Exenatide upregulates gene expression of glucagon‐like peptide‐1 receptor and nerve growth factor in streptozotocin/nicotinamide‐induced diabetic mice

Glucagon‐like peptide‐1 (GLP‐1) is an incretin hormone that has modulating effects on insulin release. GLP‐1 and receptors for GLP‐1 are widely expressed throughout the body including the brain. The expression of GLP‐1 receptors is very specific to large neurons in hippocampus, neocortex, and cerebellum. GLP‐1 receptor stimulation enhances glucose‐dependent insulin secretion and lowers blood glucose in type 2 diabetes mellitus. Studies on adipobiology of neurotrophins have focused on nerve growth factor (NGF) as an example of adipose‐derived neurotrophins. Compromised trophic factor signaling may underlie neurodegenerative diseases ranging from Alzheimer's disease to diabetic neuropathies. Exenatide, a potent and selective agonist for the GLP‐1 receptor, is currently approved for the treatment of type 2 diabetes mellitus. The aim of this study was to assess the effect of chronic exenatide treatment on the hippocampal gene expression levels of GLP‐1 receptor and NGF in diabetic mice. The effects of chronic exenatide treatment (0.1 μg/kg, s.c., twice daily for 2 weeks) on GLP‐1 receptor and NGF gene expression levels in the hippocampus of streptozotocin/nicotinamide (STZ–NA)‐induced diabetic mice were assessed by quantitative real‐time polymerase chain reaction (RT‐PCR). The results of this study revealed that hippocampal gene expression of GLP‐1 receptor and NGF were downregulated in diabetic mice. Importantly, a significant increase in the gene expression level of GLP‐1 receptor and NGF was determined after 2 weeks of exenatide administration. Increased gene expression level of GLP‐1 receptor and NGF may underlie the beneficial action of exenatide in STZ/NA‐induced diabetes.     

Subchronic administration of riparin III induces antidepressive‐like effects and increases BDNF levels in the mouse hippocampus

Riparin III (Rip III) is an alcamide isolated from Aniba riparia that has presented effects of antidepressant and anxiolytic activities in acute stress behavioral models. The trial's goal was to investigate the activity of Rip III in mice exposed to corticosterone‐induced chronic depression model. Swiss female mice, 22–25 g, were distributed in following experimental groups: control group (vehicle1: saline containing 0.1% dimethyl sulfoxide and 0.1% Tween‐80, SC+ vehicle 2: distilled water emulsified with 2% Tween‐80, PO); stressed group (corticosterone, 20 mg/kg, SC, + vehicle 2, orally); Rip III group (50 mg/kg, orally); and fluvoxamine (Flu) group (50 mg/kg, orally). The mice were exposed to the behavioral tests, and posteriorly, Brain‐derived neurotrophic factor protein levels were assessed in hippocampal samples. Statistical analysis of the data was performed by one‐way anova , followed by Newman–Keuls test. Both administrations of Rip III and Flu significantly reduced the immobility time in tail suspension and forced swimming tests after 21 days without affecting locomotor function. There was also an increase in BDNF protein levels in the mice hippocampus. These findings further support the hypothesis that Rip III could be a new pharmacological target for the treatment of mood disorders.     

The possible role of CREB‐BDNF signaling pathway in neuroprotective effects of minocycline against alcohol‐induced neurodegeneration: molecular and behavioral evidences

