Synergistic effects of citicoline and silymarin nanomicelles in restraint stress-exposed mice.

This study evaluated the effects of citicoline and silymarin nanomicelles (SMnm) in repeated restraint stress (RRS). METHOD: Mice were exposed to RRS for four consecutive days, 2 hrs. daily. On day 5 of the study, SMnm (25 and 50 mg/kg, i.p.) and citicoline (25 and 75 mg/kg), and a combination of them (25 mg/kg, i.p.) were initiated. On day 18, anxiety-like behavior, behavioral despair, and exploratory behavior were evaluated. The prefrontal cortex (PFC) and the hippocampus were dissected measuring brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), and tumor necrosis factor-alpha (TNF-α) through Western Blot and ELISA, respectively. RESULTS: In RR-exposed mice, anxiety-like behavior in the elevated plus maze (EPM) was enhanced by reductions in open arm time (OAT%) P < 0.001, and open arm entry (OAE%) P < 0.001. In the forced swimming test (FST), the immobility increased P < 0.001 while the swimming and climbing reduced P < 0.001. In the open field test (OFT), general motor activity was raised P < 0.05. Further, body weights reduced P < 0.001, and tissue BDNF and pCREB expressions decreased P < 0.001 while TNF-α increased P < 0.001. Conversely, SMnm, citicoline and their combination could reduce anxiety-like behavior P < 0.001. The combination group reduced the depressive-like behaviors P < 0.001. Moreover, body weights were restored P < 0.001. Besides, BDNF and pCREB expressions increased while TNF-α reduced, P < 0.001. CONCLUSION: The combination synergistically improved emotion-like behaviors, alleviating the inflammation and upregulating the hippocampal BDNF-mediated CREB signaling pathway.

Effect of sumatriptan on acetic acid-induced experimental colitis in rats: a possible role for the 5-HT1B/1D receptors.

Mucosal inflammation in colitis is associated with changes in the intestinal serotonin (5-HT) level. Sumatriptan, a 5-HT1B/1D receptor agonist, has demonstrated anti-inflammatory characteristics. The purpose of this study was to determine the effects of sumatriptan in a rat model of acute experimental colitis and to elucidate the probable participation of presynaptic 5-HT1B/1D receptors. To induce colitis, acetic acid (4%) was injected intrarectally. Treatments were given intraperitoneally (IP) once daily over 3 consecutive days starting 1-h post-induction. Sumatriptan was given at 0.5, 1, 2, and 5 mg/kg. GR-127935, a 5-HT1B/1D receptor antagonist, was injected (0.1 and 0.3 mg/kg) 30 min prior to the most effective dose of sumatriptan (1 mg/kg). On day 4, the colon samples were isolated. Significant enhancements of the tissue tumor necrosis factor-alpha (TNF-α), myeloperoxidase (MPO), microscopic and macroscopic damages, body weight losses, and also reductions in tissue superoxide dismutase (SOD) and 5-HT were observed in colitis rats. On the other hand, sumatriptan at doses 0.5, 1, and 2 mg/kg could diminish pathologic changes in the measured biomarkers, histopathologic damages, and body weight losses. Although GR-127935 at dose 0.3 mg/kg could markedly improve the pathologic indexes, its sub-effective dose (0.1 mg/kg) reversed the protective effect of sumatriptan (1 mg/kg). Moreover, sumatriptan (1 and 5 mg/kg) and GR-127935 (0.3 mg/kg) increased the serotonin level. Post-treatment with low-dose sumatriptan demonstrated a protective impact on this peripheral inflammatory condition. Notably, this protective effect may be mediated, at least in part, through 5-HT1B/1D receptors, as well as anti-inflammatory and anti-oxidative characteristics.

Comparative evaluation of adolescent repeated psychological or physical stress effects on adult cognitive performance, oxidative stress, and heart rate in female rats.

