventilated with 100% O(2) and receiving 1, 2, 4, or 6 ml/kg of 50 mg/kg recombinant surfactant apoprotein C (rSP-C) surfactant or 2 ml/kg of 50 mg/kg PL (control) had mean arterial PO(2) values, 4 h after treatment, of 230, 332, 130, 142, or 86 Torr, respectively. Animals receiving 1, 2, or 4 ml/kg of 100 mg/kg rSP-C surfactant or 2 ml/kg of 100 mg/kg PL (control) had mean arterial PO(2) values of 197, 214, 148, or 88 Torr, respectively. Surfactant PL distribution was homogeneous. Hyaline membrane formation was reduced in treated animals. Thus, in this model of ALI, rSP-C with PL has the capacity to improve gas exchange and possibly modify lung injury.     

Antagonism of peptidoleukotrienes and inhibition of systemic anaphylaxis by RG 12525 in guinea pigs

RG 12525 was determined to be a specific, competitive and orally effective antagonist of the peptidoleukotrienes, LTC4, LTD4 and LTE4, in several assays utilizing guinea pigs. In vitro, RG 12525 competitively inhibited 3H-LTD4 binding to lung membranes (Ki = 3.0 +/- 0.3 nM) and competitively antagonized the spasmogenic activity of LTC4, LTD4 and LTE4 on lung strips (KB values = 3 nM) with greater than 8000 fold selectivity. In vivo, RG 12525 orally inhibited LTD4 induced wheal formation (ED50 = 5 mg/kg with a t1/2 = 10 hrs at 9 mg/kg), LTD4 induced bronchoconstriction (ED50 = 0.6 mg/kg), and anaphylactic death (ED50 = 2.2 mg/kg with a t1/2 = 7 hrs at 10 mg/kg) and antigen induced bronchoconstriction (ED50 = 0.6 mg/kg). RG 12525 represents a significant improvement in receptor affinity and oral efficacy and thus, is a valuable pharmacological tool to evaluate peptidoleukotrienes in allergic diseases.     

D2-dopamine receptor and alpha2-adrenoreceptor-mediated analgesic response of quercetin

Quercetin, a bioflavonoid (100-300 mg/kg) produced dose dependent increase in tail-flick latency, the analgesic effect being sensitive to reversal by naloxone (1 mg/kg). Prior treatment with haloperidol (1 mg/kg), D1/D2 receptor antagonist haloperidol, sulpiride (50 mg/kg), a selective D2 receptor antagonist, yohimbine (5 mg/kg), a alpha2-adrenoreceptor antagonist but not by SCH 23390 a, selective D1 receptor antagonist blocked this response. Apomorphine (1 mg/kg) a mixed D1/D2 dopamine receptor agonist, and quinpirole (0.5 mg/kg), a selective D2 receptor agonist also produced antinociception, that was reversed by haloperidol (1 mg/kg), sulpiride (50 mg/kg), but not by yohimbine (5 mg/kg). The antinociceptive action of quercetin (200 mg/kg) was potentiated by D2 agonist quinpirole (0.2 mg/kg). Dopamine D1 receptor agonist SKF38393 (10 and 15 mg/kg) failed to alter the antinociceptive effect of quercetin (200 mg/kg). Quercetin (200 mg/kg) reversed reserpine (2 mg/kg-4 hr) induced hyperalgesia, which was reversed by sulpiride but not by yohimbine. Thus, a role of dopamine D2 and alpha2-adrenoreceptors is postulated in the antinociceptive action of quercetin.     

Pronounced influence of Hb-O2 saturation on red cell pH in tench blood in vivo and in vitro

At an extracellular pH of 7.9 the red cell pH in tench blood exhibits a nonlinear, strongly inverse relationship with Hb-O2 saturation, both when investigated in vitro and in vivo (in fish exposed to acid water with and without aluminium). The pHi difference between deoxygenated and oxygenated erythrocytes is large (i.e., 0.35 pH units), which can be accounted for by the Haldane effect and the buffering properties of the blood. The major shift in pHi occurs between 50 and 100% Hb-O2 saturation, indicating an almost full exploitation of the Haldane effect within the normal physiological range of blood O2 saturations.     