Abuse of alcohol triggers neurodegeneration in human brain. Minocycline has characteristics conferring neuroprotection. Current study evaluates the role of the CREB‐BDNF signaling pathway in mediating minocycline's neuroprotective effects against alcohol‐induced neurodegeneration. Seventy adult male rats were randomly split into groups 1 and 2 that received saline and alcohol (2 g/kg/day by gavage, once daily), respectively, and groups 3, 4, 5, and 6 were treated simultaneously with alcohol and minocycline (10, 20, 30 and 40 mg/kg I.P, respectively) for 21 days. Group 7 received minocycline alone (40 mg/kg, i.p) for 21 days. Morris water maze (MWM) has been used to assess cognitive activity. Hippocampal neurodegenerative and histological parameters as well as cyclic AMP response element‐binding protein (CREB) and brain‐derived neurotrophic factor (BDNF) levels were assessed. Alcohol impaired cognition, and concurrent therapy with various minocycline doses attenuated alcohol‐induced cognition disturbances. Additionally, alcohol administration boosted lipid peroxidation and levels of glutathione in oxidized form (GSSG), tumor necrosis factor alpha (TNF‐α), interleukin 1 beta (IL‐1β), and Bax protein, while decreased reducing type of glutathione (GSH), Bcl‐2 protein, phosphorylated CREB, and BDNF levels in rat hippocampus. Alcohol also decreased the activity in the hippocampus of superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR). In comparison, minocycline attenuated alcohol‐induced neurodegeneration; elevating expression levels of P‐CREB and BDNF and inhibited alcohol induced histopathological changes in both dentate gyrus (DG) and CA1 of hippocampus. Thus, minocycline is likely to provide neuroprotection against alcohol‐induced neurodegeneration through mediation of the P‐CREB/BDNF signaling pathway.     

Pharmacological blockade of TRPV1 receptors modulates the effects of 6‐OHDA on motor and cognitive functions in a rat model of Parkinson's disease

TRPV1 receptors and cannabinoid system are considered as important modulators of basal ganglia functions, and their pharmacologic manipulation represents a promising therapy to alleviate Parkinson‐induced hypokinesia. Recent evidence suggests that the blockade of cannabinoid receptors might be beneficial to alleviate motor deficits observed in Parkinson's disease. In the present study, we have evaluated the effects of AMG₉₈₁₀, a selective antagonist of TRPV1 receptors, on the motor and cognitive functions in a rat model of Parkinson's disease generated by an intracerebroventricular injection of 6‐ hydroxydopamine (6‐OHDA) (200 μg per animal). The injection of 10 nmol of AMG₉₈₁₀ for a single dose (AMG1) and for 2 weeks (AMG14) partially attenuated the hypokinesia shown by these animals in motor function evaluation tests, whereas chronic administration of AMG had destructive effects on learning and memory in 6‐OHDA‐treated rats. Animals in the AMG 1 and AMG 14 groups showed an increased latency to fall in rotarod and grasping tests in each trials compared with 6‐OHDA‐treated rats (P < 0.01) and DMSO 1 and 14 groups (P < 0.05). Our data indicate that pharmacological blockade of TRPV1 receptors by AMG ₉₈₁₀ attenuates the hypokinetic effects of 6‐OHDA and that TRPV1 receptors play an important role in 6‐OHDA‐induced hypokinesia, athough elucidation of the neurochemical substrate involved in this process remains a major challenge for the future.     

A brief primer on the mediational role of BDNF in the exercise‐memory link

One of the most amazing aspects of the human brain is its ability to learn information and use it to change behaviour. A key neurotrophin that influences memory function is brain‐derived neurotrophic factor (BDNF). This review briefly discusses the mechanistic role that BDNF may play in facilitating learning and memory. We also describe the role of exercise on this relationship. As discussed herein, BDNF may influence memory via BDNF‐induced alterations in membrane receptor expression and translocation, as well as activating several pathways (PLC‐y, PI3K, ERK) that act together to facilitate cellular effects that influence synaptic plasticity. Exercise may help to facilitate BDNF expression and its downstream cellular pathways from both direct and indirect mechanisms.     

