Assessment the satisfaction level of faculty members from virtual teaching during corona crisis in Rafsanjan School of Medicine.

BACKGROUND: Evaluating the experiences and the satisfaction level of the academic members is an important parameter in planning for virtual education during COVID-19 pandemic. The present study was designed to evaluate the satisfaction level of faculty members of Rafsanjan School of Medicine regarding virtual education in COVID-19 crisis in two stages between 2019 and 2022. MATERIAL AND METHODS: This descriptive study was conducted on the faculty members of Rafsanjan Medical School. The satisfaction level with virtual education during the COVID-19 pandemic was determined using a researcher-made questionnaire with appropriate validity and reliability. For analysing of quantitative variables, the Kolmogorov-Smirnov test, independent t tests and one-way analysis of variance and multiple linear regression were used. RESULTS: Data showed that only 15.2% of the faculty members had a previous experience of virtual teaching prior to the pandemic and 30.3% had a history of passing the empowerment course on virtual education before the COVID-19 crisis. Moreover, 68.2% passed the empowerment course on virtual education at the same time as the COVID-19 epidemic spread. The overall satisfaction with virtual education in the first and second stages of the study was 49.05 and 49.22 out of 100, respectively. The satisfaction of NAVID learning management system was 66.66 percent among faculty members. The level of satisfaction in non-clinical members was significantly more than clinical members. CONCLUSION: The overall satisfaction of faculty members with virtual education was at an average or medium level. From the point of view of the faculty members, some aspects of virtual education need to be improved. Therefore, it seems necessary to improve the infrastructure and empower the faculty members to enhance the quality of virtual education.

Gemfibrozil, a lipid-lowering drug, improves hepatorenal damages in a mouse model of aging.

Gemfibrozil (GFZ) is a medication of the fibrate category with agonistic effects on peroxisome proliferator-activated receptor-α (PPAR-α) and is effective for hypertriglyceridemia and mixed dyslipidemia. This agent also has anti-inflammatory and antioxidant properties. The current study investigated the effects of GFZ on hepatorenal damages in a D-galactose (D-gal)-induced aging model. We used 28 male mice, which were equally and randomly divided into four groups as follows: normal, D-gal (150 mg/kg/day; intraperitoneal [i.p.], for 6 weeks), GFZ (100 mg/kg/day GFZ, orally [p.o.] for 6 weeks), and the combined D-gal + GFZ. Liver and kidney function indices were measured as serum creatinine, blood urine nitrogen, alanine aminotransferase, and aspartate aminotransferase. Oxidative stress in hepatic and renal tissue was evaluated through malondialdehyde, superoxide dismutase, and glutathione peroxidase levels. Finally, the liver and kidney tissues were assessed for histopathological lesions. The results showed that D-gal-induced aging leads to abnormalities in liver and kidney function indices. D-gal also induced significant oxidative stress and histopathological lesions in these organs. GFZ improved function indices and oxidative stress compared to the D-gal-treated animals. Histological evaluations of the liver and kidney also confirmed these results. These data provide evidence for the potential therapeutic of GFZ in clinical practice for mitigating the hepatorenal damages of aging.

The effectiveness of virtual interactive video in comparison with online classroom in the stroke topic of theoretical neurology in COVID-19 pandemic.

BACKGROUND: Sufficient interaction between the trainers and the trainees in medical education is always one of the biggest challenges for an educational system. This study was designed to evaluate the effect of virtual interactions within the educational content of stroke on the effectiveness of teaching for general medicine students during COVID-19 crisis. MATERIALS AND METHODS: Eight medical students applying for stroke education were divided into two groups by simple random sampling (Rafsanjan Medical School, 2020). The first group participated in an online classroom via the Adobe Connect platform without virtual interaction. The second group used a video presentation containing interaction scenarios. The effectiveness evaluation of each type of educational content was done by comparison of the final exam scores and the results of an electronic satisfaction questionnaire in each group. Finally, using SPSS software version 18, the data were analyzed with independent samples t-test. RESULTS: This study showed that the mean of the examination scores of the interactive virtual content group (6.14 ± 1.46) was significantly higher than the online class group (4.50 ± 1.50) (P < 0.001), and also the results of satisfaction assessment showed that this group was more satisfied with their educational content (P = 0.005). CONCLUSION: Evaluation of the virtual stroke training effectiveness for general medical students shows that the educational approach of video with virtual interactions is an effective learning method in medical topics and can be considered as an efficacious educational model in online teaching.

