The effect of caffeine on MDMA-induced hydroxyl radical production in the mouse striatum

BackgroundThe psychostimulant 3,4-methylenedioxymethamphetamine (MDMA) with a strong addictive potential is widely used as a recreational drug. Neurotoxicity of MDMA is related with the generation of highly reactive free radicals.MethodsMDMA was given in doses of 20 and 40 mg/kg ip alone or in combination with caffeine (CAF) 10 mg/kg ip. Extracellular concentration of hydroxyl radical was measured using microdialysis in freely moving mice and was assayed by HPLC with electrochemical detection.ResultsMDMA dose-dependently increased production of hydroxyl radical in the mouse striatum and its effect was reversed by caffeine.ConclusionsThe data show that caffeine may have neuroprotective properties as it decreased oxidative stress induced by MDMA.     

Improvement of mitochondrial NAD+/FAD+-linked state-3 respiration by caffeine attenuates quinolinic acid induced motor impairment in rats: Implications in Huntington's disease

BackgroundChronic quinolinic acid (QA) lesions in rats closely resemble Huntington's disease like conditions. Oxidative stress and mitochondrial dysfunction have long been implicated in the neurotoxic effects of QA acting through N-methyl-d-aspartate (NMDA) receptors. Reports suggest that inhibition of adenosine A2A receptor function elicits neuroprotective effect in QA induced neurotoxicity in rats. Caffeine, a preferential A2A receptor antagonist imitates antioxidant like actions and exerts neuroprotective effects in various neurodegenerative conditions. Thus, the present study was designed to evaluate the neuroprotective effects of caffeine against QA induced neurotoxicity in rats.MethodsIn the present study, QA (200 nmol/2 μl saline) has been administered bilaterally to the striatum of rats followed by chronic caffeine (10, 20 and 40 mg/kg) administration for 21 days. Motor performance of the animals was evaluated in weekly intervals and subsequently after 21 days, the animals were sacrificed and measurement of mitochondrial complexes activity, respiration rate and endogenous antioxidant levels were carried out in the striatal region.ResultsSingle intrastriatal QA administration resulted in drastic reduction in body weight, marked motor impairment (decreased total locomotor activity in actophotometer and impaired grip strength in rotarod), increased oxidative stress, impaired mitochondrial complexes activities and decreased state 3 respiration (NAD⁺/FAD⁺-linked) in rats. However, chronic treatment of caffeine for 21 days significantly attenuated the QA induced behavioural, biochemical and mitochondrial alterations displaying neuroprotective efficacy.ConclusionThe study highlights the possible involvement of A2A receptor antagonism in the neuroprotective effect of caffeine against QA induced mitochondrial dysfunction and oxidative stress in rats.     

Beverage caffeine intakes in the U.S.

Caffeine is one of the most researched food components, with the vast majority of dietary contributions coming from beverage consumption; however, there is little population-level data on caffeine intakes in the U.S. This study estimated the caffeine intakes of the U.S. population using a comprehensive beverage survey, the Kantar Worldpanel Beverage Consumption Panel. A nationally representative sample of 37,602 consumers (aged ⩾ 2 years) of caffeinated beverages completed 7-day diaries which facilitated the development of a detailed database of caffeine values to assess intakes. Results showed that 85% of the U.S. population consumes at least one caffeinated beverage per day. The mean (±SE) daily caffeine intake from all beverages was 165 ± 1 mg for all ages combined. Caffeine intake was highest in consumers aged 50–64 years (226 ± 2 mg/day). The 90th percentile intake was 380 mg/day for all ages combined. Coffee was the primary contributor to caffeine intakes in all age groups. Carbonated soft drinks and tea provided a greater percentage of caffeine in the younger (<18 years) age groups. The percentage of energy drink consumers across all age groups was low (⩽10%). These data provide a current perspective on caffeinated beverage consumption patterns and caffeine intakes in the U.S. population.     