Arterial stiffening and cardiac hypertrophy in a new rat model of type 2 diabetes

Background We determined the effects of NIDDM on haemodynamic parameters describing arterial wall elasticity and cardiac hypertrophy in rats administered streptozotocin (STZ) and nicotinamide (NA), using the aortic impedance analysis. Methods Male Wistar rats at 2 months were administered intraperitoneally 180 mg kg⁻¹ of NA, 30 min before an intravenous injection of 50 mg kg⁻¹ STZ, to induce type 2 diabetes. The STZ‐NA rats were divided into two groups, 4 weeks and 8 weeks after induction of diabetes, and compared with untreated age‐matched controls. Pulsatile aortic pressure and flow signals were measured by a high‐fidelity pressure sensor and electromagnetic flow probe, respectively, and were then subjected to Fourier transformation for the analysis of aortic input impedance. Results In each diabetic group, the experimental syndrome was characterized by a moderate and stable hyperglycaemia and a relative deficiency of insulin secretion. However, the 8‐week but not the 4‐week STZ‐NA diabetic rats showed a decrease in cardiac output in the absence of any significant changes in mean aortic pressure, having increased total peripheral resistance. The diabetic syndrome at 8 weeks also contributed to an increase in aortic characteristic impedance, from 1·49 ± 0·33 (mean ± SD) to 1·95 ± 0·28 mmHg s mL⁻¹ (P < 0·05), suggesting a detriment to the aortic distensibility in NIDDM. Meanwhile, the STZ‐NA diabetic animals after 8 weeks had an increased wave reflection factor (0·46 ± 0·09 vs. 0·61 ± 0·13, P < 0·05) and decreased wave transit time (25·8 ± 3·8 vs. 20·6 ± 2·8 ms, P < 0·05). Ratio of the left ventricular weight to body weight was also enhanced in the 8‐week STZ‐NA diabetic rats. Conclusion The heavy intensity with early return of the pulse wave reflection may augment systolic load of the left ventricle coupled to the arterial system, leading to cardiac hypertrophy in the rats at 8 weeks after following STZ and NA administration.     

氯胺酮对子鼠学习记忆能力的影响及其机制研究

目的 探究氯胺酮对子鼠学习记忆能力的影响及其机制。方法 选取60只子鼠,使用跳台实验将子鼠分为智力及记忆能力相近的4组,每组各15只,分别为:空白组、低剂量氯胺酮组(25 mg/kg)、中剂量氯胺酮组(50 mg/kg)和高剂量氯胺酮组(100 mg/kg),氯胺酮各组腹腔注射对应剂量的氯胺酮,空白组腹腔注射等量生理盐水,每日1次,连续7 d。使用跳台法和Morris水迷宫法测定子鼠的学习记忆能力;采用HE染色观察子鼠海马体内神经细胞的变化;采用比色法测定子鼠脑组织中乙酰胆碱(Ach)、5-HT含量和乙酰胆碱酯酶(TCh E)活力;使用Western blot检测子鼠海马体内环磷腺苷效应元件结合蛋白(CREB)、磷酸化环磷腺苷效应元件结合蛋白(p-CREB)及脑源性神经营养因子(BDNF)的表达情况。结果 相比空白组,使用氯胺酮组处理各组子鼠逃避潜伏时间、出现逃避错误次数、每个象限内停留时间、TCh E活力均显著升高(P <0. 05),120 s内穿台次数、Ach水平、CREB、p-CREB及BDNF表达水平、pCREB/CREB值显著降低(P <0. 05);相比低剂量氯胺酮组,中剂量氯胺酮组和高剂量氯胺酮组子鼠逃避潜伏时间、出现逃避错误次数、每个象限内停留时间、TCh E活力均显著升高(P <0. 05),120 s内穿台次数、Ach水平、CREB、pCREB及BDNF表达水平、p-CREB/CREB值显著降低(P <0. 05);HE染色结果显示,使用氯胺酮处理后子鼠海马区细胞间隙明显增宽,结构组织松散,细胞水肿,以条索状为主,并存在大量的细胞坏死。结论 氯胺酮会损害子鼠的学习记忆能力,其作用机制可能与调控神经递质、减少BDNF表达并抑制CREB信号传导通路相关,并呈剂量依赖性。     