Multiple adult health problems are associated with adolescent stress. As the brain discriminates physical and psychological stressors by activation of different neural networks, we hypothesized that behavioral and physiological performance would be modulated differently based on the nature of the stressors. Thus, we studied the comparative effects of adolescent repeated physical and psychological stresses on adult cognitive performance, pro-oxidant-antioxidant balance (PAB) and heart rate in female rats. The aim was to differentiate disparate potency of chronic psychological and physical stresses leading to long-term behavioral and physiological alterations. Twenty-one female rats were divided randomly into three groups of seven rats each; control, physical, and psychological stress. Experimental rats were exposed to the stressors for five consecutive days (10 min daily) via a two-communication box. After verifying stress induction by serum corticosterone measurement, the rats were returned to their home cage for 6 weeks, until adulthood, elevated plus maze (EPM), forced swimming test (FST), Y-maze, object recognition task (ORT), and passive avoidance test (PAT) were used as five different behavioral tests to evaluate cognitive performance of each group. Serum PAB and heart rate were measured to assess long-term stress-induced physiological disorders. The results showed exposure to adolescent psychological stress resulted in a larger set of significant changes (in behavioral variation, oxidative stress, and elevated heart rate) 6 weeks post-stress compared to adolescent physical stress. Hence, mental health care in adolescence and therapies targeting PAB and heart rate could be prevention and treatment approaches to confront persistent adolescent stress-induced disorders. Lay summaryThe aim of our study on female laboratory rats was to differentiate disparate potency of chronic psychological and physical stresses in adolescence leading to long-term behavioral and physiological alterations. The results suggest that psychological stresses result in a greater extent of changes compared to physical stress. Adolescent chronic psychological stress may reveal itself in the form of certain behavioral and physiological variations in adulthood. Therefore, mental health care in adolescence could be a valuable prevention approach to confront a variety of adult stress-induced disorders.

Involvement of central opioid receptors in protective effects of methadone on experimental colitis in rats.

PURPOSE: There are several lines of evidence on the protective roles of opioids in gastrointestinal inflammatory conditions. This study aims to distinguish the central and peripheral roles of methadone, a non-selective opioid receptor agonist, in an acute model of ulcerative colitis in male rats. METHODS: Ulcerative colitis was induced by intrarectal administration of acetic acid 4%. Methadone was injected subcutaneously (s.c.), 5 and 10 mg/kg, and intracerebroventricular (i.c.v.), 50 and 300 ng/rat. Opioid antagonists were employed. Methylnaltrexone (MNTX; 5 mg/kg, i.p.), a peripherally acting opioid receptor antagonist, and naltrexone (NTX; 5 mg/kg, i.p. and 10 ng/rat, i.c.v.), a peripherally and centrally acting opioid receptor antagonist were injected before methadone (10 mg/kg, s.c. and or 300 ng/rat, i.c.v.) administration. NTX (5 mg/kg, i.p. and 10 ng/rat, i.c.v.) were administered 30 min prior to administration of methadone (10 mg/kg, s.c. and 300 ng/rat, i.c.v.), respectively. MNTX (5 mg/kg, i.p.) was injected 30 min prior to methadone (10 mg/kg, s.c.). Seventy-two hours following colitis induction, macroscopic and microscopic mucosal lesions, and the colonic levels of tumor necrosis factor-alpha (TNF-α) and interleukin-1ß (IL-1ß) were determined. RESULTS: Methadone (300 ng/rat, i.c.v.) and Methadone (5 and 10 mg/kg, s.c.) improved the macroscopic and microscopic scores through opioid receptors. Also, a significant reduction in TNF-α and IL-1ß was observed. Peripherally and centrally injected NTX significantly reversed methadone 10 mg/kg s.c. anti-inflammatory effects while MNTX could not completely reverse this effect. Moreover, centrally administered methadone (300 ng/rat) showed the anti-inflammatory effect which was reversed by central administration of NTX (10 ng/rat). CONCLUSIONS: The opioid receptors mainly the central opioid receptors may mediate the protective actions of methadone on the experimental model of inflammatory bowel disease in rat.

Licofelone Attenuates LPS-induced Depressive-like Behavior in Mice: A Possible Role for Nitric Oxide.