Evaluation of efficacy of natural astaxanthin and vitamin E in prevention of colistin-induced nephrotoxicity in the rat model

ObjectiveWe evaluated the effect of astaxanthin (ASX) and vitamin E (vit E) on colistin methanesulfonate (CMS) induced-nephrotoxicity in rats.MethodsAnimals were treated with sterile saline, 300 000 or 450 000 IU/kg/day of CMS, CMS + ASX (20 mg/kg), CMS + vit E (100 mg/kg), or CMS + 1 ml/kg olive oil (OO) for 7 days. The plasma/urine creatinine (Cr) level, urine γ-glutamyl-transferase (GGT) level, and renal tissue activities in malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and reductase (GSH), as well as renal histology were performed.ResultsCMS induced a tubular damage, increased the GGT and MDA levels, and decreased the activities of SOD, CAT, GPx and GSH. Co-treatment with ASX or vit E restored all biochemical parameters cited above and improved the histopathological damage.ConclusionNephrotoxicity induced by CMS might be due to oxidative damage. The improvement by ASX or vit E seems to be related to their antioxidant properties.     

Effect of benzothiazole/piperazine derivatives on intracerebroventricular streptozotocin-induced cognitive deficits

BackgroundIn this study, benzothiazole-piperazine compounds were synthesized by condensing the functional groups of donepezil (DNP), FK-960, and sabeluzole, which are known to have therapeutic potential against Alzheimer's disease, with the aim of obtaining new and potent anti-Alzheimer agents.MethodsInitially, acetylcholinesterase/butyrylcholinesterase enzyme inhibition activities of the synthesized test compounds were investigated by Ellman's method. Effects of the compounds on a streptozotocin (STZ) model of Alzheimer's disease (SMAD) were investigated in rats. SMAD was established by intracerebroventricular (icv) injection of STZ (3 mg/kg), bilaterally. The elevated plus maze, Morris water maze, and active avoidance tests were used to examine the effects of test compounds (1,5, and 10 mg/kg) on learning and memory parameters of icv STZ-injected rats. Effects of the test compounds on spontaneous locomotor activities of rats were examined with the activity cage test.ResultsThe compounds B2–B5 and DNP exhibited significant selective inhibitory potencies against acetylcholinesterase. Compounds B2 and B3 at 10 mg/kg doses and compounds B4 and B5 at 5 and 10 mg/kg doses, as well as the reference drug DNP (1 and 3 mg/kg), significantly improved the learning and memory parameters of animals in all cognition tests. None of the test compounds changed spontaneous locomotor activities.ConclusionResults of the present study revealed that compounds B2-B5 repaired the parameters related to the learning and memory deficits of icv STZ-injected rats. Potencies of these test compounds were comparable to the activity of DNP.     

Astaxanthin pretreatment attenuates acetaminophen-induced liver injury in mice

BackgroundAcetaminophen (APAP) is a conventional drug widely used in the clinic because of its antipyretic-analgesic effects. However, accidental or intentional APAP overdoses induce liver injury and even acute liver failure (ALF). Astaxanthin (ASX) is the strongest antioxidant in nature that shows preventive and therapeutic properties, such as ocular protection, anti-tumor, anti-diabetes, anti-inflammatory, and immunomodulatory effects. The aim of present study was to determine whether ASX pretreatment provides protection against APAP-induced liver failure.MethodsMale C57BL/6 mice were randomly divided into 7 groups, including control, oil, ASX (30 mg/kg or 60 mg/kg), APAP and APAP + ASX (30 mg/kg or 60 mg/kg) groups. Saline, olive oil and ASX were administered for 14 days. The APAP and APAP + ASX groups were given a peritoneal injection of 700 mg/kg or 300 mg/kg APAP to determine the 5-day survival rate and for further observation, respectively. Blood and liver samples were collected to detect alanine transaminase (ALT), aspartate transaminase (AST), inflammation, oxidative stress and antioxidant systems, and to observe histopathologic changes and key proteins in the mitogen-activated protein kinase (MAPK) family.ResultsASX pretreatment before APAP increased the 5-day survival rate in a dose-dependent manner and reduced the ALT, AST, hepatic necrosis, reactive oxygen species (ROS) generation, lipid peroxidation (LPO), oxidative stress and pro-inflammatory factors. ASX protected against APAP toxicity by inhibiting the depletion of glutathione (GSH) and superoxide dismutase (SOD). Administration of ASX did not change the expression of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and P38. However, phosphorylation of JNK, ERK and P38 was reduced, consistent with the level of tumor necrosis factor alpha (TNF-α) and TNF receptor-associated factor 2 (TRAF2).ConclusionASX provided protection for the liver against APAP hepatotoxicity by alleviating hepatocyte necrosis, blocking ROS generation, inhibiting oxidative stress, and reducing apoptosis by inhibiting the TNF-α-mediated JNK signal pathway and by phosphorylation of ERK and P38, which made sense in preventing and treating liver damage.     