Agomelatine pretreatment prevents development of hyperglycemia and hypoinsulinemia in streptozotocin‐induced diabetes in mice

The main objective of this study was to investigate potential effectiveness of agomelatine pretreatment in the prevention of diabetes itself and encephalopathy, with a focus on brain tissue oxidative stress and inflammatory processes in streptozotocin (STZ)‐induced diabetic mice. Interleukine‐1β (IL‐1β) and TACR1 (NK1), which is a tachykinine receptor, were used for the investigation of inflammation in the brain regions including raphe nucleus, periaqueductal gyrus (PAG), amygdala, and nucleus accumbens. The effects of agomelatine on total antioxidant capacity were also evaluated. In the in vitro part of the study, the effects of agomelatine on cell viability were investigated in dorsal root ganglion (DRG) neurons. Fasting blood glucose levels were measured 72 h after STZ injection to determine the diabetic condition. Agomelatine pretreatment prevented both hyperglycemia and hypoinsulinemia in STZ‐treated mice. When STZ was injected to induce diabetes in mice, neither hyperglycemia nor hypoinsulinemia was developed in agomelatine pretreated mice and 6 weeks after development of diabetes, agomelatine treatment significantly decreased levels of IL‐1β mRNA in raphe nucleus and nucleus accumbens. TACR1 mRNA levels were lower in raphe nucleus, PAG, and amygdala of agomelatine‐treated diabetic mice. The increase in total antioxidant capacity after agomelatine administration may responsible for its beneficial effect in the prevention of diabetes. We showed that agomelatine reversed high glucose–induced cell viability decreases in DRG neurons. Both the antihyperglycemic and antioxidant effects of agomelatine might have contributed to the DRG neuron viability improvement. In conclusion, agomelatine seems to both prevent development of diabetes and reverse the encephalopathic changes caused by diabetes.     

Autonomic neuropathy precedes cardiovascular dysfunction in rats with diabetes

Background Our team previously demonstrated arterial stiffening and cardiac hypertrophy in type 2 diabetic rats at 8 but not 4 weeks after being administered streptozotocin (STZ) and nicotinamide (NA). The present study focused on investigating the effects of type 2 diabetes on cardiac autonomic nerve function in the STZ‐ and NA‐treated animals, using modern spectral estimation technique. Design An autoregressive process was performed to each detrended signal of heart rate and systolic blood pressure measured in the 4‐ and 8‐week STZ‐NA rats with anaesthesia. The power of low‐frequency and high‐frequency oscillations was automatically quantified with each spectral peak by computing the residuals. The closed‐loop baroreflex gain was estimated using the square root of the ratio between heart rate and systolic blood pressure powers in the low‐frequency band. Results Compared with the age‐matched controls, both the 4‐ and 8‐week STZ‐NA diabetic rats had significantly decreased low‐frequency oscillations of heart rate but not systolic blood pressure variability, showing a decline in baroreflex gain (0·451 ± 0·060 and 0·484 ± 0·056 vs. 1·196 ± 0·064 ms mmHg^?1, P < 0·05). On the other hand, the low frequency–high frequency power ratio of the heart period was also diminished in the two diabetic groups, indicating a shift in sympatho‐vagal balance of the heart control (0·472 ± 0·109 and 0·504 ± 0·090 vs. 1·857 ± 0·336, P < 0·05). Conclusions The cardiac autonomic dysfunction in the absence of any significant changes in vascular dynamics, 4 but not 8 weeks after induction of type 2 diabetes, suggests that the diabetic autonomic neuropathy may precede arterial stiffening and cardiac hypertrophy in the STZ‐ and NA‐treated rats.     

Dual effect of cAMP agonist on ameliorative function of PKA inhibitor in morphine‐dependent mice

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.     

