Dose-Dependent Effect of Hydrogen Sulfide in Cyclophosphamide-Induced Hepatotoxicity in Rats.

BACKGROUND: Cyclophosphamide is a commonly used anticancer and immunosuppressive agent; however, hepatotoxicity is one of its severe toxicities. Hydrogen sulfide is a gaseous signaling molecule that plays crucial regulatory roles in various physiological functions. This study aimed to evaluate the hepatoprotective effect of hydrogen sulfide against cyclo phosp hamid e-ind uced hepatic damage in rats. METHODS: Hepatotoxicity was induced by the single intraperitoneal administration of cyclophosphamide (200 mg/kg). Sprague-Dawley rats were treated by hydrogen sulfide donor, sodium hydrosulfide (25, 50, and 100 µmol/kg, intraperitoneal) 7 days before and 7 days after the administration of a single intraperitoneal injection of cyclophosphamide (200 mg/kg). Cyclo phosp hamide-ind uced hepatotoxicity was evaluated by serum and tissue biochemical and histopathological assessments. The levels of hydrogen sulfide, nitric oxide, cyclic guanosine monophosphate, interleukin 6, and interleukin 10 in liver homogenates were also determined by ELISA. One-way analysis of variance and Kruskal-Wallis tests were used as statistical analyses. RESULTS: Cyclophosphamide increased liver function enzymes (alanine aminotransferase and aspartate aminotransferase), immunoreactivity to caspase-3 and Apaf-1, and proinflammatory cytokines. Cyclophosphamide also induced histopathological alterations including pycnotic nucleus with eosinophilic cytoplasm, increased sinusoidal dilatation, congestion, and edema. Hydrogen sulfide cotreatment significantly reduced cyclo phosp hamid e-ind uced inflammation, histological alterations, and apoptosis in the liver. 50 mg/kg sodium hydrosulfide was more effective against cyclo phosp hamid e-ind uced hepatotoxicity. CONCLUSION: In conclusion, hydrogen sulfide with its anti-inflammatory and anti-apoptotic effects seems to be beneficial as an adjunct to cyclophosphamide treatment to reduce cyclo phosp hamid e-ind uced hepatotoxicity and thereby can be suggested as a promising agent to increase the therapeutic efficacy of cyclophosphamide.

Protective effects of anandamide against cisplatin-induced peripheral neuropathy in rats

Background/aim: Cisplatin (CIS) is an effective antineoplastic agent used in the treatment of several cancer types. Peripheral neuropathy is a major dose-limiting side-effect in CIS therapy. Cannabinoids may alleviate this painful side effect. This study investigated the analgesic effects of anandamide (AN) on CIS-induced peripheral neuropathy, in vitro effects of AN in CIS neurotoxicity, and the contribution of nitric oxide (NO) in this effect. Materials and methods: This is an experimental animal study. Primary dorsal root ganglion (DRG) cultures were prepared from one-day-old rats for in vitro investigations. DRG cells were incubated with CIS (100­300 M), and AN (10, 50, 100, and 500 µM) was administered with the submaximal concentration of CIS. Female Sprague Dawley rats were divided into control, CIS, CIS+AN, CIS+AN+L-NG-nitro arginine methyl ester (LNAME). CIS was administered 3 mg/kg i.p once weekly for 5 weeks. AN (1 mg/kg i.p) or in combination with 10 mg/kg i.p LNAME was administrated 30 min before CIS injection. Mechanical allodynia, thermal hyperalgesia, and tail clip tests were performed. After intracardiac perfusion, sciatic nerves (SN), and DRGs were isolated and semi-thin sections were stained with toluidine blue and investigated histologically. SPSS v. 21.0 and Sigma STAT 3.5 were used for statistical analysis. One/two way ANOVA, Kruskal­Wallis, and Wilcoxon signed ranks tests were used. A p-value of 0.05 was accepted as significant. Results: CIS caused significant mechanical allodynia. AN and AN+LNAME significantly increased hind paw withdrawal latency in mechanical allodynia test. The degenerated axons significantly increased in CIS group, while decreased in AN group. The frequency of larger neurons seemed to be higher in CIS+AN group. Conclusion: AN may be a therapeutic alternative for the treatment of CIS-induced peripheral neuropathy. However, its central adverse effects must be considered.