Combined effects of oxytetracycline and Pb on earthworm Eisenia fetida

Combined effects of oxytetracycline (OTC) and Pb on lysosomal membrane stability and coelomocyte apoptosis of earthworm were studied in the paper. Compared with control, the lysosomal membrane stability decreased and coelomocyte apoptosis increased in the treatments of single OTC and Pb contamination. As for compound pollution, combined effect of (5 mg/kg OTC + 50 mg/kg Pb) treatment on earthworm lysosomal was synergistic (except 28 d). However, it was antagonistic at higher concentration of (10 mg/kg OTC + 50 mg/kg Pb) and (20 mg/kg OTC + 50 mg/kg Pb) treatment. In addition, coelomocyte apoptosis of earthworm decreased significantly compared with single OTC, indicating an antagonistic reaction. And joint toxicity of OTC and Pb decreased significantly with the increasing OTC concentration.     

Thermal sensitivity as a measure of spontaneous morphine withdrawal in mice

IntroductionOpioid withdrawal syndrome is a critical component of opioid abuse and consists of a wide array of symptoms including increases in pain sensitivity (hyperalgesia). A reliable preclinical model of hyperalgesia during opioid withdrawal is needed to evaluate possible interventions to alleviate withdrawal. The following study describes a method for assessing increases in thermal sensitivity on the hotplate in a mouse model of spontaneous morphine withdrawal.MethodsC57BL/6J mice received 5.5 days of 30, 56, or 100 mg/kg morphine or saline (s.c., twice daily). In Experiment I, thermal sensitivity data were collected at baseline and at 8, 24, 32, 48 h and 1 week following the final injection. Thermal sensitivity was assessed by examining latency to respond on a hotplate across a range of temperatures (50, 52, 54, and 56 °C). In Experiment II, 0.01 mg/kg buprenorphine was administered 30 min prior to each testing session during the withdrawal period. In Experiment III, jumping during a 30 min period was assessed at baseline and at 0, 8, 24, 32, and 48 h following the final morphine injection.ResultsDuring the withdrawal period, thermal sensitivity increased significantly in all morphine-treated mice as compared to saline-treated mice. Thermal sensitivity was greater in mice treated with 56 mg/kg morphine compared to 30 mg/kg and peaked earlier than in mice treated with 100 mg/kg (32 h v 1 wk). The increase in thermal sensitivity following 56 mg/kg morphine was attenuated by a dose of buprenorphine that did not produce antinociception alone (i.e., 0.01 mg/kg). In general, the results of the jumping experiment paralleled those obtained in Experiment I.DiscussionResponse latency on the hotplate is a reliable and sensitive measure of spontaneous morphine withdrawal in mice, making it an ideal behavior for assessing the potential of medications and environmental interventions to alleviate opioid withdrawal.     

