Effects of varenicline on lung tissue in the animal model. / Efeitos da vareniclina no tecido pulmonar em modelo animal.

OBJECTIVE: This study aimed to investigate acute and chronic effects of varenicline on lung tissue in an experimental study. METHODS: A total of 34 rats were randomly allocated into study (varenicline) and control groups. The rats were divided into two groups (i) control group, (ii) varenicline group. Then, the rats in the each group were sub-divided equally in turn as acute (C1; V1) and chronic (C2; V2) ; all rats of acute and chronic groups were sacrificed under the anesthesia on the 45th day for acute group [C1 (n=5) and V1 (n=12)] and the 90th day for chronic group [C2 (n=5) and V2 (n=12)], respectively. Thus, biochemical and histopathological analysis were carried out. RESULTS: Thirty four rats completed the study, 24 were in varenicline group and 10 were in control group. In chronic exposure to varenicline, oxidant levels comprising of malondialdehyde (MDA), and myeloperoxidase (MPO) increased and superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and glutathione peroxidase (GPx) levels, named as antioxidants, decreased significantly when compared to the control group. MDA and MPO levels were also significantly higher and SOD, CAT, GPx, GSH levels were also significantly lower in chronic varenicline group when compared to acute varenicline group. These findings were also supported by histopathological observations. CONCLUSION: This is the first study, which evaluated pulmonary effects of varenicline experimentally on an animal model. It was observed that chronic varenicline treatments cause inflammation and lung cell injury.

OBJETIVO: O objetivo deste estudo foi investigar os efeitos agudos e crônicos da vareniclina no tecido pulmonar em um estudo experimental. MÉTODOS: Um total de 34 ratos foi alocado aleatoriamente em grupos de estudo (vareniclina) e controle. Assim, os ratos foram divididos em dois grupos: (i) grupo controle e (ii) grupo vareniclina. A seguir, os ratos de cada grupo foram, por sua vez, subdivididos igualmente em agudos (C1; V1) e crônicos (C2; V2), e todos os ratos dos grupos agudos e crônicos foram sacrificados sob anestesia: no 45.º dia, para o grupo agudo [C1 (n=5) e V1 (n=12)], e no 90.º dia, para o grupo crônico [C2 (n=5) e V2 (n=12)], respectivamente. Em seguida, foram realizadas análises bioquímicas e histopatológicas. RESULTADOS: Trinta e quatro ratos completaram o estudo. Destes ratos, 24 estavam no grupo vareniclina e 10 no grupo controle. Na exposição crônica à vareniclina, os níveis de oxidante composto por malondialdeído (MDA) e mieloperoxidase (MPO) aumentaram, e os níveis de superóxido dismutase (SOD), catalase (CAT), glutationa (GSH) e glutationa peroxidase (GPx), nomeados como antioxidantes, diminuiram significativamente quando comparados com o grupo controle. Os níveis de MDA e MPO também foram significativamente mais elevados e os níveis de SOD, CAT, GPx e GSH foram significativamente mais baixos no grupo vareniclina crônico, quando comparado ao grupo vareniclina agudo. Estes achados também foram confirmados por observações histopatológicas. CONCLUSÕES: Este é o primeiro estudo que avaliou os efeitos pulmonares da vareniclina experimentalmente em um modelo animal. Observamos que o tratamento crônico da vareniclina causa inflamação e lesão pulmonar.

Efeitos da vareniclina no tecido pulmonar em modelo animal / Effects of varenicline on lung tissue in the animal model

RESUMO Objetivo O objetivo deste estudo foi investigar os efeitos agudos e crônicos da vareniclina no tecido pulmonar em um estudo experimental. Métodos Um total de 34 ratos foi alocado aleatoriamente em grupos de estudo (vareniclina) e controle. Assim, os ratos foram divididos em dois grupos: (i) grupo controle e (ii) grupo vareniclina. A seguir, os ratos de cada grupo foram, por sua vez, subdivididos igualmente em agudos (C1; V1) e crônicos (C2; V2), e todos os ratos dos grupos agudos e crônicos foram sacrificados sob anestesia: no 45.º dia, para o grupo agudo [C1 (n=5) e V1 (n=12)], e no 90.º dia, para o grupo crônico [C2 (n=5) e V2 (n=12)], respectivamente. Em seguida, foram realizadas análises bioquímicas e histopatológicas. Resultados Trinta e quatro ratos completaram o estudo. Destes ratos, 24 estavam no grupo vareniclina e 10 no grupo controle. Na exposição crônica à vareniclina, os níveis de oxidante composto por malondialdeído (MDA) e mieloperoxidase (MPO) aumentaram, e os níveis de superóxido dismutase (SOD), catalase (CAT), glutationa (GSH) e glutationa peroxidase (GPx), nomeados como antioxidantes, diminuiram significativamente quando comparados com o grupo controle. Os níveis de MDA e MPO também foram significativamente mais elevados e os níveis de SOD, CAT, GPx e GSH foram significativamente mais baixos no grupo vareniclina crônico, quando comparado ao grupo vareniclina agudo. Estes achados também foram confirmados por observações histopatológicas. Conclusões Este é o primeiro estudo que avaliou os efeitos pulmonares da vareniclina experimentalmente em um modelo animal. Observamos que o tratamento crônico da vareniclina causa inflamação e lesão pulmonar.