脑源性神经营养因子对改善东莨菪碱致学习记忆障碍的实验研究

目的：探讨脑源性神经营养因子对中枢神经系统高级机能活动的作用机理,为临床应用脑源性神经营养因子治疗学习记忆障碍疾病提供实验依据。方法：以小鼠为实验对象,采用学习记忆行为训练和生化测定的方法,观察脑源性神经营养因子对东莨菪碱致学习记忆障碍、海马脑区蛋白质含量的影响。结果：脑源性神经营养因子能显著地改善东莨菪碱所致的学习记忆障碍,使东莨菪碱实验小鼠海马脑区的蛋白质含量显著增加。结论：脑源性神经营养因子对东莨菪碱所致的小鼠学习记忆障碍的改善与康复均具有明显作用。     

Effect of subacute agomelatine treatment on painful diabetic neuropathy: involvement of catecholaminergic mechanisms

In this study, we investigated the effects of subacute agomelatine (40 and 80 mg/kg) administration on chronic hyperglycemia, metabolic parameters, and pain perception in streptozotocin‐induced diabetic rats. Fasting blood glucose measurements and oral glucose tolerance tests were performed to evaluate the effect of agomelatine on glycemia, while metabolic parameters were monitored using metabolic cages. Potential effect of agomelatine on diabetes‐induced mechanical and thermal allodynia was evaluated using dynamic plantar aesthesiometer and warm plate (38 °C) tests, respectively. Additionally, influence of agomelatine on hyperalgesia occurring in connection with diabetic neuropathy was examined using the Randall–Selitto (mechanical nociceptive stimulus), Hargreaves (thermal nociceptive stimulus), and cold plate (4 °C, thermal nociceptive stimulus) tests. Obtained data indicated that, in diabetic rats, agomelatine significantly improved hyperalgesia and allodynia responses, without no effect on hyperglycemia or the associated polydipsia, polyuria, and hyperphagia. Therapeutic potential of agomelatine on neuropathic pain was suppressed with α‐methyl‐para‐tyrosine methyl ester (an inhibitor of catecholamine synthesis), phentolamine (a nonselective α‐adrenoceptor antagonist), and propranolol (a nonselective β‐adrenoceptor antagonist) administrations. However, p‐chlorophenylalanine methyl ester (an inhibitor of serotonin synthesis) pretreatment could not be achieved to reverse these antihyperalgesic and antiallodynic effects. These results suggest that the curative effect of agomelatine on neuropathic pain is mediated through rising synaptic catecholamine levels as well as through interactions with both α‐ and β‐adrenoceptors. To our knowledge, this is the first study to show findings that indicate catecholaminergic system mediated antihyperalgesic and antiallodynic effects of agomelatine.     

Exploring mechanism of pioglitazone-induced memory restorative effect in experimental dementia

The present study was undertaken to investigate possible mechanism of pioglitazone-induced beneficial effect in memory deficits associated with experimental dementia. Dementia was induced in Swiss albino mice by administration of streptozotocin (STZ; 3 mg/kg administered intracerebroventricularly on 1st & 3rd day). Morris Water-Maze test was employed to assess learning and memory of the animals. Brain acetylcholinesterase (AChE) activity was measured by Ell Mann's method. Brain thiobarbituric acid reactive species (TBARS) levels and reduced glutathione (GSH) levels were measured by Ohokawa's and Beutler's method respectively to assess total oxidative stress. Blood glucose level was also measured. Streptozotocin (STZ) produced a significant decrease in water-maze performance of mice hence reflecting loss of learning and memory. Pioglitazone (20 mg/kg p.o. daily for 14 days) successfully attenuated STZ-induced memory deficits, without any significant per se effect on blood glucose levels. Higher levels of brain AChE activity, TBARS and lower levels of GSH were observed in STZ treated animals, which were significantly attenuated by pioglitazone. Further, the noted beneficial effect of pioglitazone on STZ-induced dementia was significantly abolished by pre-treatment of nitric oxide (NO) synthase inhibitor l -NAME (3 mg/kg i.p.) manifested in the terms of decrease in water-maze performance and increase in brain AChE activity as well as oxidative stress. It is concluded that anti-dementic effect of pioglitazone may involve central cholinergic, oxidative and NO pathways.     

