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.     

Antidepressant‐like effect of riparin II from Aniba riparia in mice: evidence for the involvement of the monoaminergic system

In a previous study conducted by our group, riparin II (ripII) isolated from the green fruit of Aniba riparia presented antianxiety effects in mice. This study investigates a possible antidepressant activity of rip II using two predictive tests for antidepressant activity in rodents: the forced swimming test (FST) and tail suspension test (TST). Additionally, the mechanisms involved in the antidepressant‐like effect in mice were also assessed. Rip II was acute administered by intraperitoneal (i.p.) and oral (p.o) routes to male mice at doses of 25 and 50 mg/kg. Results showed that ripII at both tested doses and administration routes produced a significant decrease of immobility time in FST and TST. The pretreatment of mice with prazosin (1 mg/kg, i.p., an α1‐adrenoceptor antagonist), SCH23390 (15 μg/kg, i.p., a dopamine D1 receptor antagonist), sulpiride (50 mg/kg, i.p., a dopamine D2 receptor antagonist), p‐chlorophenylalanine (100 mg/kg, an inhibitor of serotonin synthesis), or NAN‐190 (0.5 mg/kg, a serotonin 5‐HT1A receptor antagonist) completely blocked the anti‐immobility effects elicited by riparin II (50 mg/kg, p.o.) in the FST. This study indicates that riparin II produces significant antidepressant‐like activity in the forced swimming and TSTs, and this effect seems to be dependent on its interaction with noradrenergic, dopaminergic, and serotonergic systems.     

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.     

Holothuria grisea agglutinin (HGA): the first invertebrate lectin with anti‐inflammatory effects

Holothuria grisea agglutinin (HGA) is a dimeric lectin of molecular mass 228 kDa by gel filtration with monomers of 105 kDa by SDS‐PAGE. The lectin is highly thermostable as it retains full activity for 1 h at 70 °C. Unlike other lectins purified from marine invertebrates, the hemagglutination activity of HGA does not require any divalent metal ions. The affinity analysis of HGA showed that only mucin was able to inhibit the hemagglutinating activity. HGA administered intravenously was tested in classical models of nociception and inflammation. HGA was able to inhibit neutrophil migration into the peritoneal cavity induced by carrageenan. This inhibitory effect was 68% at a dose of 1 mg/kg. In acetic acid‐induced writhing tests, a significant antinociceptive effect was observed by treatment with HGA (0.1; 1 or 10 mg/kg) reducing constrictions by 27, 90 and 84%, respectively. In formalin tests, HGA at a dose of 10 mg/kg showed antinociceptive effect only in the inflammatory phase (phase 2). Nevertheless, in hot‐plate tests, HGA did not show any nociceptive effect. In rota‐rod and open‐field tests, HGA did not alter the animals' behavior. The treatment with HGA 10 mg/kg presented diminished myeloperoxidase activity activity (81.6% inhibition) and raised the circulating levels of NO by 50.4% when compared with the carrageenan group. HGA has demonstrated the ability to modulate the inflammatory response in models of inflammation in vivo. HGA is the first marine invertebrate lectin that showed an anti‐inflammatory effect. This finding opens a new perspective on the potential of lectins from the marine environment.     

A report of a galactan from marine alga Gelidium crinale with in vivo anti‐inflammatory and antinociceptive effects

The sulfated galactan of the red marine alga Gelidium crinale (SG‐Gc) was purified by ion exchange chromatography and tested by intravenous (i.v.) route in rodent experimental models of inflammation and nociception. The anti‐inflammatory activity of SG‐Gc (0.01, 0.1 and 1 mg/kg) was evaluated in the model of rat paw edema induced by different inflammatory stimuli, while SG‐Gc (0.1, 1 and 10 mg/kg) antinociceptive effect was assessed in models of nociception/hyperalgesia elicited by chemical (formalin test), thermal (hot plate), and mechanical (von Frey) stimuli in mice. In addition, the toxicity was evaluated after rat treatment with SG‐Gc (1 mg/kg; i.v.) during 10 days, followed by analysis of the wet weight of animal’s body/organs and hematological/biochemical parameters. Sulfated galactan of G. crinale inhibited the time course of dextran‐induced paw edema, at all doses, showing maximal effect at 1 mg/kg (42%) and that induced by carrageenan at 0.01 (18%) and 1 mg/kg (20%), but was ineffective on the edema elicited by zymosan. At the highest dose, SG‐Gc also inhibited the paw edema induced by histamine (49%), compound 48/80 (32%), and phospholipase A₂ (44%). Sulfated galactan of G. crinale inhibited both neurogenic and inflammatory phases of the formalin test, at all doses, and at 10 mg/kg, the animals flinch reaction in the von Frey test in the 1st and 3rd h by 19 and 26%, respectively. Additionally, SG‐Gc treatment was well tolerated by animals. In conclusion, SG‐Gc presents anti‐inflammatory effect involving the inhibition of histamine and arachidonic acid metabolites and also antinociceptive activity, especially the inflammatory pain with participation of the opioid system.     