Control and consequences of adrenergic activation of red blood cell Na+/H+ exchange on blood oxygen and carbon dioxide transport in fish.

The catecholamines, adrenaline and noradrenaline, are released into the circulation of fish during a variety of physical and environmental disturbances that share the common feature of a requirement for enhanced blood oxygen transport. Indeed, the dominant factor controlling the mobilization of catecholamines from chromaffin tissue is a depression of blood oxygen content usually coinciding with a reduction of hemoglobin-O2 (Hb-O2) binding to 50-60% saturation. The elevation of plasma catecholamine levels, under such conditions, activates a beta-adrenergic cyclic AMP-dependent Na+/H+ exchanger on the red blood cell (rbc) membrane. The adrenergic responsiveness AMP-dependent Na+/H+ exchanger on the red blood cell (rbc) membrane. The adrenergic responsiveness of the rbc Na+/H+ exchanger to catecholamines varies both within and between species. Such inter- and intra-specific differences may reflect, in part, the availability of cell surface beta-adrenoceptors that are functionally coupled to adenylate cyclase. The activation of rbc Na+/H+ exchange and the accompanying profound adjustments of intracellular and extracellular acid-base status, nucleoside triphosphate (NTP) levels, and cooperativity of Hb-O2 binding have important consequences on both O2 and CO2 transfer and transport in the blood that vary markedly at the sites of oxygenation (the gill) and deoxygenation (the tissues) thereby enabling simultaneous amelioration of O2 loading and unloading. At the gill, oxygen transfer is enhanced owing to increases in Hb-O2 affinity and capacity while at the tissues, oxygen delivery is facilitated by a reduction of Hb-O2 affinity. This reduction in affinity at the tissues is a consequence of the combined effects of increased cooperativity of Hb-O2 binding and a rise in venous PCO2 (PvCO2) caused by the titration of HCO3- by H+ extruded by the rbc Na+/H+ exchanger. This elevation of PvCO2 may contribute to the rise in arterial PCO2 (PaCO2) observed after adrenergic activation of rbc Na+/H+ exchange that is caused primarily by impairment of rbc CO2 excretion related to modification of the intracellular acid-base status.     

Effects of escins Ia, Ib, IIa, and IIb from horse chestnuts on gastrointestinal transit and ileus in mice.

The effects of saponin fraction and its principal constituents escins Ia (1), Ib (2), IIa (3), and IIb (4) from horse chestnuts on gastrointestinal transit (GIT) and ileus were investigated in mice. Ileus was induced by acetic acid peritoneal irritation or by laparotomy with manipulation. One hour after the oral administration, the saponin fraction (12.5-100 mg/kg) and 14 (12.5-50 mg/ kg, except for 3 at 12.5 mg/kg) dose-dependently accelerated GIT. The optimal effects of the saponin fraction (25 mg/kg) occurred 5-240 min (applied intervals between the fraction and the charcoal meal) after the oral administration. The fraction (12.5-100 mg/ kg) and 1-4 (12.5-50 mg/kg, except for 1 and 2 at 12.5 mg/kg) dose-dependently prevented the inhibition of GIT induced by the acetic acid peritoneal irritation. They (12.5-100mg/kg) also dose-dependently prevented the inhibition of GIT induced by the laparotomy with manipulation. Desacylescins I (5) and II (6) (50 mg/kg) showed no such effects. These results demonstrated that the saponin fraction and 1-4 accelerated GIT and prevented the experimental ileus, and indicate that the 21, 22-acyl groups are essential for the accelerative effects of 1-4. The accelerations of GIT by 1-4 were completely abolished by the pretreatment with streptozotocin (100 mg/kg, iv), but not by the pretreatment with capsaicin (75 mg/kg in total, sc) or atropine (10 mg/kg, sc). These results imply that the sympathetic nervous system may be, but neither capsaicin-sensitive sensory nerves nor the cholinergic mechanism, involved in the accelerations of GIT by escins 1-4.     