ABSTRACT Objective This study aimed to investigate acute and chronic effects of varenicline on lung tissue in an experimental study. Methods A total of 34 rats were randomly allocated into study (varenicline) and control groups. The rats were divided into two groups (i) control group, (ii) varenicline group. Then, the rats in the each group were sub-divided equally in turn as acute (C1; V1) and chronic (C2; V2) ; all rats of acute and chronic groups were sacrificed under the anesthesia on the 45th day for acute group [C1 (n=5) and V1 (n=12)] and the 90th day for chronic group [C2 (n=5) and V2 (n=12)], respectively. Thus, biochemical and histopathological analysis were carried out. Results Thirty four rats completed the study, 24 were in varenicline group and 10 were in control group. In chronic exposure to varenicline, oxidant levels comprising of malondialdehyde (MDA), and myeloperoxidase (MPO) increased and superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and glutathione peroxidase (GPx) levels, named as antioxidants, decreased significantly when compared to the control group. MDA and MPO levels were also significantly higher and SOD, CAT, GPx, GSH levels were also significantly lower in chronic varenicline group when compared to acute varenicline group. These findings were also supported by histopathological observations. Conclusion This is the first study, which evaluated pulmonary effects of varenicline experimentally on an animal model. It was observed that chronic varenicline treatments cause inflammation and lung cell injury.

Evaluation of reproductive and renal toxicity of varenicline in male rats.

OBJECTIVES: Varenicline is a selective partial agonist for the nicotinic acetylcholine receptor a4b2 subtype, which is widely used to treat smoking addiction. However, there is still no data about its potential toxic effects on tissues. In this study, we aimed to determine the varenicline-induced toxicity on reproductive and renal tissues in rats. MATERIALS AND METHODS: Rats were randomly divided into two groups: control (n=10) and varenicline (n=24). Then, rats in each group were sub-divided equally as acute and chronic groups. The control rats were orally given distilled water only. Varenicline was administrated orally as follows: 1st-3rd days 9 µg/kg/day, 4th-7th days 9 µg/kg twice daily, and 8th-90th days 18 µg/kg twice daily. The rats of acute and chronic groups were sacrificed on the 45th and 90th days, respectively. Some tissue markers related to oxidative stress were measured, and sperm characteristics were observed. RESULTS: In the acute group, varenicline led to a significant decrease in SOD activities in both kidney and testis tissues. In the chronic group, varenicline significantly increased MDA and MPO production, and reduced CAT and GPx levels in the kidneys and testes. Also, SOD and GSH levels significantly decreased in the testes. Moreover, sperm characteristics were negatively affected; histopathological deformation was observed in the testes and kidneys in all groups. CONCLUSION: This study showed that varenicline could detrimentally affect the kidneys and testes in both acute and chronic term usage. Further studies will provide more insights into the molecular dynamics of this damage.

Protective and therapeutic effects of dexpanthenol on isoproterenol-induced cardiac damage in rats.

The purpose of the study was to explore the protective and therapeutic effects of dexpanthenol (DEX) on isoproterenol (ISO)-induced cardiac damage. Forty rats were distributed into four groups: group I (Control); group II (ISO); ISO (150 mg/kg/day) was given to rats once a day for 2 consecutive days with an interval of 24 h; group III (DEX+ISO): DEX (250 mg/kg) was applied 30 min before the first ISO administration and continued in the next two days after second ISO administration; group IV (ISO+DEX): After the ISO treatment at 1st and 2nd days, DEX was given at 3rd and 4th days. Rats were monitored for mean arterial blood pressure (BP), heart rate, oxygen saturation (%SO2 ), and electrocardiography (ECG). Heart tissue levels of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), reduced glutathione (GSH), total oxidant status (TOS); total antioxidant capacity (TAC), oxidative stress index (OSI), and caspase-3 were determined. BP and SO2 values indicated a significant decrease in the ISO group. Also, T wave negativity was observed in 6 of 10 rats, SOD, CAT, and GPX levels were significantly lower in ISO group than control group. ISO administration increased TOS and OSI levels, whereas DEX treatment significantly reduced these parameters. Also, ISO-induced morphological alterations such as disorganization of cardiomyocytes, loss of myofibrils and cytoplasmic vacuolization whereas these histological damages were significantly decreased in ISO+DEX and DEX+ISO groups when compared to the ISO group. This study implies the cardioprotective effects of DEX on ISO-induced cardiotoxicity.