Sunitinib–ibuprofen drug interaction affects the pharmacokinetics and tissue distribution of sunitinib to brain,liver, and kidney in male and female mice differently

Tyrosine kinase inhibitor sunitinib (used in GIST, advanced RCC, and pancreatic neuroendocrine tumors) undergoes CYP3A4 metabolism and is an ABCB1B and ABCG2 efflux transporters substrate. We assessed the pharmacokinetic interaction with ibuprofen (an NSAID used by patients with cancer) in Balb/c male and female mice. Mice (study group) were coadministered (30 min apart) 30 mg/kg of ibuprofen and 60 mg/kg of sunitinib PO and compared with the control groups, which received sunitinib alone (60 mg/kg, PO). Sunitinib concentration in plasma, brain, kidney, and liver was measured by HPLC as scheduled and noncompartmental pharmacokinetic parameters estimated. In female control mice, sunitinib AUC_0→∞ decreased in plasma (P < 0.05), was higher in liver and brain (P < 0.001), and lower in kidney (P < 0.001) vs. male control mice. After ibuprofen coadministration, female mice showed lower AUC_0→∞ in plasma (P < 0.01), brain, liver, and kidney (all P < 0.001). However, in male mice, AUC_0→∞ remained unchanged in plasma, increased in liver and kidney, and decreased in brain (all P < 0.001). The tissue‐to‐plasma AUC_0→∞ ratio was similar between male and female control mice, but changed after ibuprofen coadministration: Male mice showed 1.6‐fold higher liver‐to‐plasma ratio (P < 0.001) while remained unchanged in female mice and in kidney (male and female mice) but decreased 55% in brain (P < 0.05). The tissue‐to‐plasma partial AUC ratio, the drug tissue targeting index, and the tissue‐plasma hysteresis‐like plots also showed sex‐based ibuprofen–sunitinib drug interaction differences. The results illustrate the relevance of this DDI on sunitinib pharmacokinetics and tissue uptake. These may be due to gender‐based P450 and efflux/transporters differences.     

Elucidation of molecular mechanism involved in neuroprotective effect of Coenzyme Q10 in alcohol‐induced neuropathic pain

The aim of the present investigation was to evaluate the effect of Coenzyme Q10 and its combination with vitamin E in alcohol‐induced chronic neuropathic pain. Male Wistar rats were orally treated with alcohol (10 g/kg, 35% v/v, b.i.d.) for 10 weeks. Coenzyme Q10 (25, 50, and 100 mg/kg) and vitamin E (100 mg/kg) were coadministered orally for 1 h after ethanol administration for 10 weeks. Various nerve functions, biochemical, and molecular parameters were assessed. Chronic administration of ethanol for 10 weeks resulted significant development of neuropathic pain. Treatment with Coenzyme Q10 (50 and 100 mg/kg) for 10 weeks showed significant and dose dependently increased in level of nociceptive threshold, endogenous antioxidant, and Na,K‐ATPase enzyme. Coenzyme Q10 (50 and 100 mg/kg) significantly restored the levels of motor nerve conduction velocity and sensory nerve conduction velocity. It also showed significant decrease in levels of endogenous calcium, oxidative–nitrosative stress, TNF‐α, IL‐1β, and IL‐4 level. Alteration in protein expression of polymerase gamma (pol γ) was significantly restored the Coenzyme Q10 treatment. The important finding of the study is that, Coenzyme Q10 (100 mg/kg) and α‐tocopherol (100 mg/kg) combination‐treated rats showed more significant prevention of behavioral, biochemical, and molecular neurotoxic effect of alcohol administration than Coenzyme Q10 or α‐tocopherol alone treated group. It is evident from the finding of present investigation that plethora of mechanism including inhibition of oxido‐nitrosative stress, release of pro‐inflammatory cytokine, modulation of endogenous biomarker, and protection of pol γ protein expression simultaneously orchestrate to exhibits neuroprotective effect of Coenzyme Q10, vitamin E and their combination.     