Protective effect of nimesulide against hepatic ischemia/reperfusion injury in rats: Effects on oxidant/antioxidants,DNA mutation and COX-1/COX-2 levels

BackgroundNimesulide is a pharmacological agent and selective COX-2 inhibitor. It has anti-inflammatory, analgesic and antipyretic properties. The purpose of this study was to investigate the effect of nimesulide on oxidant/antioxidant, DNA mutation and COX-1/COX-2 activities in rat liver tissue with induced ischemia/reperfusion (I/R).MethodsBefore the experiment, rats were divided into four groups; liver ischemia/reperfusion (LIR), 50 mg/kg nimesulide + liver ischemia/reperfusion (NLIR50), 100 mg/kg nimesulide + liver ischemia/reperfusion (NLIR100) and a control group to be given a sham operation (SG). Malondialdehyde (MDA), total glutathione (GSH) levels and myeloperoxidase (MPO), COX-1/COX-2 enzyme activities and DNA damage product level results from liver tissues and serum AST and ALT levels were determined. The data obtained were compared with the results from the liver ischemia/reperfusion and sham operation groups.ResultsMDA levels, MPO and COX-2 activities and products of DNA injury were significantly lower in the groups given nimesulide, and particularly the NLIR100 group, compared to the LIR group (p < 0.05), while tGSH levels were significantly higher (p < 0.05). There was no significant difference between the NLIR50 and NLIR100 groups and the LIR group in terms of COX-1 levels (p > 0.05). AST and ALT levels were significantly lower in the other groups compared to the LIR group (p < 0.05).ConclusionsNimesulide at 100 mg/kg prevented oxidative liver damage induced with I/R significantly better than at a dose of 50 mg/kg. These experimental findings indicate that nimesulide may be useful in the treatment of hepatic I/R damage.     

Ketamine attenuates sepsis-induced acute lung injury via regulation of HMGB1-RAGE pathways

High mobility group box protein 1 (HMGB1) and receptor for the advanced glycation end product (RAGE) play important roles in the development of sepsis-induced acute lung injury (ALI). Ketamine is considered to confer protective effects on ALI during sepsis. In this study, we investigated the effects of ketamine on HMGB1-RAGE activation in a rat model of sepsis-induced ALI. ALI was induced in wild type (WT) and RAGE deficient (RAGE^−/−) rats by cecal ligation and puncture (CLP) or HMGB1 to mimic sepsis-induced ALI. Rats were randomly divided to six groups: sham-operation + normal saline (NS, 10 mL/kg), sham-operation + ketamine (10 mg/kg), CLP/HMGB1 + NS (10 mL/kg), CLP/HMGB1 + ketamine (5 mg/kg), CLP/HMGB1 + ketamine (7.5 mg/kg), and CLP/HMGB1 + ketamine (10 mg/kg) groups. NS and ketamine were administered at 3 and 12 h after CLP/HMGB1 via intraperitoneal injection. Pathological changes of lung, inflammatory cell counts, expression of HMGB1and RAGE, and concentrations of various inflammatory mediators in bronchoalveolar lavage fluids (BALF) and lung tissue were then assessed. Nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPK) signaling pathways in the lung were also evaluated. CLP/HMGB1 increased the wet to dry weight ratio and myeloperoxidase activity in lung, the number of total cells, neutrophils, and macrophages in the BALF, and inflammatory mediators in the BALF and lung tissues. Moreover, expression of HMGB1and RAGE in lung tissues was increased after CLP. Ketamine inhibited all the above effects. It also inhibited the activation of IκB-α, NF-κB p65, and MAPK. Ketamine protects rats against HMGB1-RAGE activation in a rat model of sepsis-induced ALI. These effects may partially result from reductions in NF-κB and MAPK.     