PURPOSE: Licofelone, a dual cyclooxygenase/5-lipoxygenase inhibitor, possesses antioxidant, antiapoptotic, neuroprotective, and anti-inflammatory properties. The aim of the present study was to investigate the effect of licofelone on lipopolysaccharide (LPS)-induced depression in a mouse model and also a possible role for nitric oxide (NO). METHODS: To elucidate the role of NO on this effect of licofelone (5 and 20 mg/kg, i.p.), L-NAME, a non-specific NO synthase (NOS) inhibitor; aminoguanidine (AG), a specific inducible NOS (iNOS) inhibitor; 7-nitroindazole (7-NI) a preferential neuronal NOS inhibitor (nNOS) and; L-arginine (L-Arg), as a NO donor, were used. The animal's behaviors were evaluated employing forced swimming test (FST), tail suspension test (TST) and open field test (OFT). RESULTS: LPS (0.83 mg/kg, i.p.) induced depressive-like behavior increasing immobility time in FST and TST. Conversely, licofelone (20 mg/kg i.p.) reversed the depressive effect of LPS and lowered the immobility time in FST and TST. On the other hand, pretreatment with L-Arg also reversed the antidepressant-like effect of licofelone (20 mg/kg) in FST and TST. On the other hand, L-NAME (10 and 30 mg/kg), AG (50 and 100 mg/kg) and 7-NI (60 mg/kg) could potentiate licofelone (5 mg/kg) and lowered the immobility duration. CONCLUSIONS: NO down-regulation possibly through iNOS and nNOS inhibition may involve in the antidepressant property of licofelone. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

The role of nitric oxide in anticonvulsant effect of nanocurcumine on pentylenetetrazole-induced seizure in mice.

A plant alkaloid obtained from Curcuma longa, curcumin possesses anti-oxidant and anti-inflammatory effects. Nanoformulations have been developed for preclinical studies which demonstrate enhanced therapeutic efficacy. Effect of acute intraperitoneal (i.p.) administration of curcumin C3 complex nanoparticles [1,5, 10, 20, 40, 80mg/kg, (i.p.)] 75min prior to PTZ, on clonic seizure thresholds induced by intravenous infusion of pentylenetetrazole (PTZ) 0.5% was investigated in comparison with curcumin (40 and 80mg/kg, i.p.) in male mice. Moreover, to clarify the probable role of NO in the anticonvulsant property of nanocurcumin, non-effective doses of l-arginine (l-Arg), a NO donor; 7-nitroindazole, 7-NI, a preferential neuronal NO synthase inhibitor; L-NAME, a non-selective NO synthase inhibitor and aminoguanidine (AG), a selective inducible NO synthase inhibitor (iNOS), in combination with nanocurcumin (80mg/kg, i.p.), 15-30min before it were employed. RESULTS: While curcumin did not show any anticonvulsant effect, nanocurcumin revealed dose-dependent anticonvulsant property at the doses 20, 40 and 80mg/kg, P<0.01, P<0.01 and P<0.001, respectively. l-Arg (30 and 60mg/kg) dose-dependently reversed the anticonvulsant effect of the most effective nanocurcumin dose (80mg/kg), P<0.01 and P<0.001, respectively. On the other hand, L-NAME (3 and 10mg/kg, i.p.) markedly potentiated the sub effective dose of nanocurcumin (10mg/kg), P<0.01 and P<0.001, respectively. Similarly, AG (50 and 100mg/kg, i.p.) profoundly augmented the seizure thresholds of nanocurcumin (10mg/kg), P<0.01 and P<0.001, respectively. In addition, 7-NI (10, 30 and 60mg/kg, i.p.) failed to influence the responses. CONCLUSION: These data may support excess of NO production following PTZ infusion probably resulting from iNOS source. Consequently, nanocurcumin probably down regulated NO. To conclude, nanocurcumin showed anticonvulsant effect. Furthermore, this effect was reversed following l-arginine as an external NO precursor. However, both the non-selective NOS inhibitor and selective iNOS inhibitor increased the thresholds. It is evident that nanocurcumin may influence the seizure thresholds at least in part through a decrease in NO.

Assessment of Clinical Teachers' Professionalism in Iran: From Residents and Fellowships' Perspective.

In the present study, professional conduct of clinical teachers in Tehran University of Medical Sciences in Iran was assessed by their residents (n=292) and fellowships (n=48) using a standard questioner called self-reported measurement equipment. This evaluation was a descriptive cross-sectional study. Professionalism was questioned in four domains including clinical teacher-patient, clinical teacher-student, inter-professional and clinical teacher-self relationships. Accordingly, mean scores of the teachers in cases of clinical teacher-patient; clinical teacher-student, inter-professional (teamwork) and clinical teacher-self relations were 61%, 62.2%, 60.6% and 57.6%, respectively. Generally, the teachers achieved 60.35% of the positive scores, and as a result, they were assessed intermediate in the professional behaviors. The residents and fellowships stated that they were not completely satisfied with their teacher's professional conduct and had hidden concerns. It shows that the clinical teachers in our project may not be ideal role models. As a result, developing a comprehensive professionalism and implementing regulations to ensure a successful professionalism are necessary. The precise evaluation of professional conduct in clinical faculty could encourage the maintenance of professional behaviors and potentially decrease negative role modeling and positively influence the hidden curriculums. Operational approaches to formulating regulations and appropriate measures for establishing professional ethics are of great importance.