Potential of telmisartan in the treatment of benign prostatic hyperplasia

Benign prostatic hyperplasia (BPH) is a common health problem in ageing men. This study was carried out to investigate the protective effect of telmisartan on testosterone‐induced BPH in rats. Fifty‐four male Wistar rats (200–250 g) were randomly divided into nine groups (n = 6) and orally treated for 28 consecutive days: group 1 – vehicle normal, olive oil (10 mL/kg); group 2 – BPH model control (10 mL/kg); groups 3–5 – telmisartan (5, 10 or 20 mg/kg, respectively); group 6 – pioglitazone (20 mg/kg); group 7 – celecoxib (20 mg/kg); group 8 – combination of telmisartan (5 mg/kg) and pioglitazone (20 mg/kg); group 9 – combination of telmisartan (5 mg/kg) and celecoxib (20 mg/kg). Animals in groups 2–9 were given testosterone propionate in olive oil (3 mg/kg) subcutaneously 15 min after pretreatments. On day 29, blood was collected for the estimation of serum testosterone and prostate‐specific antigen (PSA). The prostates were excised, weighed and subjected to biochemical and histological studies. Testosterone injection induced significant increase in prostatic index, serum testosterone and PSA suggesting BPH as well as increased prostate oxidative stress which were ameliorated with the pretreatment of rats with telmisartan or co‐administration of celecoxib and pioglitazone. Histological examination showed that testosterone disrupted the morphology of the prostate epithelial cells evidenced in the involution of the epithelial lining of the acini into the lumen indicating BPH which was reversed by telmisartan. Findings from this study showed that telmisartan alone or in combination with pioglitazone prevented the development of testosterone‐induced prostatic hyperplasia.     

Effects of D-004, a lipid extract from Cuban royal palm fruit, on inhibiting prostatic hypertrophy induced with testosterone or dihydrotestosterone in a rat model: A randomized, controlled study

Background:

Benign prostatic hypertrophy is the nonmalignant, uncontrolled growth of prostatic epithelial cells and stroma that, left untreated, may lead to difficult urination and other complications. A common treatment of BPH is lipid extract from saw palmetto fruit, and lipid extract from Cuban Royal palm (a palm of the same family) fruit is being studied for this use. One study found that the latter, D-004, at 100 to 400 mg/kg daily prevented prostatic hypertrophy (PH) induced with testosterone (T) in a rat model.

Objectives:

This study comprised 2 experiments in a rat model. The first assessed the effects of different doses of D-004 on T-induced PH; the second investigated the effects of D-004 on PH induced with dihydrotestosterone (DHT).

Methods:

In experiment 1, rats were distributed in 6 groups of 10 rats each. One group received an SC injection of soy oil and oral treatment with Tween 65/water vehicle (negative control). The other 5 groups received an SC injection of T 3 mg/kg daily and oral treatment with vehicle (positive control) or D-004 at 50, 200, 400, or 800 mg/kg daily suspended in vehicle. In experiment 2, rats were distributed in 3 groups of 10 rats each. A negative control group received treatment as in experiment 1. Positive controls received an SC injection of DHT 1.5 mg/kg and vehicle orally. The third group received an SC injection of DHT and oral treatment with D-004 at 800 mg/kg suspended in vehicle. All treatments were given for 14 days. At sacrifice, prostates were removed and weighed. Mean prostatic weights and prostatic/body weight ratios were calculated.