Ischemic post-conditioning is neuroprotective even at delayed tPA administration after embolic stroke in female rats.

Objectives: Delayed tissue plasminogen activator (tPA) thrombolysis is accompanied by different complications in stroke patients. Studies reported sex differences in stroke therapy. Ischemic postconditioning (PC) unveils neuroprotection in stroke models. In this study, we investigate the combined effect of delayed tPA therapy and PC procedure during an embolic stroke experimental model in female rats. Materials and Methods: Female Wistar rats were randomly divided into control (saline), tPA, PC, and tPA+PC groups after stroke induction via clot injection to the middle cerebral artery. tPA treatment was initiated 6 hr after stroke, and PC procedure was performed 6.5 hr post-ischemia induction (occlusion: 10 sec; reopening: 30 sec; 5 cycles). The cerebral blood flow (CBF) was recorded up to 60 min from IV tPA injection time. The parameters of brain edema, infarct volume, disruption of the blood-brain barrier (BBB), behavioral tests, and matrix metalloproteinases-9 (MMP-9) were evaluated. Results: This study revealed that PC conduction prevents excessive CBF increase by tPA and played a protective role in infarct volume reduction (P<0.05). The combination of PC and tPA reduced the infarct volume, brain edema, and protected BBB. tPA+PC could alleviate neurobehavioral disorders compared with control or tPA. Moreover, PC had the capability of MMP-9 reduction when combined with delayed tPA (P<0.05). Conclusion: Conduction of PC not only alleviated some stroke complications but also enhanced the therapeutic time window of tPA in female rats under embolic stroke.

Whole body hypothermia extends tissue plasminogen activator treatment window in the rat model of embolic stroke.

Late treatment with tissue plasminogen activator (tPA) leads to reperfusion injury and poor outcome in ischemic stroke. We have recently shown the beneficial effects of local brain hypothermia after late thrombolysis. Herein, we investigated whether transient whole-body hypothermia was neuroprotective and could prevent the side effects of late tPA therapy at 5.5 h after embolic stroke. After induction of stroke, male rats were randomly assigned into four groups: Control, Hypothermia, tPA and Hypothermia+tPA. Hypothermia started at 5 h after embolic stroke and continued for 1 h. Thirty min after hypothermia, tPA was administrated. Infarct volume, brain edema, blood-brain barrier (BBB) and matrix metalloproteinase-9 (MMP-9) were assessed 48 h and neurological functions were assessed 24 and 48 hour post-stroke. Compared with the control or tPA groups, whole-body hypothermia decreased infarct volume (P < 0.01), BBB disruption (P < 0.05) and MMP-9 level (P < 0.05). However, compared with hypothermia alone a combination of hypothermia and tPA was more effective in reducing infarct volume. While hypothermia alone did not show any effect, its combination with tPA reduced brain edema (P < 0.05). Hypothermia alone or when combined with tPA decreased MMP-9 compared with control or tPA groups (P < 0.01). Although delayed tPA therapy exacerbated BBB integrity, general cooling hampered its leakage after late thrombolysis (P < 0.05). Moreover, only combination therapy significantly improved sensorimotor function as well as forelimb muscle strength at 24 or 48 h after stroke (P < 0.01). Transient whole-body hypothermia in combination with delayed thrombolysis therapy shows more neuroprotection and extends therapeutic time window of tPA up to 5.5 h.

Pro-neurocognitive and anti-sarcopenic benefits of one-year metformin therapy in ovariectomized aged mice.