Role of benzodiazepine-GABAA receptor complex in attenuation of U-50,488H-induced analgesia and inhibition of tolerance to its analgesia by ginseng total saponin in mice

In the present study, the role of benzodiazepine-GABAA receptor complex in the attenuation of U-50,488H (U50), a selective kappa opioid agonist-induced analgesia and inhibition of tolerance to its analgesia by ginseng total saponin (GTS) was investigated using the mice tail-flick test. The intraperitoneal (i.p.) treatment of GTS (100 and 200 mg/kg) and diazepam (0.1-1 mg/kg) dose-dependently attenuated the U50 (40 mg/kg, i.p.)-induced analgesia. GTS (0.001-10 microg/ml) did not alter binding of [3H]naloxone to mice whole brain membrane. The attenuation effect of GTS (100 mg/ kg) and diazepam (0.5 mg/kg) on U50-induced analgesia was blocked by flumazenil (0.1 mg/kg, i.p.), a benzodiazepine receptor antagonist, and picrotoxin (1 mg/kg, i.p.), a GABAA-gated chloride channel blocker. However, bicuculline (1 mg/kg, i.p.), a GABAA receptor antagonist blocked the attenuation effect of diazepam (0.5 mg/kg) but not GTS (100 mg/kg) on U50-induced analgesia. Chronic treatment (day 4-day 6) of GTS (50-200 mg/kg) and diazepam (0.1-1 mg/kg) dose-dependently inhibited the tolerance to U50-induced analgesia. Flumazenil (0.1 mg/kg) and picrotoxin (1 mg/kg) on chronic treatment blocked the inhibitory effect of GTS (100 mg/kg) and diazepam (0.5 mg/kg) on tolerance to U50-induced analgesia. On the other hand, chronic treatment of bicuculline (1 mg/kg) blocked the inhibitory effect of diazepam (0.5 mg/kg) but not GTS (100 mg/kg) on tolerance to U50-induced analgesia. In conclusion, the findings suggest that GTS attenuates U50-induced analgesia and inhibits tolerance to its analgesia and this action involves benzodiazepine receptors and GABAA-gated chloride channels.     

Anthelmintic profile of methyl 5(6)-(4-methylpiperidin-1-yl) carbonylbenzimidazole-2-carbamate in experimental helminthiases

Biological evaluation of methyl 5(6)-(4-methylpiperidin-1-yl) carbonylbenzimidazole-2-carbamate against Ancylostoma ceylanicum, Nippostrongylus brasiliensis, Syphacia obvelata, Hymenolepis nana, H. diminuta and Cysticercus fasciolaris in experimental animals is reported. The compound (mg/kg) causes 100% elimination of A. ceylanicum (25 x 1), N. brasiliensis (100 x 1), S. obvelata (50 x 1), H. nana (250 x 3) and C. fasciolaris (50 x 10). It was also effective against the developing larvae (L3, L4 and L5) of A. ceylanicum at a single oral dose of 100 mg/kg. Another study indicated that the compound elicits 100% response within 32 hr of drug administration. The drug is well tolerated and LD50 is greater than 4500 mg/kg.     

Effects of nootropic drugs on brain cholinergic and dopaminergic transmission

High affinity choline uptake (HACU) in the hippocampus and striatal concentration of dopamine (DA) and homovanillic acid (HVA) as measures of the in vivo acetylcholine and DA turnover, respectively, were estimated in male rats, Long-Evans, following 6-day administration of various nootropics in clinically relevant doses: piracetam and its derivatives pramiracetam and oxiracetam (100 mg/kg/day), pyritinol (50 mg/kg/day). Piracetam treatment was without effect on HACU, but induced significant increase of HVA in the striatum leaving striatal DA concentration unchanged. On the contrary, pyritinol, pramiracetam and oxiracetam increased HACU, but did not change striatal DA and HVA levels.     

Anti-ulcer compound from Voacanga africana with possible histamine H2 receptor blocking activity.