Results:

In experiment 1, in the groups receiving D-004 at 200, 400, or 800 mg/kg daily, prostatic weight was significantly lower compared with the positive control group (P < 0.05, P < 0.01, and P < 0.001, respectively); this effect was not seen in the group receiving 50 mg/kg daily. In the groups receiving D-004 at 400 and 800 mg/kg daily, prostatic/body weight ratio was significantly lower compared with positive controls (both, P < 0.05); this effect was not seen in the groups receiving 50 or 200 mg/kg daily. In experiment 2, prostatic weight and prostatic/body weight ratio in the group receiving D-004 were similar to those of positive controls. Body weight was not affected in any of the groups receiving D-004.

Conclusions:

This study of rats with T- or DHT-induced PH suggests that D-004 at 200 to 800 mg/kg daily administered orally prevents T-induced PH, and that D-004 at 800 mg/kg daily does not prevent DHT-induced PH.     

Memantine delayed N‐methyl‐D‐aspartate ‐induced convulsions in neonatal rats

Memantine (1‐amino‐3,5‐dimethyladamantane) is a moderate‐affinity uncompetitive antagonist of N‐methyl‐d‐aspartate (NMDA) receptors. In this study, we have explored the effect of memantine against N‐methyl‐d‐aspartate (NMDA)‐induced seizures in neonatal rats. Here, we evaluated various behavioral seizure abnormalities in neonatal rats (Sprague–Dawley; postnatal day 9) after an intraperitoneal administration of NMDA. Further, we explored whether an acute administration of memantine could protect these neonates against different phases of convulsions induced by NMDA. In a separate study, we have compared the effect of levetiracetam in the same animal model. Exogenous administration of NMDA (30 mg/kg., i.p.) in neonatal rats resulted in arrest of activity, emprosthotonos curvature (trunk is bent forward by the entire muscles), myoclonic jerks, and forelimb/hindlimb clonus. The clonus phase in neonates was followed by loss of righting reflex and continuous seizures (for more than 5 min) suggesting status epilepticus, tonic extension, and death. Pretreatment of memantine hydrochloride (10–30 mg/kg., i.p.) dose‐dependently delayed the onset of different phases of convulsions induced by NMDA. Memantine at the highest dose was found to be ataxic in rat neonates, while lower doses were free of any observed behavioral signs of toxicity. Levetiracetam (25 mg/kg., i.p.) when administered 30 min before the NMDA challenge blocked only the jerk phase and did not affect other phases of NMDA‐induced convulsions. These data indicated that memantine and other safer uncompetitive NMDA receptor antagonists may be protective in the management of neonatal seizures.     

Analysis of the antiepileptic,ethosuximide impacts on neurogenesis of rat forebrain stem cells

Specific GABAergic interneurons in the hilus are lost in animal models with temporal‐lobe epilepsy (TLE). Some preclinical evidence has indicated that GABAergic cells may provide relief from seizures in these models. This study was aimed to examine the ability of ethosuximide, an anticonvulsant drug, to promote neurogenesis in 3‐day‐old rat forebrain cortex stem cells. Most of the cells were found to be nestin‐positive undifferentiated neural stem cells prior to their exposure to ethosuximide. It was noted that the number and percentage of tubulin β‐III immunopositive neurons were increased after 6 days treatment with ethosuximide. Upon bFGF withdrawal, exposure to ethosuximide differentiated the stem cells to MAP2 positive neural cells (7.18 ± 0.43, 21.766 ± 0.55 and 41.57 ± 0.5 for control, 0.1 and 1 μm, respectively). GABA immunofluorescence images illustrated that ethosuximide increased GABAergic neurons (7.19 ± 0.32, 23.23 ± 0.55, and 46.30 ± 0.44 for control, 0.1 and 1 μm, respectively). Additionally, BrdU immunofluorescence assay showed that ethosuximide‐enhanced nucleus proliferation in the neuronal stem cells. Therefore, the results of this study suggest that ethosuximide may compensate damage caused by seizure attacks and possibly other neuronal loss disorders.     