Health promotion and healthy nutrition significantly increased life expectancy around the world. Aging is associated with an increase in age-related diseases. The use of metformin (Met) as an anti-aging drug has recently been proposed based on its widespread use in clinical practice. Reports have shown that Met acts as an anti-aging agent. In this study, the effects of long-term, 1 year, Met administration on aging-related behaviors and longevity in ovariectomized mice was studied. Met (1 and 10 mg/kg, daily) was administered orally in ovariectomized mice. The anxiety-like behavior, working memory, and physical strength were measured through elevated plus maze, Y-maze, vertical grid holding, and the obligatory swimming capacity tests. Brains were harvested to measure brain-derived neurotrophic factor (BDNF) level. Also, the Kaplan-Meier survival curves were used to show differences and similarities in survival patterns. Met (10 mg/kg) decreased anxiety-like behaviors as well as increased muscle strength and working memory in the ovariectomized mice. Moreover, Met increased the physical strength and longevity as well as the level of BDNF in the ovariectomized mice. Our results indicate that Met administration can be an effective strategy for having a healthy aging in the absence of female gonadal hormones and reverses deleterious effects of ovariectomy-induced aging possibly through BDNF.

Effect of oleuropein on morphine-induced hippocampus neurotoxicity and memory impairments in rats.

Oleuropein, as an olive leaf extract antioxidant polyphenol, has been reported to be a free radical scavenger. This study was done to investigate the effects of oleuropein, against morphine-induced hippocampus neurotoxicity and memory impairment in rats. The Morris water maze (MWM) test was used to assess the effect of oleuropein (5, 15, and 30 mg/kg, i.p., co-administrated with morphine) on spatial learning and memory of male Wistar rats which were treated with morphine sulfate (45 mg/kg, s.c., 4 weeks). In order to evaluate the cleaved caspase-3, Bax, and Bcl2 protein expression (as biochemical markers of apoptosis) in CA1 area of hippocampus tissue, the western blot test was used. Also, to evaluate the oxidative stress status of hippocampus CA1 area tissue, the malondialdehyde (MDA) level, superoxide dismutase (SOD) activity, and glutathione peroxidase (GPx) activity were assessed. The data showed that oleuropein treatment (15 and 30 mg/kg) improves the spatial learning and memory impairments in morphine-treated animals. Also, oleuropein treatment decreased the apoptosis and oxidative stress levels in the hippocampus CA1 area of morphine-treated rats. Oleuropein can prevent the spatial learning and memory impairments in morphine-treated rats. Molecular mechanisms underlying the observed effects could be at least partially related to the inhibition of neuronal apoptosis and oxidative stress in the hippocampus CA1 area of morphine-treated rats.

Nitric oxide and glutamate are contributors of anti-seizure activity of rubidium chloride: A comparison with lithium.

The neuro-protective effects of rubidium and lithium as alkali metals have been reported for different central nervous system dysfunctions including mania and depression. The aim of this study was evaluating as well as comparing the effects of rubidium chloride (RbCl) and lithium chloride (LiCl) on different seizures paradigms in mice and determining the involvement of NMDA receptors and nitrergic pathway. To assess the seizures threshold, animals received intravenous pentylenetetrazole (PTZ, 0.5%; 1 mL/min). Male NMRI mice (6-8 weeks) received intraperitoneal (i.p.) injections of different doses of RbCl and LiCl. Doses greater than 10 mg/kg of RbCl showed a significant anticonvulsant activity 60 min after administration; the anticonvulsant effects of LiCl was observed at the doses more than 5 mg/kg and after 30 min in PTZ-induced seizure threshold. But, RbCl (10, 20 mg/kg, i.p) or LiCl (5, 10 mg/kg, i.p) injection did not induce protection against maximal electroshock (MES) or intraperitoneal injection of PTZ lethal dose (80 mg/kg)-induced seizure models. Pre-treatment with L-NAME (non-selective nitric oxide synthase (NOS) inhibitor, 10 mg/kg; i.p.) and 7-nitroindazole (selective neuronal NOS inhibitor, 30 mg/kg; i.p.) enhanced the anticonvulsive effects of both RbCl (5 mg/kg, i.p.) and LiCl (1 mg/kg, i.p.) in PTZ-induced seizure threshold model. Injection of MK-801 (NMDA receptor antagonist, 0.05 mg/kg; i.p.) before RbCl (5 mg/kg, i.p.; P < 0.001) and LiCl (1 mg/kg, i.p.; P < 0.001) administration increased the anti-seizure activity. But, treatment with L-arginine (precursor of nitric oxide, 100 mg/kg; i.p.) decreased the seizure threshold of both RbCl (20 mg/kg, i.p.; P < 0.001) and LiCl (10 mg/kg, i.p.; P < 0.001). Measurement of nitrite levels in hippocampus of animals revealed a remarkable reduction after treatment with RbCl (20 mg/kg, i.p; P < 0.05) and LiCl (10 mg/kg, i.p; P < 0.01). To conclude, rubidium may protect central nervous system against seizures in PTZ-induced seizures threshold model through NMDA/nitrergic pathways with a similarity to lithium effects in mice.