Involvement of PPARγ in the protective action of tropisetron in an experimental model of ulcerative colitis.

Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal (GI) tract. Tropisetron, a selective 5-HT3 receptor antagonist, is highly used to counteract chemotherapy-induced emesis. Previous studies revealed the anti-inflammatory properties of this drug. The aim of this study was to evaluate the role of peroxisome proliferator-activated receptor gamma (PPARγ) receptor in the protective effect of tropisetron in an animal model of ulcerative colitis. Experimental colitis was induced by a single intra-colonic instillation of 4% (V/V) acetic acid in male rats. Tropisetron (3 mg/kg) and GW9662 (PPARγ antagonist) (5 mg/kg) were given twice daily for 2 days after colitis induction. Forty-eight hours after induction of colitis, colon was removed and macroscopic and microscopic features were given. Moreover, colonic concentrations of malondialdehyde (MDA), nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) levels, myeloperoxidase (MPO), and PPARγ activity were assessed. Both macroscopic and histopathological features of colonic injury were markedly ameliorated by tropisetron. Likewise, levels of NO, MDA, TNF-α, and IL-1ß diminished significantly (p < .05). GW9662 reversed the effect of tropisetron on these markers partially or completely. In addition, tropisetron increased the PPARγ and decreased the MPO activity (p < .05). Tropisetron exerts notable anti-inflammatory effects in acetic acid-induced colitis in rats, which is probably mediated through PPARγ receptors.

Effect of 5-HT7 receptor agonist, LP-211, on micturition following spinal cord injury in male rats.

BACKGROUND AND PURPOSE: Central and peripheral 5-hydroxytryptamine (5-HT) receptors play a critical role in regulation of micturition reflex. The aim of this study was to evaluate effect of a 5-HT7 receptor agonist, LP-211 (N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide) on micturition reflex in acute spinal cord-injured (SCI) rats during infusion of vehicle into the bladder. METHODS: SCI was induced by compressing T10 segment using an aneurysm clip, extradurally in male rats. Following two weeks, LP-211 doses (0.003-0.3 mg/kg) were administered cumulatively (intraperitoneally, i.p.) with 20 min interval. The 5-HT7 antagonist, SB-269970 ((R)-3-[2-[2-(4-Methylpiperidin-1-yl) ethyl] pyrrolidine-1-sulfonyl] phenol hydrochloride), was administered after achievement of LP-211 dose-response. A cystometric study was performed 2 weeks after spinal crushing in all the animals. Cystometric variables consisting of micturition volume (voided volume), residual volume (volume remaining in the bladder after voiding), and bladder capacity (micturition volume plus residual volume). Voiding efficiency was calculated as the percent of micturition volume to bladder capacity. FINDINGS: Intact and sham-operated rats showed few significant changes in micturition reflex. SCI rats responded to LP-211 (0.003-0.3, mg/kg, i.v.) with dose-dependent increases in bladder capacity, and residual volume. In this treatment group, LP-211 induced significant dose-dependent increases in micturition volume, resulting in significant increases in voiding efficiency (P<0.001) compared to intact and sham-operated rats, SB-269970 (0.1 mg/kg, i.v.) completely reversed the LP-211-induced changes on micturition volume and voiding efficiency was decreased significantly. CONCLUSION: The 5-HT7 receptors activation by LP-211 facilitated the micturition reflex. Furthermore, 5-HT7 receptors do seem to play an important role in physiological regulation of micturition, and as a result, may represent a new strategy to improve voiding efficiency after SCI in patients in the future perspective.

Effect of glatiramer acetate on short-term memory impairment induced by lipopolysaccharide in male mice.