The Effect of Methylnaltrexone on the Side Effects of Intrathecal Morphine after Orthopedic Surgery under Spinal Anesthesia

Methylnaltrexone is a peripheral opioid receptor antagonist that does not cross the blood–brain barrier; so without interference with pain relief, it could reverse the peripheral opioid side effects such as constipation, pruritus, postoperative ileus, and urinary retention. This study has been designed to evaluate the effect of methylnaltrexone on postoperative side effects of intrathecal morphine. In seventy‐two 18‐ to 55‐year‐old patients scheduled for elective orthopedic operations under spinal anesthesia, neuraxial blockade was achieved using 10 mg 0.5% hyperbaric bupivacaine and 0.1 mg preservative‐free morphine sulfate. The first group (M) received 12 mg methylnaltrexone, while the second group (P) received normal saline, subcutaneously, immediately after spinal block in a randomized, double‐blind fashion. There was a significant decrease in the rate of nausea and vomiting in group M, but there was no significant difference in the rate of pruritus or urinary retention between the two groups. Pain score was significantly lower in group M. Respiratory depression or decreased level of consciousness was not reported in any patient. Subcutaneous administration of methylnaltrexone was not effective in decreasing postoperative urinary retention and pruritus, but lowered the rate of nausea and vomiting and pain score after intrathecal bupivacaine and morphine.     

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.     

Study on cerebroprotective actions of Clerodendron glandulosumleaves extract against long term bilateral common carotid artery occlusion in rats

Stroke is a major cause of death and disability worldwide. The resulting burden on the society continues to grow, with increase in the incidence of stroke. Oxidative stress has been involved in the pathogenesis of several neurological diseases including acute stroke.Focal and global cerebral ischemia represents diseases that are common in the human population.In recent years much attention is being paid towards the exploration of herbal preparation, antioxidant agents and combination therapies including COX-2 inhibitors in experimental model of stroke.Possible effect of a hydroalcoholic leaf extract of Clerodendron glandulosumColeb (C. glandulosum)on oxidant-antioxidant status in ischemia-hypoperfusion injury in the rat forebrain has been investigated.Healthy adult male Wistar albino rats were divided into five groups (n = 8). Group I was served as Sham control (normal saline 1 ml/kg, orally), group II was served hypoperfusion control (normal saline 1 ml/kg, orally), group III, group IV were served as hydroalcoholic extract treated (200 and 400 mg/kg, orally) and group V was treated with Quercetin (10 mg/kg, orally) for 14 days to assess preventive and curative effects of C. glandulosum. Flavonoid and phenolic compounds exhibit a broad spectrum of biological activity, including antioxidant. C. glandulosum extract (200 and 400 mg/kg, p.o) was administered orally, once daily for a period of 2 weeks after the occlusion of BCCA. After 14th days rats were subjected to behavioral studies. After behavioral studies animals were sacrificed and brain was removed and homogenized. Estimation of Lipid peroxidation (LPO) Myeloperoxidase (MPO), estimation of protein levels and the activities of Superoxide dismutase (SOD), Catalase (CAT), were performed. Infarct size and histopathological changes were observed in treated groups.     

Investigating the role of nisoldipine in foot‐shock‐induced post‐traumatic stress disorder in mice

This study was designed to investigate the effectiveness of nisoldipine, an L‐type voltage‐sensitive calcium channel blocker, to ameliorate anxiety and fear response in a mouse model of post‐traumatic stress disorder (PTSD). Acute trauma was induced in Swiss albino mice in a 2‐day electric foot‐shock paradigm consisting of 15 intermittent foot‐shocks of 0.8 mA intensity, 10‐s duration and 10‐s intershock interval, during 5 min, followed by 3 weekly situational reminders, that is, once per week in the same context on three successive weeks. PTSD‐induced behavioral changes were assessed using actophotometer, open‐field, social interaction test, and freezing behavior. Biochemically, the serum corticosterone levels were estimated. Electric foot‐shock and situational reminders produced behavioral alterations and decreased corticosterone levels, assessed on the 21st day following the traumatic event. Administration of sertraline (Ser 15 mg/kg), a selective serotonin reuptake inhibitor (SSRI) and nisoldipine (20 and 40 mg/kg), significantly attenuated the foot‐shock‐trauma‐induced behavioral changes along with normalization of the corticosterone levels. It may be concluded that nisoldipine produces beneficial effects in re‐establishing behavioral alterations, which may be due to normalization of reduced corticosterone levels in PTSD in mice.     