Effect of risperidone on the fluoxetine-induced changes in extracellular dopamine,serotonin and noradrenaline in the rat frontal cortex

BackgroundSeveral clinical reports have documented a beneficial effect of the addition of a low dose of risperidone to the ongoing treatment with antidepressants, in particular selective serotonin reuptake inhibitors, in the treatment of drug resistant depression. The aim of our study was to understand the mechanism of the clinical efficacy of a combination of fluoxetine (FLU) and risperidone (RIS) in drug-resistant depression.We studied the effect of FLU and RIS, given separately or jointly on the extracellular levels of dopamine (DA), serotonin (5-HT) and noradrenaline (NA) in the rat frontal cortex.MethodsAnimals were given single intraperitoneal injections of RIS at a doses of 0.1 or 1 mg/kg and FLU at a dose of 10 mg/kg. The release of DA, 5-HT and NAin the rat frontal cortex was investigated using microdialysis in freely moving animals. The extracellular level of DA, 5-HT and NA was assayed by HPLC with coulochemical detection.ResultsRIS (0.1 and 1 mg/kg) and FLU (10 mg/kg) increased the extracellular level of cortical DA, 5-HT and NA. Co-treatment of both drugs was more effective in increasing DA release than administration of each of the drugs alone at doses of RIS 1 mg/kg and FLU 10 mg/kg. Co-treatment of FLU and RIS 0.1 mg/kg was more potent than FLU alone, while the effect of joint injection of FLU and RIS 1 mg/kg was stronger than RIS 1 mg/kg alone on 5-HT release. The combination of FLU with both doses of RIS was not effective in increasing NA release as compared to drugs given alone.ConclusionsOur data indicate that the effect of the combined administration of RIS and FLU on DA and 5-HT release in the rat frontal cortex may be of crucial importance to the pharmacotherapy of drug resistant depression.     

Effect of caffeine on the anticonvulsant effects of oxcarbazepine,lamotrigine and tiagabine in a mouse model of generalized tonic-clonic seizures

Caffeine has been reported to be proconvulsant and to reduce the anticonvulsant efficacy of a variety of antiepileptic drugs (carbamazepine, phenobarbital, phenytoin, valproate and topiramate) in animal models of epilepsy and to increase seizure frequency in patients with epilepsy. Using the mouse maximal electroshock model, the present study was undertaken so as to ascertain whether caffeine affects the anticonvulsant efficacy of the new antiepileptic drugs lamotrigine, oxcarbazepine and tiagabine. The results indicate that neither acute nor chronic caffeine administration (up to 46.2 mg/kg) affected the ED₅₀ values of oxcarbazepine or lamotrigine against maximal electroshock. Similarly, caffeine did not modify the tiagabine electroconvulsive threshold. Furthermore, caffeine had no effect on oxcarbazepine, lamotrigine and tiagabine associated adverse effects such as impairment of motor coordination (measured by the chimney test) or long-term memory (measured by the passive avoidance task). Concurrent plasma concentration measurements revealed no significant effect on lamotrigine and oxcarbazepine concentrations. For tiagabine, however, chronic caffeine (4 mg/kg) administration was associated with an increase in tiagabine concentrations. In conclusion, caffeine did not impair the anticonvulsant effects of lamotrigine, oxcarbazepine, or tiagabine as assessed by electroconvulsions in mice. Also, caffeine was without effect upon the adverse potential of the studied antiepileptic drugs. Thus caffeine may not necessarily adversely affect the efficacy of all antiepileptic drugs and this is an important observation.     

Anti-inflammatory and antinociceptive effects of 6-(4-chlorophenoxy)-tetrazolo[5,1-a]phthalazine in mice