Sumatriptan ameliorates renal injury induced by cisplatin in mice.

OBJECTIVES: Cisplatin (Cis) is an anticancer compound, which is used for the treatment of various cancers. Sumatriptan (Suma) is a selective agonist of 5-hydroxytryptamine 1B/1D (5HT1B/1D) receptor, which is prescribed for the management of migraine. It is well-established that Suma has anti-inflammatory and antioxidant properties. We have explored the protective effects of Suma in the mitigation of Cis-induced nephrotoxicity. MATERIALS AND METHODS: The mice received a single IP injection of Cis (20 mg/kg) on the first day of the experiment. Suma treatment (0.1 and 0.3 mg/kg/day, IP) was started on day 1 and continued for 3 consecutive days. RESULTS: Creatinine (Cr), blood urea nitrogen (BUN) and malondialdehyde (MDA) levels were elevated and glutathione peroxidase (GPx) as well as superoxide dismutase (SOD) activities were decreased in Cis-treated mice. Suma (more potently 0.3 mg/kg) reduced Cr, BUN and MDA levels and increased SOD and GPx levels. Suma also reduced the acute renal injury (tubular degeneration, tubular cells vacuolation, tubular necrosis and cast), which corresponded to kidney damage in Cis-treated mice. CONCLUSION: These findings demonstrate that Suma mitigates Cis-induced renal injury by inhibition of oxidative stress and enhancing the antioxidant enzymes activities.

The effects of fluoxetine on the human adipose-derived stem cell proliferation and differentiation.

Fluoxetine is one of the most commonly used antidepressants. Fluoxetine could prevent the mesenchymal stem cell differentiation in lung fetus of rat. Moreover, the mesenchymal stem cells are also present in adult tissues. Therefore, in the current study, we aimed to investigate the effects of fluoxetine (FLX) on both proliferation and adipogenic/osteogenic differentiation of human adipose-derived stem cells (ADSCs). After culturing of human ADSCs, these cells were treated with two concentrations of FLX (10 and 20 µm). Then, cells were differentiated by adding osteogenic and adipogenic media. The effect of FLX on human ADSCs proliferation was evaluated by MTT assay. Fluoxetine role on adipogenic and osteogenic differentiation of human ADSCs was analyzed by oil red and alizarin red staining and RT-PCR reaction. According to MTT assay, FLX showed a time- and concentration-dependent proliferation response and eventually decreased human ADSCs proliferation. RT-PCR analysis indicated that FLX significantly diminished the expression of osteogenesis-related genes such as RUNX2 and alkaline phosphatase (ALP). Data also revealed a significant reduction in the expression of peroxisome proliferator-activated receptor γ (PPARγ) and fatty acid-binding protein (FABP) (specific genes of adipogenic lineage). In addition, FLX decreased mineralized matrix and the amount of lipid droplets in human ADSCs by staining methods. Our observation demonstrated that the effects of FLX may be time-dependent. This drug possesses an increasing phase in proliferation and survival of human ADSCs (first 24 h) following a decreasing phase (after 48 h). Moreover, FLX could attenuate both osteogenic and adipogenic differentiation of human ADSCs.

Acute foot-shock stress decreased seizure susceptibility against pentylenetetrazole-induced seizures in mice: Interaction between endogenous opioids and cannabinoids.