Involvement of monoaminergic system in the antidepressant‐like effect of riparin I from Aniba riparia (Nees) Mez (Lauraceae) in mice

In past studies conducted by our group, riparin I (rip I) isolated from the green fruit of Aniba riparia presented antianxiety effects in mice, while its analogs rip II and III showed anxiolytic and antidepressant‐like actions. This time around, we investigated a possible antidepressant activity of rip I using the forced swimming test (FST) and tail suspension test (TST) as predictive tests for antidepressant activity in rodents. In addition, the involvement of the monoaminergic system in this effect was also assessed. rip I was acutely administered by intraperitoneal (i.p.) and oral (p.o) routes to male mice at doses of 25 and 50 mg/kg. Results showed that rip I at both tested doses and administration routes produced a significant decrease in immobility time in FST and TST. The pretreatment of mice with prazosin (1 mg/kg, i.p., an α₁‐adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an α₂‐adrenoceptor antagonist), SCH23390 (15 μg/kg, i.p., a dopamine D1 receptor antagonist), sulpiride (50 mg/kg, i.p., a dopamine D2 receptor antagonist), p‐chlorophenylalanine (100 mg/kg, an inhibitor of serotonin synthesis) or ritanserin (4 mg/kg, a serotonin 5‐HT2_a/2_c receptor antagonist) blocked the anti‐immobility effects elicited by rip I (50 mg/kg, p.o.) in the FST. Taken together, results indicate that rip I produces significant antidepressant‐like activity in the FST and TST, and this effect seems to be dependent on its interaction with noradrenergic, dopaminergic and serotonergic systems.     

Comparative study between atorvastatin and losartan on high fat diet‐induced type 2 diabetes mellitus in rats

Obesity is often associated with chronic inflammatory state which contributes to the development of insulin resistance (IR) and type 2 diabetes mellitus (T2DM). This study investigated the effects of single and combined administration of atorvastatin (ATOR, lipid‐lowering drug) and losartan (LOS, angiotensin receptor antagonist) on metabolic disorders and inflammatory status that are implicated in the development of T2DM with the use of pioglitazone (PIO) as a standard antidiabetic drug. T2DM was induced in male rats by high‐fat diet (HFD) feeding for 16 weeks. Oral administrations of ATOR (10 mg/kg), LOS (20 mg/kg), PIO (3 mg/kg), their binary combinations, or vehicle were started in the last 4 weeks. Fasting serum glucose, oral glucose tolerance, fasting serum insulin, IR, serum lipid profile, serum TNF‐α and body composition index were determined. Results showed that all drugs and their combinations had positive impact effect on all measured parameters, and better results were achieved from binary drug combinations than administration of each drug alone. Combination of PIO with either ATOR or LOS provided better improvements on T2DM‐associated metabolic abnormalities and inflammatory status with respect to each drug alone. However, the most pronounced effects of drugs and their combinations regarding the above parameters were attributed to LOS + PIO combination. In conclusion, this study indicates that combination of ATOR + PIO and, in particular, LOS + PIO can be used as promising effective therapies in the management of HFD‐induced T2DM. This concept may be attributed to the combined effects of the respective monotherapies to improve lipid profile, insulin sensitivity, and TNF‐α level.     

Atorvastatin attenuates testosterone‐induced benign prostatic hyperplasia in rats: role of peroxisome proliferator‐activated receptor‐γ and cyclo‐oxygenase‐2