Glatiramer acetate (GA) demonstrates neuroprotective, neurogenesis, and anti-inflammatory properties. This study examines the probable protective effect of acute GA on lipopolysaccharide (LPS)-induced memory impairment in male mice and further explores which routes of administration [subcutaneous (s.c.) or intracerebroventricular (i.c.v.)] exert optimum effect. Memory performance was evaluated in two-trial recognition Y-maze and passive-avoidance tasks evaluating special recognition memory and fear memory, respectively. Memory impairment was induced by LPS [100 µg/kg, intraperitoneally (i.p.)], 4 h before training. In Y-maze, GA (10, 2.5, 0.625, 0.153, and 0.03 mg/kg, s.c.; 250 µg/mouse; i.c.v.) was administered 10 min following LPS, and special memory was assayed in Y-maze apparatus. In passive avoidance, LPS (100, 250 µg/kg; i.p.) was injected 4 h before receiving foot shock, and GA (10, 2.5; s.c.) or (250 µg/mouse; i.c.v.) was administered 4 h before the shock. Following 24 h, the fear memory was evaluated. Memory impaired significantly following LPS (100, 250 µg/kg; i.p.) in Y-maze and passive-avoidance tasks, P < 0.001 and P < 0.05, respectively. The data revealed that GA (250 µg/mouse, i.c.v.) and GA (10, 2.5 mg/kg; s.c.) in Y-maze reversed memory impairment (LPS 100 µg/kg, i.p.) (P < 0.01). In passive-avoidance task, GA (2.5, 10 mg/kg; s.c.) reversed LPS-induced impairment and the mice showed significantly longer latency times during the retention trial (P < 0.01). GA improved memory impairment both centrally and systemically. It improved spatial recognition memory increasing the average time in the novel arm and improved fear memory increasing latency time. GA administration improved memory impairment profoundly through both systemic and central routs.

Effect of Withania somnifera Dunal Root Extract on Behavioral Despair Model in Mice: a Possible Role for Nitric Oxide.

Withania somnifera (WS) possess anti-inflammatory and antioxidant properties. WS preparations have a potential therapeutic role in the central nervous system (CNS) related disorders in animal models. In this study, the possible protective effect of acute aqueous WS root extract on behavioral despair was explored and compared with fluoxetine, an antidepressant with selective serotonin (5-HT) reuptake inhibitor activity (SSRI). Further, the probable involvement of nitric oxide (NO) determined to measure immobility time in forced swimming test (FST) and tail suspension test (TST) in male mice. Immediately after assessment of locomotor activity, the immobility time was evaluated. WS was administered intraperitoneally (200, 400 mg/kg; i.p.) 60 min before the behavioral tests. To assess the involvement of NO in the possible protective effect of WS, a non-specific NO synthase inhibitor, NG-L-arginine methyl ester (L-NAME, 10 mg/kg, i.p.) was administered 30 min before the extract administration (400 mg/kg, i.p.), 90 min before the tests. Acute WS extract (200, 400 mg/kg, i.p.) dose-dependently decreased the immobility time in FST, P<0.05, P<0.001, respectively and 400 mg/kg proved the most effective dose and this dose was comparable to fluoxetine (20 mg/kg, i.p. WS (400 mg/kg, i.p.) also lowered the immobility measure in TST (P<0.05). However, these effects were not related to change in locomotor activity. Moreover, L-NAME (10 mg/kg, i.p.) did not influence the effect of the extract on the behavioral tests. As a consequence, the immobility time was virtually constant between the group received the extract (400 mg/kg) alone, and the group received L-NAME (10 mg/kg) before the extract. It is probable that NO does not mediate this beneficial effect, and WS may affect other neurochemical systems and pathways.

Evaluating Knowledge, Attitude and Practice of Health-Care Workers Regarding Patient Education in Iran.

The objective of the study was to evaluate the position of patient education measuring knowledge, attitude, and practice (KAP) among health care workers (HCWs). It is also aimed to emphasize the need for a real position for patient education. This survey was performed among a group of HCWs in Iran. The scores had an acceptable level. However, nurses, females and younger people received higher scores. The staff was already aware of patient education necessity and considered it as the duty of all medical team. Often HCWs cannot include patient education in their routine due to time shortage, lack of staff's financial motivation, fatigue, and loads of work, etc. There is still need for a real training in the educational curriculum. Additionally, the various HCWs-related obstacles should be taken into account.

Behavioral despair associated with a mouse model of Crohn's disease: Role of nitric oxide pathway.