BACKGROUND: Stressful conditions affect the brain's neurotransmission and neural pathways that are involved in seizure susceptibility. Stress alters the intensity and/or frequency of seizures. Although evidence indicates that chronic stress exerts proconvulsant effects and acute stress has anticonvulsant properties, the underlying mechanisms which mediate these effects are not well understood. In the present study, we assessed the role of endogenous opioids, endocannabinoids, as well as functional interaction between opioid and cannabinoid systems in the anticonvulsant effects of acute foot-shock stress (FSS) against pentylenetetrazole (PTZ)-induced seizures in mice. METHODS: Prolonged intermittent FSS was chosen as an acute stress model. Seizure threshold was determined after 30 min of stress induction in male Naval Medical Research Institute (NMRI) mice (20-30 g). Opioid and cannabinoid receptor antagonists were administered before animal placement in the FSS apparatus. RESULTS: Acute FSS significantly decreased seizure susceptibility in animals. The administration of the cannabinoid receptor 1 (CB1) antagonist, AM251, completely blocked the anticonvulsant effect of acute FSS at the doses of 1 pg/kg-100 µg/kg but not at 1 fg/kg. Pretreatment with the nonspecific opioid receptor antagonist, naltrexone (NTX), significantly inhibited the anticonvulsant effects of acute FSS at 1 and 2 mg/kg but not at 0.3 mg/kg. However, coadministration of the subeffective doses of AM251 (1 fg/kg) and NTX (0.3 mg/kg) reversed the anticonvulsant effects of acute FSS. CONCLUSIONS: Opioid and cannabinoid systems are involved in the anticonvulsant effects of acute FSS, and these neurotransmission systems interact functionally in response to acute FSS.

Sumatriptan effects on morphine-induced antinociceptive tolerance and physical dependence: The role of nitric oxide.

Sumatriptan, a 5HT (5-hydroxytryptamine)1B/1D receptor agonist, showed neuroprotection in different studies. The aim of the present study was to investigate the effect of sumatriptan on morphine-induced antinociceptive tolerance and physical dependence. We also investigated the possible role of nitric oxide (NO) on sumatriptan effects. Tolerance was induced by morphine injection (50, 50, 75 mg/kg) three times daily for five days. Antinociceptive latency after acute and chronic treatment with sumatriptan (0.001, 0.01, 0.1 and 1 mg/kg) was measured by hot plate test in morphine-dependent animals. To investigate the possible involvement of NO, different isoforms of nitric oxide synthase (NOS) inhibitors including L-NAME, aminoguanidine and 7-nitroindazole were co-administered with sumatriptan. Nitrite level in mice hippocampus was quantified by Griess method. To examine the role of sumatriptan on physical dependence, three parameters of withdrawal signs were recorded after injection of naloxone (4 mg/kg). Acute treatment with sumatriptan (0.01, 0.1 and 1 mg/kg) attenuated the antinociceptive tolerance (P < 0.001). Chronic injection of sumatriptan (0.001, 0.01 and 0.1 mg/kg), as well, decreased the antinociceptive tolerance (P < 0.001). Moreover, co-administration of NOS inhibitors prevented the effects of sumatriptan. Sumatriptan significantly increased the level of nitrite only after chronic administration. Sumatriptan administration showed no alteration in naloxone-precipitated withdrawal signs. Acute and chronic administration of sumatriptan attenuated morphine antinociceptive tolerance; at least in chronic phase via nitrergic pathway. Our data did not support beneficial effects of sumatriptan on morphine-induced physical dependence in mice.

Effect of maternal fluoxetine exposure on lung, heart, and kidney development in rat neonates.

OBJECTIVES: Depression during pregnancy negatively affects fetal development. Fluoxetine as a selective serotonin reuptake inhibitor (SSRIs) is used for treatment of gestational depression. This study is trying to determine the effects of fluoxetine on the renal, heart and lung development. MATERIALS AND METHODS: Fifteen pregnant rats were treated with fluoxetine at 7 mg/kg from days 0 to 21 of gestation. Immediately after born, heart and kidney samples were evaluated for genes expression and histological assessment. Lung sample were fixed for immunohistochemical study. RESULTS: The gene expression of BMP7 and WNT4 were reduced in the kidney of fluoxetine-treated group (P-value<0.05), but in the heart of both groups no significant difference was found in gene expression (P-value>0.05). Histological assessment showed that the glomeruli of the kidneys in treated group are more primordial compared to control. There was a developmental deficiency in Bowman's capsule, and the capsular space was not clear. The arrangements of the filaments, the position of the nucleus and cells morphology were normal in the hearts of both groups. Immunohistochemical analysis demonstrated that in the fluoxetine-exposed group HoxB5 is more expressed in the mesenchymal cells, but in the control group the expression is limited to alveolar cells. CONCLUSION: According to developmental changes in kidney, heart and lung, fluoxetine affects neonatal growth during pregnancy, which may lead to delay of some organs growth. So, it is essential to survey the roles of antidepressant drugs on fatal and neonatal development during pregnancy.