Diabetes and obesity have been reported to alter sex steroid hormone metabolism. In this study, an attempt was made to investigate the protective effect of atorvastatin (ATR) in combination with celecoxib (CEL) or pioglitazone (PIO) on testosterone‐induced BPH in rats. Male Wistar rats (200–250 g) were randomly divided into nine groups (n = 8) and orally treated as follows for 28 consecutive days: group 1: vehicle control (10 mL/kg); group 2: vehicle testosterone (10 mL/kg); groups 3 ‐ 5: ATR (0.5, 2.5, and 5 mg/kg, respectively); group 6: CEL (20 mg/kg); group 7: PIO (20 mg/kg); and groups 8–9: ATR 0.5 mg/kg, and 15 min later, animals were given CEL (20 mg/kg) or PIO (20 mg/kg), respectively. One hour post‐treatment, animals in groups 2–9 were given testosterone propionate (3 mg/kg, s.c.). Twenty‐four hours after last treatment on day 28, blood was collected for serum testosterone and prostate‐specific antigen (PSA) analysis. Prostate was harvested for biochemical and histological assays. Subcutaneous injection of testosterone increased serum levels of testosterone and PSA which was ameliorated by pretreatments of rat with ATR, celecoxib, or pioglitazone. Similarly, testosterone‐induced increase in MDA and reduction in the activity of GSH, superoxide dismutase (SOD), and catalase were attenuated by ATR. Conversely, celecoxib or pioglitazone treatment failed to affect the activity of antioxidant enzymes. The histology of the prostate showed significant improvement in prostatic cells of ATR, celecoxib, or pioglitazone treated. Findings from the study showed that atorvastatin attenuated testosterone‐induced BPH. Moreover, synergistic effect was observed when atorvastatin was combined with celecoxib.     

Assessment of Circulating Biochemical Markers in Mice Receiving Cinnamon and Glycyrrhizin Under Carbon Tetrachloride Induced Hepatic Injury

The study evaluated the hepatoprotective activity of plant extracts of cinnamon and glycyrrhizin in distinct dosage ways to minimize the oxidative stress induced by carbon tetrachloride (CCl₄) in BALB/cJ inbred albino mice. Fifteen albino mice were divided into five groups, each group containing three mice. Group A was referred as positive control while group B, C, D and E were injected intraperitoneally with 1 mL/kg body weight of CCl₄ twice a week for 1 month. Group C and D were treated orally with isolated extracts of cinnamon @50 mg/kg and glycyrrhizin @50 mg/kg respectively on daily basis for 1 month. However, group E was treated orally with combination dose of cinnamon @50 mg/kg + glycyrrhizin @50 mg/kg body weight. The increase in the levels of alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP), triglyceride (TG), malondialdehyde (MDA) and glucose were recorded in CCl₄ induced liver injury in mice while there is decrease in the levels of total protein (TP), reduced glutathione (GSH), Superoxide dismutase (SOD) and catalase (CAT) in CCL₄ intoxicated mice. Isolated therapy of plant extracts of cinnamon and glycyrrhizin decreased the levels of ALT, AST, ALP, MDA, TG and glucose whereas increase in TP, GSH, SOD and CAT was observed in plant extracts treated mice. The best restoration of all the above said parameters near to control was observed in group of mice treated with combination dose of cinnamon and glycyrrhizin @50 mg/kg. Therefore, the present study declared the antioxidative, anti-inflammatory and hepatoprotective activity of standardized extracts of cinnamon and glycyrrhizin and their potent defensive property.

     

Melatonin treatment decreases c-fos expression in a headache model induced by capsaicin

The aim of the present work was to analyze c-fos response within the trigeminal nucleus caudalis (TNC) of pinealectomized rats and animals that received intraperitoneal melatonin, after intracisternal infusion of capsaicin, used to induce intracranial trigeminovascular stimulation. Experimental groups consisted of animals that received vehicle solution (saline–ethanol–Tween 80, 8:1:1, diluted 1:50) only (VEI, n = 5); animals that received capsaicin solution (200 nM) only (CAP, n = 6); animals submitted to pinealectomy (PX, n = 5); sham-operated animals (SH, n = 5); animals submitted to pinealectomy followed by capsaicin stimulation (200 nM) after 15 days (PX + CAP, n = 7); and animals that received capsaicin solution (200 nM) and intraperitoneal melatonin (10 mg/kg) (CAP + MEL, n = 5). Control rats, receiving vehicle in the cisterna magna, showed a small number of c-fos-positive cells in the TNC (layer I/II) as well as the sham-operated and pinealectomized rats, when compared to animals stimulated by capsaicin. On the other hand, pinealectomized rats, which received capsaicin, presented the highest number of c-fos-positive cells. Animals receiving capsaicin and melatonin treatment had similar expression of the vehicle group. Our data provide experimental evidence to support the role of melatonin and pineal gland in the pathophysiology of neurovascular headaches.