Crohn's disease (CD) is associated with increased psychiatric co-morbidities. Nitric oxide (NO) is implicated in inflammation and tissue injury in CD, and it may also play a central role in pathogenesis of the accompanying behavioral despair. This study investigated the role of the NO pathway in behavioral despair associated with a mouse model of CD. Colitis was induced by intrarectal (i.r.) injection of 2,4,6-trinitrobenzenesulfonic acid (10mg TNBS in 50% ethanol). Forced swimming test (FST), pharmacological studies and tissues collection were performed 72 h following TNBS administration. To address a possible inflammatory origin for the behavioral despair following colitis induction, tumor necrosis factor-alpha (TNF-α) level was measured in both the hippocampal and colonic tissue samples. In parallel, hippocampal inducible nitric oxide synthase (iNOS) and nitrite level were evaluated. Pharmacological studies targeting the NO pathway were performed 30-60 min before behavioral test. Colitis was confirmed by increased colonic TNF-α level and microscopic score. Colitic mice demonstrated a significantly higher immobility time in the FST associated to a significant increase of hippocampal TNF-α, iNOS expression and nitrite content. Acute NOS inhibition using either Nω-nitro-l-arginine methyl ester (a non-specific NOS inhibitor) or aminoguanidine hydrochloride (a specific iNOS inhibitor) decreased the immobility time in colitic groups. Moreover, acute treatment with both NOS inhibitors decreased the TNF-α level and nitrite content in the hippocampal samples. This study suggests that the NO pathway may be involved in the behavioral effects in the mouse TNBS model of CD. These findings endow new insights into the gut-brain communication during the development of colonic inflammation, which may ultimately lead to improved therapeutic strategies to combat behavior changes associated with gastrointestinal disorders.

Serotonin 5-HT7 receptor agonist, LP-211, exacerbates Na(+), K(+)-ATPase/Mg(2+)-ATPase imbalances in spinal cord-injured male rats.

BACKGROUND: The observed controversy that N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (LP-211), a selective serotonin (5-HT7) receptor agonist, may either modify or exacerbate imbalances in serum electrolyte concentrations and renal tissue of spinal cord trauma cases has not been reported yet. The aim of this study was to better understand the effects of a new 5-HT7 receptor agonist, LP-211, on serum electrolyte changes in spinal cord injured- (SCI) rats. METHODS: Sixty male rats were assigned to the following groups: A) Intact (saline as vehicle, 1 ml/kg, i.p.), B) Intact [LP-211, (0.003-0.3 mg/kg, i.p.)], C) Sham-operated [laminectomy + vehicle (1 ml/kg, i.p.)], D) Sham-operated [laminectomy + LP-211 (0.003-0.3 mg/kg, i.p.)], E) Treatment [laminectomy + spinal trauma (SCI) + vehicle (1 ml/kg, i.p.)], F) Treatment [laminectomy + spinal trauma + LP-211 (0.003-0.3 mg/kg, i.p.)]. SCI was performed by placing an aneurysm clip, extradurally at the level of T10. After two weeks, LP-211 was administered cumulatively and each dose was injected (i.p.) with 20 min interval. At the end of the experiment, blood samples were collected for biochemical evaluations of the electrolytes employing standard commercial kits. RESULTS: The present results indicate elevated serum levels of Na(+), K(+), and Mg(2+) in SCI rats and significant differences demonstrated between the groups [P < 0.001, F(5, 35) = 23.92], [P < 0.001, F(5, 35) = 67.63], [P < 0.001, F(5, 35) = 71.144], respectively. So that, in groups B, D and F, there was a significant increase in K(+) and Mg(2+) serum levels compared to the groups A, C, and E (P < 0.001). Furthermore, Na(+) serum levels in SCI (LP-211), laminectomy (LP-211), and intact (LP-211) groups tended to be statistically lower than SCI (saline), laminectomy (saline) and intact (saline) groups. Infact, hyponatremia, hyperkalemia and hypermagnesemia was obtained in group F. Nevertheless, in the remaining measured serum electrolytes such as calcium (Ca(2+)), iron (Fe(2+)) and phosphorus (P(3-)), chlorine (Cl(-)), copper (Cu(+)), and zinc (Zu(+)), no significant changes were observed. CONCLUSION: It was shown that acute additive LP-211 treatments in the SCI group led to hyponatremia, hyperkalemia and hypermagnesemia, it may be stated that LP-211 treatment as a promising candidate for treating SCI complications in some systems especially urinary tract might take into consideration and further studies would be needed to clarify its benefits or drawbacks. The observed discrepancies, nevertheless; will also pose new questions. Altogether, this will ultimately contribute to further understanding the pathophysiological role regarding 5-HT7 receptor activation.