Cirrhosis induced by bile duct ligation alleviates acetic acid intestinal damages in rats: Involvements of nitrergic and opioidergic systems.

BACKGROUND: Colitis, a colonic inflammatory condition, showed a linkage with hepatobiliary disorders such as cirrhosis. It has been reported that both endogenous opioids and nitric oxide (NO) play critical roles in colitis pathogenesis. Moreover, opioid and NO levels showed elevation in patients with cirrhosis. The aim of this study was to evaluate the effect of cirrhosis on the experimental model of colitis and the possible involvement of opioidergic/nitrergic systems in rats. METHODS: Colitis was induced by acetic acid 28days after bile duct ligation (BDL). L-NAME, as an inhibitor of NO synthase and naltrexone, as an antagonist of opioid receptors were administered intraperitoneally to animals during 3days after induction of colitis. Macroscopic colitis lesion area, inflammatory mediators change, NO metabolite levels, and colon microscopic injuries were assessed 3days after induction. RESULTS: Cirrhosis significantly reduced the severity of damages to the colon. Administration of L-NAME (10mg/kg), naltrexone (10mg/kg) and co-administration of L-NAME (1mg/kg) and naltrexone (5mg/kg) significantly decreased the protective effect of BDL on colitis. Nitrite elevated levels in BDL rats were significantly diminished in L-NAME- and naltrexone-treated animals. Histopathology parameters and cytokines level alterations in the colon of acetic acid-treated animals after BDL was reversed after injection of L-NAME, naltrexone, and co-administration of L-NAME (1mg/kg) + naltrexone (5mg/kg). CONCLUSION: Cirrhosis improved the intestinal damages induced by acetic acid in rats which may be mediated through interaction of nitrergic and opioidergic systems.

Anticonvulsant effect of minocycline on pentylenetetrazole-induced seizure in mice: involvement of nitric oxide and N-methyl-d-aspartate receptor.

Anticonvulsant effects of minocycline have been explored recently. This study was designed to examine the anticonvulsant effect of acute administration of minocycline on pentylenetetrazole-induced seizures in mouse considering the possible role of the nitric oxide/N-methyl-d-aspartate (NMDA) pathway. We induced seizure using intravenous administration of pentylenetetrazole. Our results showed that acute administration of minocycline increased the seizure threshold. Furthermore, co-administration of subeffective doses of the nonselective nitric oxide synthase (NOS) inhibitor NG-l-arginine methyl ester (10 mg/kg) and the neuronal NOS inhibitor 7-nitroindazole (40 mg/kg) enhanced the anticonvulsant effect of subeffective doses of minocycline (40 mg/kg). We found that inducible NOS inhibitor aminoguanidine (100 mg/kg) had no effect on the antiseizure effect of minocycline. Moreover, l-arginine (60 mg/kg), as a NOS substrate, reduced the anticonvulsant effect of minocycline. We also demonstrated that pretreatment with the NMDA receptor antagonists ketamine (0.5 mg/kg) and MK-801 (0.05 mg/kg) increased the anticonvulsant effect of subeffective doses of minocycline. Results showed that minocycline significantly decreased the hippocampal nitrite level. Furthermore, co-administration of a neuronal NOS inhibitor like NMDA receptor antagonists augmented the effect of minocycline on the hippocampal nitrite level. In conclusion, we revealed that anticonvulsant effect of minocycline might be, at least in part, due to a decline in constitutive hippocampal nitric oxide activity as well as inhibition of NMDA receptors.

Transient brain hypothermia reduces the reperfusion injury of delayed tissue plasminogen activator and extends its therapeutic time window in a focal embolic stroke model.