Voacanga africana is used in Cameroonian ethnomedicine for the treatment of peptic ulcers. We have tested the cytoprotective, anti-secretory and ulcer healing actions of an alkaloid (TN) obtained from the fruit extract. Oral administration of TN (50-100 mg/kg) dose-dependently prevented ulcer formation by HCl/ethanol (36-75%), absolute ethanol (43-75%), HCl-ethanol/indomethacin (58-84%), Pylorus ligation (31-100%), cold restraint stress (68-100%) and histamine (49-100%). The inhibitory effect at 50 and 100 mg/kg against HCl/ethanol was not suppressed by pre-treatment with indomethacin (20 mg/kg, i.p.). TN reduced Shay-ligated gastric acid secretion from 77 mEq/l in the controls to 46 and 25 mEq/l for the 50 and 100 mg/kg doses. Augmented histamine-induced gastric acid secretion was reduced from 84 mEq/l in the controls to 45 and 21 mEq/l for the two doses of TN, with total inhibition of gastric and duodenal ulcers by the 50 mg/kg dose. Healing rate of chronic acetic acid-induced ulcers was 62 and 83%, respectively, for the dose of 50 and 100 mg/kg of TN compared with the controls. TN has gastric anti-secretory effects similar to histamine receptor blockers. Its cytoprotective and ulcer healing properties are related to its ability to strengthen gastric mucosal defenses through enhanced gastric mucus production.     

Effects of the heavy metal Cu2+ on growth, development, and population dynamics of Spodoptera litura (Lepidoptera: Noctuidae)

Spodoptera litura (F.) larvae were fed with artificial food containing four different concentrations of copper (25, 50, 100, and 200 mg/kg). Copper affected growth, development, and population dynamics of late instar larvae. Our results indicate that the fourth and fifth instar survival rates were significantly reduced at 50-200 mg/kg copper (Cu2+). Moreover, all the Cu2+ treatments significantly reduced pupation and moth emergence rates in a dose-dependent manner. Larvae fed 25 or 50 mg/kg Cu2+ showed significant reductions in development period compared with non-Cu controls, and the pupation duration of animals fed 200 mg/kg was significantly longer than in non-Cu controls. All Cu2+ concentrations significantly reduced individual pupal weights compared with controls. In addition, Cu2+ at some concentrations significantly affected fertility parameters, such as doubling population time (DT), the net reproduction rate (R(o)), the mean generation time (T), the intrinsic rate of increase (r(m)), and the finite increase rate (A). Our study demonstrates that low concentrations of Cu2+ in the diet (25 and 50 mg/kg) shorten the generation time by 4-5 d, whereas higher Cu2+ concentrations (100 and 200 mg/kg) increase DT for 1-2 d.     

Species differences in the behavioral effects of cerulein--an agonist of the receptors of the octapeptide cholecystokinin--in white mice and rats

It has been shown in the behavioural experiments that combined pretreatment with haloperidol (0.25 mg/kg) and caerulein (40 micrograms/kg), and to a lesser extent pretreatment with caerulein alone caused long-term reversal of amphetamine (2 mg/kg) induced hyperexcitability in rats. Administration of proglumide (50 mg/kg), an antagonist of CCK-8 receptors, did not reverse long-term antiamphetamine effect of caerulein. In mice pretreatment with caerulein (50 and 100 micrograms/kg) alone or in combination with haloperidol (0.25 mg/kg) caused hypersensitivity to the behavioural effect of amphetamine (3 mg/kg). Intraventricular (I ng), but not systemic (100-500 micrograms/kg) administration of caerulein selectively antagonized seizures in mice induced by intraventricular administration of quinolinic acid (5 micrograms) and N-methyl-D-aspartate (0.2 microgram). Pretreatment with proglumide (50 mg/kg) reversed the anticonvulsive effect of caerulein in mice. In rats, caerulein failed to affect the seizures caused by intraventricular administration of quinolinic acid. The results of the present study demonstrate the existence of obvious interspecies differences in the behavioural effects of caerulein, the agonist of CCK-8 receptors, in mice and rats.     