Effects of Molsidomine on Retinopathy and Oxidative Stress Induced by Radiotheraphy in Rat Eyes.

PURPOSE: To determine the role of Molsidomine in preventing radiation-induced retinopathy after head and neck region irradiation of rats with a single radiation dose of 15 Gy. MATERIALS AND METHODS: Male Wistar albino rats were randomly grouped into five as follows: (1) control group rats, which were applied through an intraperitoneal (i.p.) vehicle without radiotherapy (RT); (2) RT group rats received a single dose of 15 Gy irradiation and after daily 0.1 ml vehicle i.p. for 5 consecutive days; (3) molsidomine (MOL) group rats were treated for 5 consecutive days by i.p. with 4 mg/kg/day MOL; (4) irradiation plus MOL group (RT+MOL) rats received irradiation and after 10 days single daily i.p. dose of MOL for 5 consecutive days; and (5) MOL+RT group rats were treated for 5 consecutive days by i.p. with MOL before RT. At the end of the work the rats were sacrificed under high-dose anesthesia on the 16th day and then eye tissues were taken for histopathological, immunohistochemical (caspase-3), and biochemical analyses (superoxide dismutase [SOD], glutathione peroxidase [GSH], and malondialdehyde [MDA]). RESULTS: RT significantly decreased both the content of GSH and the activity of SOD, and significantly increased the production of MDA level in the rat eyes. MOL treatment significantly increased the SOD and GSH levels and significantly decreased the MDA production (p < 0.0001). In addition, RT significantly increased the number of ganglion cells (GCs; p = 0.001), whereas especially pretreatment with MOL improved (p = 0.013). RT led to significant retinopathy formation, and MOL therapy protected the retina from radiation-induced retinopathy (p < 0.0001). CONCLUSIONS: We suggest that MOL is a powerful antioxidant and free radical scavenger that prevents the rat eyes from radiation-induced retinopathy and oxidative stress.

Protective effects of molsidomine against doxorubicin-induced renal damage in rats.

PURPOSE: The purpose of this study was to investigate the therapeutic and protective effects of molsidomine (MLS) against doxorubicin (DOX)-induced renal damage in rats. METHODS: Forty rats were randomly divided into five groups (control, MLS, DOX, DOX+MLS and MLS+DOX groups). Thiobarbituric acid reactive substance (TBARS), reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), nitric oxide (NO) and glutathione peroxidase (GPx) levels were determined from kidney tissues and blood urea nitrogen (BUN), creatinine (Cr) and albumin (Alb) levels also determined. RESULTS: DOX treatment caused a significant increase in TBARS levels and a significant decrease in the GSH and CAT levels compared with the control group. In comparison, MLS administration before DOX injection caused a significant decrease in TBARS levels and also increases in GSH and CAT levels, whereas treatment of MLS after DOX injection did not show any beneficial effect on these parameters. All groups showed a significant increase in NO levels compared to the control group. There were no significant differences among the all groups for BUN and Cr levels. Serum level of Alb decreased in the DOX-treated groups when compared with control and MLS groups. The histopathological findings were in accordance with the biochemical results. MLS treatment reversed the DOX-induced kidney damage in group 4. MLS treatment before DOX injection exerted a protective effect against DOX-induced kidney damage. CONCLUSIONS: MLS shows promise as a possible therapeutic intervention for the prevention of kidney injury associated with DOX treatment. Additional studies are warranted.

Evaluation of the cardiovascular effects of varenicline in rats.