BackgroundQUAN-0808 (6-(4-chlorophenoxy)-tetrazolo[5,1-a]phthalazine), a new phthalazine tetrazole derivative, was evaluated for the anti-inflammatory and analgesic effects.MethodsXylene-induced ear edema, carrageenan (Carr)-induced paw edema, and acetic acid-induced capillary permeability hyperactivity in mice were used to assess the anti-inflammatory effect; acetic acid-induced writhing and hot plate responses for the analgesic activity.ResultsIn the present study, QUAN-0808 (100, 200, 400 mg/kg) and indomethacin (Indo) significantly decreased xylene-induced ear edema by 33.3, 37.5, 46.6, and 45.1%, respectively, decreased Carr-induced paw edema at 1, 2, 4 h after Carr injection, and decreased the prostaglandin E2 (PGE2) and nitric oxide (NO) levels on the edema paw at 4 h after Carr injection; QUAN-0808 (100, 200, 400 mg/kg), and aspirin (Asp, 200 mg/kg) significantly decreased Evans blue exudation in acetic acid-induced capillary permeability hyperactivity model by 26.7, 28.7, 32.3 and 29.1%, respectively, and decreased the numbers of acetic acid-induced writhing response in 15 min by 40.4, 53.6, 66.4, and 64.5%, respectively. Morphine (10 mg/kg) significantly increased the latency of the hot plate response by 136.5,117.4,67.5, and 22.7%, respectively, at 30, 60, 90, 120 min after intraperitoneal injection of morphine; however, QUAN-0808 (100, 200 and 400 mg/kg) did not produce significantly antinociceptive effects in the hot plate test, suggesting that its antinociceptive action occurs via peripheral rather than a central-acting mechanism.ConclusionsThese results show that QUAN-0808 produced potential anti-inflammatory and peripheral antinociceptive effects, and indicated that the antinociceptive effects of QUAN-0808 were related to its anti-inflammatory activity in a dose-dependent manner. Therefore, as inflammation is a peripheral process, it is suggested that QUAN-0808 exerted peripheral effects. The peripheral effect mechanisms of QUAN-0808 may be related to a decrease in the production of PGE₂, NO, bradykinin and other inflammatory mediators.     

Caffeine and caffeinated beverage consumption and fecundability in a preconception cohort

Caffeine is an adenosine receptor antagonist that may influence fertility by affecting ovulation, menstrual characteristics, or sperm quality. We studied the association between female and male preconception caffeine intake and fecundability in a North American prospective cohort study of 2135 pregnancy planners. Frequency of caffeinated beverage intake was self-reported at baseline. Outcome data were updated every 8 weeks until reported pregnancy; censoring occurred at 12 months. Adjusted fecundability ratios (FR) and 95% confidence intervals (CI) were estimated using proportional probabilities regression. Total caffeine intake among males, but not females, was associated with fecundability (FR for ≥300 vs. <100 mg/day caffeine among males = 0.72, 95% CI = 0.54–0.96), although the association was not monotonic. With respect to individual beverages, caffeinated tea intake was associated with slight reductions in fecundability among females, and caffeinated soda and energy drink intake were associated with reduced fecundability among males.     

Comparison of the effects of crocin,safranal and diclofenac on local inflammation and inflammatory pain responses induced by carrageenan in rats

BackgroundCrocin and safranal are the active substances of saffron and have many biological properties. In the present study, we compared the effects of crocin, safranal and diclofenac on local inflammation and its induced pain in rats.MethodsLocal inflammation was induced by intraplantar (ipl) injection of carrageenan (100 μl, 2%). Paw thickness was measured before and after carrageenan injection. Inflammatory pain responses including cold allodynia, mechanical allodynia and hyperalgesia were assessed using acetone spray and von Frey filament tests, respectively. The number of neutrophils in inflammatory zone was counted 6.5 h after injection of carrageenan.ResultsCarrageenan produced edema, cold allodynia, mechanical allodynia and hyperalgesia and caused neutrophil infiltration in paw tissues. Crocin at doses of 25, 50 and 100 mg/kg, safranal at doses of 0.5, 1 and 2 mg/kg and diclofenac (as a reference drug) at a dose of 10 mg/kg attenuated edema, suppressed inflammatory pain responses and decreased the number of neutrophils.ConclusionThe present study showed anti-inflammatory and antinociceptive activities for crocin, safranal and diclofenac in carrageenan model of local inflammation and inflammatory pain.     