It has been reported that restriction of reperfusion after thrombolytic therapy in ischemic stroke may reduce tissue plasminogen activator (tPA) adverse effects and extend its time window. We examined whether shortIt has been reported that restriction of reperfusion after thrombolytic therapy in ischemic stroke may reduce tissue plasminogen activator (tPA) adverse effects and extend its time window. We examined whether short-term and mild local brain cooling can prevent hyperemia and/or adverse effects of delayed tPA in rat embolic stroke model. Male animals were subjected to embolic stroke and then randomly classified into control (saline), tPA (1mg/kg; i.v.), local hypothermia (LH), and tPA+LH. The drug was injected at 6 h after ischemia. LH was conducted by direct ipsilateral (injured) hemisphere cooling at 6.5h after stroke and maintained for approximately 30min. Cerebral blood flow was monitored in duration of 60 minute after tPA administration and hyperemic response was measured. Infarct volume, blood-brain barrier (BBB) disruption, edema formation, neurological deficits, and matrix metalloproteinase-9 (MMP-9) level were measured 48 h later. A combination of tPA+LH significantly diminished infarct volume in comparison with the tPA (P< 0.001) and control (P<0.05) groups. Combination therapy also decreased BBB leakage (P<0.001), MMP-9 level or edema (P<0.05) and improved neurological functions at 24 and 48h after stroke. LH caused a gradual decrease in hyperemic response after thrombolysis compared to the control (P<0.05) or tPA (P<0.001) groups. LH alone also reduced infarct volume, BBB leakage or edema (P<0.05). The short-term local brain hypothermia may mitigate reperfusion injury following delayed tPA therapy and extend its time window up to 6h.

Oxytocin mitigated the depressive-like behaviors of maternal separation stress through modulating mitochondrial function and neuroinflammation.

Mother-infant contact has a critical role on brain development and behavior. Experiencing early-life adversities (such as maternal separation stress or MS in rodents) results in adaptations of neurotransmission systems, which may subsequently increase the risk of depression symptoms later in life. In this study, we show that Oxytocin (OT) exerted antioxidant and anti-inflammatory properties. Previous studies indicate that neuroinflammation and mitochondrial dysfunction are associated with the pathophysiology of depression. To investigate the antidepressant-like effects of OT, we applied MS paradigm (as a valid animal model of depression) to male mice at postnatal day (PND) 2 to PND 14 (3h daily, 9AM to 12AM) and investigated the depressive-like behaviors of these animals at PND 60 in different groups. Animals in this work were divided into 4 experimental groups: 1) saline-treated, 2) OT-treated, 3) atosiban (OT antagonist)-treated and, 4) OT+ atosiban-treated mice. We used forced swimming test (FST), splash test, sucrose preference test (SPT) and open field test (OFT) for behavioral assessment. Additionally, we used another set of animals to investigate the effects of MS and different treatments on mitochondrial function and the expression of the relevant genes for neuroinflammation. Our results showed that MS provoked depressive- like behaviors in the FST, SPT and splash test. In addition, our molecular findings revealed that MS is capable of inducing abnormal mitochondrial function and immune-inflammatory response in the hippocampus. Further, we observed that treating stressed animals with OT (intracerebroventricular, i.c.v. injection) attenuated the MS-induced depressive-like behaviors through improving mitochondrial function and decreasing the hippocampal expression of immune-inflammatory genes. In conclusion, we showed that MS-induced depressive-like behaviors in adult male mice are associated with abnormal mitochondrial function and immune-inflammatory responses in the hippocampus, and activation of OTergic system has protective effects against negative effects of MS on brain and behavior of animals.

Thalidomide attenuates the development and expression of antinociceptive tolerance to µ-opioid agonist morphine through l-arginine-iNOS and nitric oxide pathway.