BACKGROUND: Cardiovascular disease is an important cause of morbidity and mortality among tobacco users. Varenicline is widely used worldwide to help smoking cessation, but some published studies have reported associated cardiovascular events. OBJECTIVE: To determine the cardiovascular toxicity induced by varenicline in rats. MATERIALS AND METHODS: We randomly separated 34 rats into two groups: 1) the control group (given only distilled water orally, n=10) and the varenicline group (given 9 µg/kg/day varenicline on days 1-3, 9 µg/kg twice daily on days 4-7, and 18 µg/kg twice daily on days 8-90 [total 83 days], n=24). Each group was then subdivided equally into acute and chronic subgroups, and all rats in these groups were euthanized with anesthesia overdose on days 45 and 90, respectively. Body and heart weights, hemodynamic (mean oxygen saturation, mean blood pressure, and heart rate, electrocardiographic (PR, QRS, and QT intervals) biochemical (oxidants and antioxidants), and histopathological analyses (including immunostaining) were performed. RESULTS: Acute varenicline exposure resulted in loss of body weight, while chronic varenicline exposure caused heart weight loss and decreased mean blood pressure, induced lipid peroxidation, and reduced antioxidant activity. Both acute and chronic varenicline exposure caused impairment of mean oxygen saturation. QT interval was prolonged in the chronic varenicline group, while PR interval prolongation was statistically significant in both the control and acute varenicline groups. Caspase-9 activity was also significantly increased by chronic exposure. Moreover, histopathological observations revealed severe morphological heart damage in both groups. CONCLUSION: Adverse effects of chronic varenicline exposure on cardiovascular tissue were confirmed by our electrocardiographic, biochemical, and histopathological analyses. This issue needs to be investigated with new experimental and clinical studies to evaluate the exact mechanism(s) of the detrimental effects of varenicline. Physicians should bear in mind the toxic effects of varenicline on the cardiovascular system when prescribing it for smoking cessation.

Protective Effects of Molsidomine Against Cisplatin-Induced Nephrotoxicity.

BACKGROUND: Cisplatin, an effective chemotherapeutic agent, is used for the treatment of several types of cancers. However, cisplatin has some severe side effects such as nephrotoxicity. On the other hand, molsidomine, a NO donor, has anti-oxidative and vasodilator effects. OBJECTIVES: The aim of this study was to estimate the protective effects of molsidomine on cisplatin-induced nephrotoxicity. MATERIAL AND METHODS: Thirty-two rats were randomly divided into 4 groups as follows: (1) control; (2) received a single-dose intraperitoneal (i.p.) injection of 5 mg/kg cisplatin; (3) received single i.p. dose of molsidomine (4 mg/kg/day) for 3 consecutive days before cisplatin treatment; (4) received single i.p. dose of molsidomine (4 mg/kg/day) for 3 consecutive days. The specific biochemical markers, including antioxidants, and the histopathological alterations were evaluated. RESULTS: Cisplatin significantly increased malondialdehyde (MDA) and myeloperoxidase (MPO) levels and decreased glutathione peroxidase (GPX) level. Molsidomine significantly decreased MPO level nearly to control level; however, its ameliorating effects on MDA, SOD, CAT and GPX did not reach to significant levels. Cisplatin-induced elevation of blood-urea-nitrogen and serum-creatinine were diminished after molsidomine administration. Cisplatin also induced severe tubular degeneration, nuclear condensation, apoptosis and scattered patchy inflammation in the histological examination. Molsidomine improved all of these histological damages. CONCLUSIONS: In this study, the beneficial effect of molsidomine against cisplatin nephrotoxicity has been evaluated for the first time.

Mode of delivery changes oxidative and antioxidative properties of human milk: a prospective controlled clinical investigation.

OBJECTIVE: To evaluate the influence of delivery mode on oxidative stress in human breast milk. METHODS: Thirty-three women who delivered by vaginal birth and 55 women who underwent cesarean section (CS) were included in this study. Colostral samples were collected on the second day after delivery. Total antioxidative status (TAS), total oxidative status (TOS), oxidative stress index (OSI), malonyldialdehyde (MDA), and glutathione peroxidase (GSH-Px) levels were determined and compared. RESULTS: Colostrum TAS was significantly higher in women of vaginal birth, than in women with CS (p < 0.001). Milk TOS and OSI were found to be significantly increased in women with CS under general anesthesia. A marked increase in colostral GSH-Px levels after vaginal delivery was also noticed (p < 0.001). CONCLUSION: This study revealed that vaginal birth is associated with decreased oxidative stress in colostrum than CS, which suggest that mode of delivery plays an important role in the antioxidative production of breast milk.

The protective effect of apocynin on testicular ischemia-reperfusion injury.