Taurine mitigates cognitive impairment induced by chronic co-exposure of male Wistar rats to chlorpyrifos and lead acetate

Organophosphate pesticides and heavy metals are ubiquitous environmental pollutants and neurotoxicants. We investigated the effects of taurine (an antioxidant; TA) on oxidative stress and cognition in male Wistar rats co-treated with chlorpyrifos (an organophosphate pesticide; CPF) and lead acetate (heavy metal; LA). The Wistar rats were divided into 5 groups of 10 rats each. The first two groups were administered with distilled water and soya oil respectively. The remaining three groups were administered with taurine (TA), 50 mg/kg body weight, CPF + LA group [CPF (4.25 mg/kg, 1/20 LD50] and LA (233.25 mg/kg, 1/20 LD50) and TA + CPF + LA group [TA (50 mg/kg), CPF (4.25 mg/kg) and LA (233.25 mg/kg)]. The xenobiotics were administered once daily by oral gavage for 16 weeks. The results showed reductions in the activities of brain antioxidant enzymes and acetylcholinesterase, increased lipoperoxidation and histopathological alterations of the cerebral cortex in the CPF + LA group. However, TA mitigated perturbations in the activities of the antioxidant enzymes and acetylcholinesterase, counteracted oxidative stress and brain lipoperoxidation and attenuated neuronal degeneration induced by joint CPF and LA-induced neurotoxicity. The results suggested that TA is neuroprotective following chronic co-exposure of rats to CPF and LA.     

Zidovudine and isoniazid induced liver toxicity and oxidative stress: Evaluation of mitigating properties of silibinin

HIV/AIDS patients are more prone for opportunistic TB infections and they are administered the combined regimen of anti-retroviral drug zidovudine (AZT) and isoniazid (INH) for therapy. However, AZT + INH treatment has been documented to induce injury and remedial measures to prevent this adversity are not clearly defined. Silibinin (SBN) is a natural hepatoprotective principle isolated from medicinal plant Silybum marianum and is currently used for therapy of various liver diseases. This study investigate the hepatotoxic potentials of AZT alone, INH alone and AZT + INH treatments and the mitigating potentials of SBN against these drugs induced toxic insults of liver in rats. Separate groups of rats (n = 6 in each group) were administered AZT alone (50 mg/kg b.w.), INH alone (25 mg/kg, b.w.), AZT + INH (50 mg/kg, b.w. and 25 mg/kg, b.w.), SBN alone (100 mg/kg, b.w.) and SBN + AZT + INH daily for sub-chronic period of 45 days orally. The control rats received saline/propylene glycol. INH alone and AZT + INH-induced parenchymal cell injury and cholestasis of liver was evidenced by highly significant increase in the activities of marker enzymes (aspartate and alanine transaminase, alkaline phosphatase, argino succinic acid lyase), bilirubin, protein, oxidative stress parameters (lipid peroxidation, superoxide dismutase, catalase, reduced glutathione, vitamins C and E) and membrane bound ATPases were evaluated in serum/liver tissue homogenates. Histopathological studies show ballooning degradation, inflammatory lesions, lipid deposition and hydropic changes in the liver tissue. All the above biochemical and pathological changes induced by AZT + INH treatments were mitigated in rats receiving SBN simultaneously with these hepatotoxins, indicating its hepatoprotective and antioxidant potentials against AZT + INH-induced hepatotoxicity. The moderate hepatoprotective and oxidant potentials of SBN could be due to its low bioavailability and this deficiency could be prevented by supplementation of phosphatidylcholines and studies are warranted on these lines to improve the therapeutic efficiency of SBN.     

The role of potassium channels in the vasodilatory effect of caffeine in human internal mammary arteries

There is little information about the direct effect of caffeine in human blood vessels. The purpose of this study was to evaluate the direct vascular effect of caffeine on human internal mammary artery (IMA) and the involvement of potassium channels in this response. Segments of IMA were obtained from 29 patients who underwent coronary artery bypass graft surgery. They were cut into rings, suspended between two wire hooks in organ bath chambers and constricted submaximally with norepinephrine. Caffeine (3.16 × 10^? 9 to 10^? 4 mol/L) was added in a cumulative fashion to rings with or without functional endothelium and concentration response curves were constructed. The response to caffeine was also evaluated after incubation with adenosine 3′,5′-triphosphate (ATP)-dependent potassium channel blocker glibenclamide, voltage-dependent potassium channel blocker 4-aminopyridine and large-conductance calcium-activated potassium channel inhibitor tetraethylammonium. Caffeine produced a potent, concentration-dependent relaxation of IMA. The relaxant responses did not differ significantly between endothelium-intact and endothelium-denuded preparations. Incubation with different potassium channel inhibitors (glibenclamide, 4-aminopyridine and tetraethylammonium) did not cause significant alterations in the relaxant responses to caffeine. These results suggest that the vasodilatory response to caffeine in human IMA is independent of endothelial function and is not mediated by potassium channels.     