Possible involvement of nitric oxide in antidepressant-like effect of silymarin in male mice.

CONTEXT: Silymarin (SM) is extracted from milk thistle Silybum marianum L. [Asteraceae (Compositae)] and known for antioxidative and anti-inflammatory effects. OBJECTIVE: The potential antidepressant-like effect of acute SM and possible involvement of nitric oxide (NO) were determined in male mice. MATERIAL AND METHODS: SM was administered orally (5, 10, 20, 50, 100, and 200 mg/kg; p.o.) 60 min before the tests. After assessment of locomotor activity, the immobility time was measured in forced swimming test (FST) and tail suspension test (TST). To assess the possible involvement of NO, a non-specific NO synthase inhibitor, L-NAME (10 mg/kg, i.p.), and a specific iNOS inhibitor, aminoguanidine (AG) (50 mg/kg, i.p.), were administered separately 30 min before SM (20 and 100 mg/kg). RESULTS: SM at its effective doses 10, 20, 50, and 100 mg/kg decreased the immobility time in a dose-dependent manner (p < 0.01, p < 0.05, p < 0.05, and p < 0.001, respectively) in FST. SM (10, 20, 50, and 100 mg/kg) also lowered the immobility measure dose dependently in TST (p < 0.01, p < 0.05, p < 0.01, and p < 0.001, respectively). In addition, 50% of maximum response (ED50) of SM was around 10 mg/kg. The dose 100 mg/kg proved the most effective dose in both the tests. Further, this effect was not related to changes in locomotor activity. Moreover, L-NAME reversed the effect of SM (20 and 100 mg/kg) in FST and SM (100 mg/kg) in TST. However, AG did not influence this impact. CONCLUSION: The antidepressant-like effect of SM is probably mediated at least in part through NO and SM may increase NO tune.

The role of structural C--H compared with phenolic OH sites on the antioxidant activity of oleuropein and its derivatives as a great non-flavonoid family of the olive components: a DFT study.

Oleuropein and its derivatives are the main phenolic compounds of Olea europaea L. leaf and fruit. The structure-antioxidant activity relationship was considered for studying the radical scavenging activity of this non-flavonoid family of the olive components using density functional theory (DFT). The structure of these compounds were optimized employing the B3LYP/6-31G (d,p) and the role of some structural CH positions was compared with phenolic OH sites on radical scavenging. As a result, a radical unique position (C3) in the oleuropein, characterized by low BDE (Bond Dissociation Enthalpy), reasonable spin density and electron distribution, was identified. The experimental results of the previous publications of oleuropein for NO and OH scavenging confirmed the presence of this unique active site in its molecular structure. According to the results, 2,2-diphenylpicrylhydrazyl (DPPH) cannot find this non-marginal active site. Therefore, DPPH may not be a determinant assay for all antioxidant comparisons. Solvent effects were considered in all calculations using a Polarized Continuum Model (PCM) at the B3LYP/6-31G (d,p) level. Solvation calculations were carried out for benzene (ε=2.3) to simulate the oil environment compared to gas phase.

Protective effect of hydroalcoholic olive leaf extract on experimental model of colitis in rat: involvement of nitrergic and opioidergic systems.

The aim of the present study is to investigate the possible protective effect of dry olive leaf extract (OLE) against acetic acid-induced ulcerative colitis in rats, as well as the probable modulatory effect of nitrergic and opioidergic systems on this protective impact. Olive leaf extract was administered (250, 500 and 750 mg/kg) orally for two successive days, starting from the colitis induction. To assess the involvement of nitrergic and opioidergic systems in the possible protective effect of OLE, L-NG-Nitroarginine Methyl Ester (10 mg/kg) and naltrexone (5 mg/kg) intraperitoneal (i.p.) were applied 30 min before administration of the extract for two successive days, respectively. Colonic status was investigated 48 h following induction through macroscopic, histological and biochemical analyses. Olive leaf extract dose-dependently attenuated acetic acid-provoked chronic intestinal inflammation. The extract significantly reduces the severity of the ulcerative lesions and ameliorated macroscopic and microscopic scores. These observations were accompanied by a significant reduction in the elevated amounts of TNF-α and interlukin-2 markers. Moreover, both systems blockage reversed protective effects of OLE in the rat inflammatory bowel disease model. These finding demonstrated, for the first time, a possible role for nitrergic and opioidergic systems in the aforementioned protective effect, and the extract probably exerted its impact increasing nitric oxide and opioid tones.