Agmatine co-treatment attenuates allodynia and structural abnormalities in cisplatin-induced neuropathy in rats.

Cisplatin is a widely used antineoplastic agent in the treatment of various cancers. Peripheral neuropathy is a well-known side effect of cisplatin and has potential to result in limiting and/or reducing the dose, decreasing the quality of life. Thus, effective treatments are needed. Agmatine is an endogenous neuromodulator that has been shown to exert antiallodynic effects in various animal studies. The first aim of this study was to investigate the in vitro effects of agmatine on cisplatin-induced neurotoxicity. Primary cultures of dorsal root ganglia (DRG) which are the primary target of drug injury were prepared. DRG cells were incubated with cisplatin (100, 200, 500 µm). Then, agmatine (10, 100, 500 µm) was administered with the submaximal concentration of cisplatin. Cisplatin caused concentration-dependent neurotoxicity, and agmatine did not alter this effect. The second aim was to investigate the effects of agmatine on cisplatin-induced peripheral neuropathy in rats and the influence of nitric oxide synthase (NOS) inhibitor, L-NAME, in this effect. Female Sprague Dawley rats received intraperitoneal saline (control), cisplatin (3 mg/kg), cisplatin+agmatine (100 mg/kg), or cisplatin+agmatine+L-NAME (10 mg/kg) once a week for 5 weeks. The mechanical allodynia, thermal hyperalgesia [corrected], and tail clip tests were performed, and DRG cells and sciatic nerves were analyzed. Agmatine and agmatine+L-NAME combination attenuated CIS-induced mechanical allodynia and degeneration in DRG cells and sciatic nerves. However, L-NAME did not potentiate the antiallodynic or neuroprotective effect of agmatine. These findings indicate that agmatine co-administration ameliorates cisplatin-induced neuropathy and may be a therapeutic alternative.

Gamma-aminobutyric acid loaded halloysite nanotubes and in vitro-in vivo evaluation for brain delivery.

Gamma-aminobutyric acid (GABA) is a key neurotransmitter where it usually inhibits impulse transmission. GABA release blockage or postsynaptic reaction were determined to provoke epileptic convulsions. The aim of the present study was the development of brain-targeted, nanosized, nontoxic, biocompatible, highly specific formulations. Incorporation of GABA into halloysite nanotubes (HNT) was performed using different methods. Particle size, zeta potential and pH measurements, morphological, thermal, XRD, FTIR analyses and GABA quantification by validated HPLC method were used for the characterization of the systems prepared. Release pattern of GABA from the nanotubes was determined using a dialysis membrane. Following successful incorporation of GABA into HNTs for brain delivery, nanotube formulation coded HNT-GABA H1 was selected for in vivo studies. Smaller particle size with narrow size distribution, possible HNT-GABA interaction indicated by thermal, XRD and FTIR analyses and prolonged release were the parameters considered in this selection. Moreover, HNT-GABA H1 remained stable for 3-month storage period and showed higher cell viability values than GABA. Rats were used in in vivo studies and potential of anticonvulsant effect of GABA was determined in the pentylenetetrazole model of seizure. HNT-GABA H1 was found to increase latency of seizure, decrease ending time of the convulsion, duration of severe convulsion and mortality rate significantly compared to pure GABA. After administration of HNT-GABA H1, GABA concentration in Stratum corsatum measured by enzyme immune assay showed that it was not significantly higher than GABA administered alone. These findings suggest that GABA loaded HNTs reduces the duration of all phases of convulsion indicating efficient delivery of GABA to all brain areas to interfere with epileptic mechanism.