Cannabidiol reverses the mCPP‐induced increase in marble‐burying behavior

Cannabidiol (CBD), one of the main components of Cannabis sp., presents clinical and preclinical anxiolytic properties. Recent results using the marble‐burying test (MBT) suggest that CBD can also induce anticompulsive‐like effects. Meta‐chloro‐phenyl‐piperazine (mCPP) is a nonspecific serotonergic agonist (acting mainly at 5HT1A, 5HT2C and 5HT1D receptors) reported to increase symptoms in OCD patients and block the anticompulsive‐like effect of serotonin reuptake inhibitors (SRIs) in animal models. The aim of this study was to investigate the interference of CBD on mCPP effects in repetitive burying. Administration of mCPP showed dual effects in the MBT, increasing the number of buried marbles at lower (0.1 mg/kg) while decreasing it at higher doses (1 mg/kg), an effect not related to a general increase in anxiety‐like behavior. As found previously, CBD (30 mg/kg) and the positive control fluoxetine (FLX; 10 mg/kg) decreased burying behavior without changing general exploratory activity. A similar effect was found when subeffective doses of CBD (15 mg/kg) and FLX (3 mg/kg) were administered together. These subeffective doses alone were also able to block mCPP‐induced repetitive burying. The results, in addition to reinforcing a possible anticompulsive effect of CBD, also suggest that mCPP‐induced repetitive burying could be a useful test for the screening of compounds with presumed anticompulsive properties.     

Exenatide suppresses 1,2-dimethylhydrazine-induced colon cancer in diabetic mice: Effect on tumor angiogenesis and cell proliferation

Colon cancer is the third leading cause of cancer mortality worldwide, which results from interactions of different factors. It is frequently a pathological consequence of persistent inflammation. Diabetes affects several cancers and is positively correlated with the incidence of colon cancer. This study aimed to study the effect of exenatide in ameliorating inflammation, angiogenesis and cell proliferation in 1,2-dimethyl hydrazine (DMH) induced colorectal carcinoma in diabetic mice. Mice were randomly allocated into six groups, 8 mice each. Group 1: vehicle control group. Group 2: diabetic control group. Group 3: DMH control group: diabetic mice treated with DMH (20 mg/kg/week, s.c.) for 15 week. Group 4: DMH-cisplatin group: mice received cisplatin (4 mg/kg/week, i.p.). Groups 5 & 6: DMH-exenatide (10 and 20 μg/kg) group: mice received exenatide (10 or 20 μg/kg/day, s.c.), respectively. The present results highlighted an increase in angiogenic markers and cell proliferation in the DMH-diabetic group in comparison with the control group with greater expression of endothelial marker (CD₃₄) and Ki-67 in colon tissue. Monotherapy with cisplatin or exenatide (10 and 20 μg/kg) downregulated these markers to different extents. The current results provided evidence that exenatide represents a promising chemopreventive effect against DMH-induced colon carcinogenesis in diabetic mice, at least in part, attributed to its anti-angiogenic and anti-proliferative mechanisms.     