Biochemical and morphological evaluation of the effects of propolis on cisplatin induced kidney damage in rats

Cisplatin (CP) is a chemotherapeutic agent used to treat various types of cancer; nephrotoxicity is the most common adverse effect of the drug. We investigated the protective effects of propolis against CP induced kidney injury. Thirty-six male rats were divided into six equal groups: untreated control group, 50 mg/kg/day propolis group, 100 mg/kg/day propolis group, single-dose 7 mg/kg CP group, 7 mg/kg CP + 50 mg/kg/day propolis and 7 mg/kg CP + 100 mg/kg propolis. Rats were sacrificed after 14 days and kidneys were removed for histopathological and biochemical analyses. We used hematoxylin & eosin and periodic acid-Schiff staining to evaluate kidney histopathology and we used the TUNEL technique to assess apoptosis. We also measured total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI), ischemia-modified albumin (IMA) and malondialdehyde (MDA) levels in tissue and blood specimens. Normal morphology was observed in the control, 50 mg/kg/day propolis and 100 mg/kg/day propolis groups by light microscopy. Degeneration of tubule cells, edema and tubule dilation were increased in the CP group compared to the control group. Degeneration of tubule cells and dilation of Bowman’s spaces were decreased in the CP + 50 mg/kg/day propolis and CP + 100 mg/kg/day propolis groups compared to the CP group. Tubule dilation decreased significantly in the CP + 100 mg/kg propolis group compared to the CP group. Also, the 7 mg/kg CP group exhibited altered proximal tubule epithelial cells, loss of brush border and thickening of the parietal layer of Bowman’s capsule in glomeruli and basal laminae of tubules. A normal brush border was observed in the CP + 50 mg/kg/day propolis and CP + 100 mg/kg/day groups. Serum OSI and MDA levels were increased in the CP group compared to the control group. Serum MDA levels decreased significantly in the CP + 50 mg/kg/day propolis and 100 mg/kg CP + propolis groups compared to the CP group. CP caused significant damage to kidney tissue; propolis exhibited dose-dependent prevention of tissue damage.     

Cortical alpha-adrenoceptor downregulation by tricyclic antidepressants in the rat brain

The aim of the present study was to examine the effect of chronic tricyclic antidepressants (TCAs) treatment on the density of -adrenoceptors in the rat brain. Density of ₁- and ₂-adrenoceptors was measured in cortex and hippocampus of rats treated with imipramine (IMI, 5 mg/kg body weight), desipramine (DMI, 10 mg/kg body weight), clomipramine (CMI, 10 mg/kg body weight) and amitriptyline (AMI, 10 mg/kg body weight), for 40 days, using [³H]prazosin and [³H]clonidine, respectively. The density of cortical ₁-adrenoceptors was significantly decreased with IMI (46%), DMI (21%), CMI (50%) and AMI (67%) treatment, without altering the affinity of the receptor. The density of cortical ₂-adrenoceptors was also significantly decreased with DMI (69%), CMI (81%) and AMI (80%) treatment, without affecting the affinity for [³H]clonidine. The density of hippocampal ₁-adrenoceptors was significantly decreased only with AMI treatment (47%), without affecting the affinity for [³H]prazosin. However, no change in hippocampal ₂-adrenoceptor density was observed with any of these TCAs. The results suggest that chronic antidepressant (AD) treatment downregulates the cortical, but not hippocampal, ₁- and ₂-adrenoceptors in rat brain. The region-specific downregulation of ₁- and ₂-adrenoceptors density, which occur after prolonged AD treatment, may underline the therapeutic mechanism of action.     

Imine derivatives as new potent and selective CB2 cannabinoid receptor agonists with an analgesic action

In this study, a novel series of CB(2) receptor agonist imine derivatives, 1-6, was synthesized and evaluated for activity against the CB(2) receptor. In a previous paper we reported the synthesis and SARs of thiazole derivative 1, a potent CB(2) receptor agonist, but we had not assessed chemical modifications of the 5-membered heteroring of 1. In the present study, we therefore tried chemically modifying the 5-membered heteroring of 1 in an attempt to further improve binding affinity for the CB(2) receptor. In the course of making the structural modifications, we discovered that a novel pyrazole derivative 6b (CBS0550) had high affinity for the CB(2) receptor (IC(50)=2.9 nM, EC(50)=1.8 nM, E(max)=85%), high selectivity for CB(2) (CB(1) IC(50)/CB(2) IC(50)=1400), and good physicochemical properties (solubility in water: 5.9 mg/100mL at 25 degrees C). Oral administration of 6b to rats at a dose of 10mg/kg resulted in significant plasma concentrations, and orally administered compound 6b significantly reversed mechanical hyperalgesia in the Randall-Selitto model of inflammatory pain in rats.