Muscimol delays lipopolysaccharide-induced preterm delivery in mice: role of GABA(A) receptors and nitric oxide.

OBJECTIVES: Immunologic processes are involved in preterm delivery (PTD). Considering the anti-inflammatory properties of muscimol (GABA(A) agonist), the effect of this drug was evaluated in lipopolysaccharide-induced PTD in mice. METHODS: PTD was induced by two intraperitoneal injections of lipopolysaccharide (35 µg/kg; n = 11), on gestational day 15 (d15). Muscimol was administered twice on d14 and twice on d15 (1 h prior to each lipopolysaccharide injection; 0.05, 0.1, 0.2 mg/kg; intraperitoneally; n = 8-12). To assess the involved mechanisms, either bicuculline (GABA(A) antagonist; 0.1 and 1 µg/kg; intraperitoneally; n = 6-7) or N(ω)-nitro-l-arginine methyl ester (l-NAME; non-selective inhibitor of nitric oxide (NO) synthase enzymes; 2 mg/kg; intraperitoneally; n = 6) were administered 1 h before each muscimol administration on d14 and the first dose of muscimol on d15. Maternal plasma and amniotic fluid nitrite + nitrate levels, placental histopathologies and uterine contractions were assessed. RESULTS: Muscimol (0.1 mg/kg) significantly decreased lipopolysaccharide-induced PTD rates from 100 to 50% and delayed delivery time from d16 to d18. Muscimol moderately increased maternal plasma and amniotic fluid nitrite + nitrate concentrations and decreased lipopolysaccharide-induced placental inflammation and surge in nitrite + nitrate levels. Contrary to bicuculline, l-NAME reversed the beneficial effects of muscimol. Muscimol did not affect myometrial contractions. CONCLUSIONS: Muscimol inhibits lipopolysaccharide-induced PTD through modulating NO release.

Atorvastatin improved scopolamine-induced impairment in memory acquisition in mice: involvement of nitric oxide.

UNLABELLED: Atorvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, widely used in treatment of hypercholesterolemia, slows the progression of mild-to-moderate Alzheimer's disease. In this study, effects of atorvastatin on acquisition of spatial recognition memory and the involvement of nitric oxide (NO) have been determined in a two-trial recognition Y-maze test and passive avoidance. Atorvastatin (1, 5mg/kg, p.o.) was administered prior to acquisition phase, either in presence or in absence of a non-specific NO synthase inhibitor, L-NAME (3, 10mg/kg, i.p.); a specific inducible NO synthase inhibitor, aminoguanidine (100mg/kg); and a NO precursor, l-arginine (750mg/kg). RESULTS: Atorvastatin significantly improved memory performance in a dose-dependent manner in acquisition of recognition memory, in both Y-maze and passive avoidance tests. 1) Atorvastatin (5mg/kg) significantly increased both exploration time and number of arm entries in scopolamine-treated mice in Y-maze. 2) The beneficial effects of atorvastatin on memory acquisition were significantly reversed by L-NAME (3mg/kg) and aminoguanidine (100mg/kg). 3) The effects of sub-effective dose of atorvastatin (1mg/kg) on memory acquisition were not potentiated by l-arginine (750mg/kg); 4) Administration of atorvastatin (5mg/kg) significantly increased step-through latency in scopolamine-induced memory-impaired mice. 5) Beneficial effect of atorvastatin on passive avoidance was not reversed by L-NAME (up to 10mg/kg). 6) The effects of sub-effective dose of atorvastatin (1mg/kg) on passive avoidance were not potentiated by l-arginine (750mg/kg). The present study demonstrates that atorvastatin improved both short-spatial recognition memory and fear memory. As this effect is reversed by L-NAME and aminoguanidine in short-term memory acquisition, it is concluded that NO might be involved in spatial memory improvement by atorvastatin.