Morphine is a µ-opioid analgesic drug which is used in the treatment and management of chronic pain. However, due to development of antinociceptive tolerance its clinical use is limited. Thalidomide is an old glutamic acid derivative which recently reemerged because of its potential to counteract a number of disorders including neurodegenerative disorders. The potential underlying mechanisms and effects of thalidomide on morphine-induced antinociceptive tolerance is still elusive. Hence, the present study was designed to explore the effect of thalidomide on the development and expression of morphine antinociceptive tolerance targeting l-arginine-nitric oxide (NO) pathway in mice and T98G human glioblastoma cell line. When thalidomide was administered in a dose of 17.5mg/kg before each dose of morphine chronically for 5days it prevented the development of antinociceptive tolerance. Also, a single dose of thalidomide 20mg/kg attenuated the expression phase of antinociceptive tolerance. The protective effect of thalidomide was augmented in development phase when co-administration with NOS inhibitors like L-NAME (non- selective NOS inhibitor; 2mg/kg) or aminoguanidine (selective inducible NOS inhibitor; 50mg/kg). Also, the reversal effect of thalidomide in expression phase was potentiated when concomitantly administrated with L-NAME (5mg/kg) or aminoguanidine (100mg/kg). Co-administration of ODQ (a guanylyl cyclase inhibitor) 10mg/kg in developmental phase or 20mg/kg in expression phase also progressively increased the pain threshold. In addition, thalidomide (20µM) also significantly inhibited the overexpression of iNOS gene induced by morphine (2.5µM) in T98G cell line. Hence, our findings suggest that thalidomide has protective effect both in the development and expression phases of morphine antinociceptive tolerance. It is also evident that this effect of thalidomide is induced by the inhibition of NOS enzyme predominantly iNOS.

New Aspects of Silibinin Stereoisomers and their 3-O-galloyl Derivatives on Cytotoxicity and Ceramide Metabolism in Hep G2 hepatocarcinoma Cell Line.

Ceramide as a second messenger is a key regulator in apoptosis and cytotoxicity. Ceramide-metabolizing enzymes are ideal target in cancer chemo-preventive studies. Neutral sphingomyelinase (NSMase), acid ceramidase (ACDase) and glucosyl ceramide synthase (GCS) are the main enzymes in ceramide metabolism. Silymarin flavonolignans are potent apoptosis inducers and silibinin is the most active component of silymarin. This study evaluated the effects of silybin A, silybin B and their 3-O-gallyl derivatives (SGA and SGB) at different concentrations (0-200 micro molar) on ceramide metabolism enzymes in Hep G2 hepatocarcinoma cell line. Cell viability, caspase-3 and 9 activities, total cell ceramide and the activities of ACDase, NSMase and GCS were evaluated. Under silibinin derivatives treatments, cell viability decreased and the activities of caspase-3 and 9 increased in a dose dependent manner among which SGB was the most effective one (P<0.05). Total cell ceramide and the activity of NSMase, the enzyme which elevates ceramide level, increased by silibinin derivatives. Furthermore, the activities of removing ceramide enzymes (ACDase and GCS) decreased efficiently. The galloyl esterification increased the activity of silibinin isomers. Consequently, this study reveals new sibilinin effects on ceramide metabolism and potential strategies to enhance the antineoplastic properties of this compound.

Atorvastatin attenuates the antinociceptive tolerance of morphine via nitric oxide dependent pathway in male mice.

The development of morphine-induced antinociceptive tolerance limits its therapeutic efficacy in pain management. Atorvastatin, or competitive inhibitor of 3-hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase, is mainstay agent in hypercholesterolemia treatment. Beyond the cholesterol-lowering activity, exploration of neuroprotective properties of this statin indicates its potential benefit in central nervous disorders. The aim of the present study was to assess the effects of atorvastatin in development and expression of morphine-induced analgesic tolerance in male mice and probable involvement of nitric oxide. Chronic and acute treatment with atorvastatin 10 and 20mg/kg, respectively, could alleviate morphine tolerance in development and expression phases. Chronic co-administration of nitric oxide synthase (NOS) inhibitors including L-NAME (non selective NOS inhibitor; 2mg/kg), aminoguanidine (selective inducible NOS inhibitor; 50mg/kg) and 7-NI (selective neuronal NOS inhibitor; 15mg/kg) with atorvastatin blocked the protective effect of atorvastatin in tolerance reversal. Moreover, reversing the atorvastatin effect was also observed in acute simultaneous treatment of L-NAME (5mg/kg) and aminoguanidine (100mg/kg) with atorvastatin. Co-treatment of guanylyl cyclase inhibitor, ODQ (chronic dose: 10mg/kg and acute dose: 20mg/kg) was associated with prevention of atorvastatin anti-tolerance properties. Our results revealed that the atorvastatin modulating role in morphine antinociceptive tolerance is mediated at least in part via nitric oxide in animal pain models of hot plate and tail flick.