PURPOSE: We investigated the protective effect of the NADPH oxidase inhibitor apocynin on testicular damage induced by ischemia-reperfusion injury in rats. MATERIALS AND METHODS: A total of 32 rats were randomly divided into 4 groups. Controls underwent left scrotal exploration only. The 3 groups with ischemia-reperfusion underwent 4-hour torsion followed by 1-hour detorsion. The ischemia-reperfusion only group underwent left testicular torsion and detorsion. The ischemia-reperfusion plus saline group underwent left testicular torsion, received 10 ml/kg saline intraperitoneally at minute 210 of ischemia and then underwent detorsion. The ischemia-reperfusion plus apocynin group underwent left testicular torsion, received 20 mg/kg apocynin intraperitoneally at minute 210 of ischemia and then underwent detorsion. We determined histopathological findings and performed specific biochemical analyses. RESULTS: In the ischemia-reperfusion only and the ischemia-reperfusion plus saline groups malondialdehyde, total oxidative capacity and the oxidative stress index were significantly higher. Superoxide dismutase, catalase, glutathione peroxidase and glutathione were significantly lower. Apocynin significantly decreased malondialdehyde, total oxidative capacity and the oxidative stress index, and significantly increased superoxide dismutase and catalase. There was a significantly increase in the number of giant, degenerated and desquamated cells in the ischemia-reperfusion group. Apocynin significantly improved these histological alterations. CONCLUSIONS: These histopathological and biochemical findings show the beneficial effects of apocynin on testicular ischemia-reperfusion injury.

Effects of perineural administration of dexmedetomidine in combination with levobupivacaine in a rat sciatic nerve block.

OBJECTIVE: The aim of this study was to assess if perineural administration of dexmedetomidine combined with levobupivacaine increases the duration of the sensory and motor blockade of a sciatic peripheral nerve block in rats. METHODS: Forty male Sprague-Dawley rats were randomly divided into 5 experimental groups: Group 1, sham; Group 2, perineural levobupivacaine (0.2 mL of a 0.5% solution) and subcutaneous saline; Group 3, perineural levobupivacaine (0.2 mL of a 0.5% solution) plus dexmedetomidine (20 µg/kg dexmedetomidine) and subcutaneous saline; Group 4, perineural saline and subcutaneous dexmedetomidine; and Group 5, perineural saline and subcutaneous saline. Pain reflexes in response to a thermal stimulus were measured at 0 and 240 minutes after drug administration by using a hot-plate and tail-flick tests. Neurobehavioral status, including sensory and motor functions, was assessed by an investigator who was blinded to the experimental groups every 30 minutes until normal functioning resumed. RESULTS: The sensory and motor blockades of the rats did not increase in the treatment with dexmedetomidine plus levobupivacaine when compared with the treatment with levobupivacaine alone at all the time points (P > 0.05). Compared with rats in Group 2, those in Group 3 showed significantly higher latency times at 30 and 60 minutes in the hot plate test (P < 0.01). At 30 and 60 minutes, the latency times of the rats in Group 3 were longer than those in Group 2 in the tail-flick test (P < 0.01). Furthermore, the durations of the complete sensory and motor blockade were similar when treatment with levobupivacaine plus dexmedetomidine was compared with treatment with levobupivacaine alone. CONCLUSIONS: A 20µg/kg dose of dexmedetomidine added to levobupivacaine did not increase the duration of the sensory and motor blockades in rats. However, treatment with dexmedetomidine plus levobupivacaine increased the quality of analgesia in rats.

Effects of melatonin or acetylsalicylic acid on gastric oxidative stress after bile duct ligation in rats.

BACKGROUND: Antioxidant enzyme activities decrease after bile duct ligation. The aim of this study was to assess the effect of melatonin and acetylsalicylic acid on antioxidant enzyme activities in gastric oxidative stress induced by bile duct ligation. METHODS: Sixty-four animals were divided into eight groups of eight rats each. Male Sprague-Dawley rats were subjected to either a sham operation or common bile duct ligation (BDL) before treatment with melatonin (MEL) or acetylsalicylic acid (ASA). Gastric superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities, and malondialdehyde (MDA) and nitric oxide (NO) levels were determined by spectrophotometers and evaluated. RESULTS: Our results indicated that BDL caused a significant increase in lipid peroxidation, whereas coadministration of MEL with ASA significantly decreased MDA and NO levels in BDL rats. Moreover, coadministration of MEL and ASA increased antioxidant enzyme activities after the BDL, and these increases were statistically significant for CAT and GPx. On the other hand, the increase in SOD activity was not significant. CONCLUSIONS: Melatonin administration, either alone or together with acetylsalicylic acid, decreases lipid peroxidation and increases antioxidant enzyme activities in gastric tissues of rats after bile duct ligation. ASA administration, however, either alone or with a vehicle, increases lipid peroxidation and decreases antioxidant enzyme activities.