Differential profile of letrozole and exemestane on bone turnover markers in vinylcyclohexene diepoxide treated ovotoxic female mice

The third generation aromatase inhibitors are currently the drugs of choice for the treatment of early and advanced breast cancer in postmenopausal women. One of the significant limiting factor during therapy is their negative impact on bone health. In this study, we compared the effects of a nonsteroidal (letrozole) and a steroidal aromatase inhibitor (exemestane) on bone mineral density and markers of bone turnover including alkaline phosphatase (ALP), tartrate‐resistant acid phosphatase (TRAP), hydroxyproline (HxP), receptor activator of nuclear factor kappa B ligand (RANKL), sclerostin, and dickkopf‐1 (DKK‐1) in vinylcyclohexene diepoxide (VCD)‐induced ovotoxic female mice. VCD administration for 15 days mimicked a postmenopausal state with reduced serum estradiol levels. Ovotoxicity was accompanied by reduced ALP, HxP and enhanced TRAP, sclerostin and DKK‐1 activity in femoral epiphysis and lumbar vertebrae of mice. While letrozole (1 mg/kg) administration for 1 month enhanced bone turnover in ovotoxic mice, exemestane (3.25 mg/kg) was devoid of such effects in both normal and ovotoxic mice. The latter, however, reduced ALP in femoral epiphysis of ovotoxic mice. Letrozole depleted estradiol levels in ovotoxic mice and enhanced RANKL activity while exemestane neither affected estradiol nor RANKL in both normal and ovotoxic mice, and enhanced sclerostin and DKK‐1 in femoral epiphysis only. The study indicates that the two aromatase inhibitors possesses differential profile in terms of their effects on bone and that exemestane could be a better option for the treatment of breast cancer in postmenopausal women at least in terms of its effects on bone.     

12-脂氧化酶基因敲除对1型糖尿病肾病小鼠肾小球内纤维连接蛋白表达的影响

目的探讨12-脂氧化酶（12-lipoxygenase,12-LO）对1型糖尿病肾病小鼠肾小球内纤维连接蛋白（Fibronectin,FN）表达的影响。方法用链脲佐菌素（Streptozotocin,STZ）诱导1型糖尿病模型。野生型和12-LO基因敲除C57BL/6小鼠随机分成4组：野生型对照组;12-LO基因敲除组;野生型糖尿病组;12-LO基因敲除糖尿病组。采用RT-PCR和免疫组化方法分别检测肾小球内FN mRNA和蛋白表达的变化。结果与野生型对照组比较,野生型1型糖尿病小鼠血糖（P〈0.01）、肾重/体重比值（P〈0.01）和24小时尿白蛋白明显增高（P〈0.01）,但12-LO基因敲除糖尿病小鼠尿白蛋白（P〈0.05）、肾重/体重比值（P〈0.05）明显低于野生型糖尿病小鼠。基础情况下,野生型和12-LO基因敲除小鼠肾小球内FN表达无差异。与野生型对照组相比,野生型糖尿病小鼠肾小球内FN表达明显增加（P〈0.01）,但12-LO基因敲除可阻止糖尿病小鼠肾小球FN表达的增加（P〈0.05）。结论 12-LO基因敲除延缓1型糖尿病肾病小鼠蛋白尿的进展,降低肾小球内FN表达。     

Opioid‐like antinociceptive effects of oral administration of a lectin purified from the seeds of Canavalia brasiliensis

The objective of this study was to evaluate the antinociceptive effects of a lectin from Canavalia brasiliensis (ConBr) when administered orally to murine models of chemical and thermal nociception. ConBr up to 100 mg/kg produced significant and dose‐dependent antinociceptive effects: 81% reduction in abdominal writhing induced by 0.6% acetic acid; 26 and 52% reduction in early‐ and late‐stage paw licking, respectively, induced by 2.5% formalin; and 155% increase in reaction latency (heightened thermal pain threshold). In all models, the antinociceptive effect was reversed by the lectin‐binding carbohydrate α‐d ‐methyl‐mannoside and by the nonselective opioid antagonist naloxone. The antinociceptive effect observed in the formalin test was inhibited by the δ‐selective antagonist naltrindole and the κ‐selective antagonist nor‐binaltorphimine but not by the μ‐selective antagonist cyprodime. In conclusion, when administered orally to Swiss mice, the ConBr lectin displayed antinociceptive activity, both peripheral and central, mediated by the opioid system and involving δ‐and κ‐receptors and the lectin domain.