Trigonelline ameliorates diabetic hypertensive nephropathy by suppression of oxidative stress in kidney and reduction in renal cell apoptosis and fibrosis in streptozotocin induced neonatal diabetic (nSTZ) rats

Oxidative stress and apoptotic cell death in kidney have been suggested as contributing factors in the development and complication of diabetes especially in diabetic nephropathy (DN). This study investigated the effects of trigonelline (TG) on the renal functional, morphological changes and renal apoptosis in neonatal diabetic rats, a model of non-insulin-dependent diabetes mellitus. Diabetes mellitus was induced in one day old neonatal Wistar rat pups by an intraperitoneal (i.p.) injection of streptozotocin (STZ) (50 mg/kg) and monitored for 16 weeks thereafter. The diabetic rats were divided as follows: the nSTZ diabetic group, the TG (50 mg/kg) treated diabetic group, and the TG (100 mg/kg) treated diabetic group. The age matched nondiabetic group received an injection of citrate buffer (0.1 M, pH 4.5). At the end kidney samples were taken for light microscopic examinations. The levels of serum creatinine and BUN were significantly low in TG (100 mg/kg) treated diabetic rats. Glomerular filtration rate was improved in TG treated rats. The activities of antioxidant enzyme and membrane bound enzyme were decreased and the levels of tumor necrotic factor (TNF-α) and hydroxyproline content were increased in renal tissues of the diabetic group. TG (100 mg/kg/day) treatment for a period of 4 weeks showed significant ameliorative effects on all the biochemical parameters studied. Biochemical findings were supported by histological studies. The degenerative changes in kidney tissue and fibrosis were alleviated in the TG treated groups. These results suggested that TG might have a significant role in alleviating kidney damage in nSTZ-diabetic rats.     

Assessment of propofol,midazolam and ziprasidone,or the combinations for the prevention of acute cocaine toxicity in a mouse model

Study objectiveTo evaluate the effects of pretreatment, midazolam (M), propofol (P), ziprasidone (Z), and two combinations of [(midazolam plus propofol (MP); midazolam plus ziprasidone (MZ)] in mice models in the prevention of seizures, and death due to acute cocaine toxicity.Methods180 male CF-1 mice were randomized to 6 groups (30/group) in this experimental study. The animals were administered intraperitoneal injections of M (2 mg/kg), P (25 mg/kg), Z (4 mg/kg), MP (2 mg/kg and 25 mg/kg) and MZ (2 mg/kg and 4 mg/kg) or saline (S) as a pretreatment. 10 min later, the mice were administered intraperitoneal injections of 105 mg/kg cocaine. The groups were observed for cocaine-induced seizure and lethality.ResultsThe MP and MZ combinations showed the highest protective effect in terms of seizure and lethality relative to P and S (p < 0.001). M and Z were found effective compared to P and S (p < 0.001). There were no significant differences among MP and MZ, however there were significant differences between MP and Z in terms of lethality (p = 0.05). There were no significant differences among MP, MZ, M and Z groups in terms of seizure (p > 0.05). No death was observed in the MP combination group. Seizure rate was observed o be least in the MZ group with respect to the other groups.ConclusionAccording to our particular mouse model, this study suggests that MP and MZ combinations may be more effective than M or Z only for the prevention of cocaine-induced seizure and lethality. However, P alone does not prevent cocaine-induced seizure and lethality.