Chlorogenic acid co-administration alleviates cisplatin-induced peripheral neuropathy in rats.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is still an unresolved problem in cisplatin (CIS) use. OBJECTIVES: This study investigates possible anti-neuropathic effect of chlorogenic acid (CGA) against CIS-induced CIPN in rats while also investigating the contribution of nitric oxide (NO) to this phenomenon. METHODS: Initially, CGA (250-1000 µM) was tested by MTT assay on primary DRG neurons. Subsequently, CIPN was induced in Sprague-Dawley rats by 3 mg/kg intraperitoneal injections of CIS once/week for 5 weeks. CGA (100 mg/kg) was co-administered with CIS, both alone and in combination with l-arginine (LARG) or l-nitro-arginine-methyl-ester (LNAME), to elucidate the contribution of nitrergic system to anti-neuropathic effects. Mechanical allodynia, thermal hyperalgesia, and cold plate tests were performed to test CIPN. Rotarod, footprint analysis, and activitymeter were used to evaluate motor coordination and performance. Tumor necrosis factor alpha (TNF-α) was measured as a marker of inflammation. Histological evaluations of DRG and sciatic nerves (SNs) were performed utilizing toluidine blue staining. Two-way analysis of variance and Kruskal-Wallis following Tukey's test were used as statistical analysis. RESULTS: Higher concentration of CGA (1000 µM) exhibited protective effect against in vitro neurotoxicity. Neither LARG nor LNAME exerted significant change in this effect. Co-administration of CGA alleviated histological abnormalities and neuropathic effects induced by CIS. Ameliorative effect of CGA was not changed in mechanical allodynia but attenuated in cold allodynia, and motor activity/coordination tests by LARG and LNAME. Neuropathic effects of CIS remained unchanged with LARG and LNAME in behavioral experiments. CONCLUSION: The study identified CGA as candidate agent in mitigating CIPN. NO seems to play a modulatory role in this effect.

2-Aminoethoxydiphenyl borate ameliorates functional and structural abnormalities in cisplatin-induced peripheral neuropathy.

AIM OF THE STUDY: Cisplatin is a platinum-derived chemotherapeutic agent commonly used in the treatment of various tumors. Ototoxicity, nephrotoxicity, and peripheral neuropathy are the most common side effects of this drug. 2-Aminoethoxydiphenyl borate (2-APB), boron- containing compound, has some protective effects against various tissue damage. The present study aimed to investigate the potential protective effects of 2-APB on in vitro and in vivo cisplatin-induced neurotoxicity. MATERIALS AND METHODS: MTT assay was used to determine cell viability in DRG cells. Peripheral neuropathy was induced in forty male Sprague-Dawley rats (200-250g) by administering cisplatin (3 mg/kg/week) intraperitoneally (i.p) for five weeks. 2-APB (2, 4, and 8 mg/kg, i.p) was administered. Mechanical allodynia, thermal hyperalgesia, cold allodynia, mechanical stimuli, motor coordination, and locomotor activity tests were performed. DRG cells and sciatic nerves were analyzed histologically. NGF, BDNF, TNF-α, GSH, MDA, and LDH levels were investigated in rat DRG tissue homogenates. RESULTS: Our results revealed that 2-APB ameliorated cisplatin-induced neurotoxicity by improving mechanical and cold allodynia and motor coordination impairment. It also reduced cisplatin-induced structural toxicity in peripheral tissues. CONCLUSION: These findings demonstrated that 2-APB could be considered as a potential therapeutic strategy for the treatment of cisplatin-induced peripheral neuropathy.

The Role of Ionic Homeostasis in Cisplatin-Induced Neurotoxicity: A Preliminary Study.

OBJECTIVE: The aim of the present study was to investigate the role of ionic homeostasis in cisplatin (cisdiamminedichloroplatinum (II), CDDP)-induced neurotoxicity. CDDP is a severely neurotoxic antineoplastic agent that causes neuronal excitotoxicity. According to some studies, calcium influx increases, whereas potassium efflux decreases neuronal death. Nimodipine and glibenclamide were used to analyze the role of ionic flows in CDDP-induced neurotoxicity in rat primary cerebellar granule cell (CGC) culture. MATERIALS AND METHODS: CGC culture was prepared from the cerebella of Sprague Dawley 5-day-old pups. The submaximal concentration of CDDP was determined and then given with 1, 10, or 50 µM of drugs into culture. Neurotoxicity was investigated using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, a tetrazole) assay. One-way analysis of variance, Kruskal-Wallis H test, and Tukey test were applied for statistical analysis. RESULTS: CDDP induced neurotoxicity in a concentration-dependent manner. Neither nimodipine nor glibenclamide was able to protect CGCs against CDDP neurotoxicity. CONCLUSION: By blocking L-type voltage-gated calcium channels, nimodipine did not prevent CDDP neurotoxicity in CGCs. Ca2+ influx via these channels seemed to be insufficient to cause a change in CDDP-induced neurotoxicity. Similarly, glibenclamide failed to prevent CDDP neurotoxicity. Further studies are needed to elucidate the mechanisms of these preliminary results.

Cannabinoids and agmatine as potential therapeutic alternatives for cisplatin-induced peripheral neuropathy.

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 the potential to result in limiting and/or reducing the dose, decreasing the quality of life. Unfortunately, the mechanism for cisplatin-induced neuropathy has not been completely elucidated. Currently, available treatments for neuropathic pain (NP) are mostly symptomatic, insufficient and are often linked with several detrimental side effects; thus, effective treatments are needed. Cannabinoids and agmatine are endogenous modulators that are implicated in painful states. This review explains the cisplatin-induced neuropathy and antinociceptive effects of cannabinoids and agmatine in animal models of NP and their putative therapeutic potential in cisplatin-induced neuropathy.

Protective role of resveratrol on testicular germ cells in mice with testicular toxicity.

OBJECTIVE: The aim of the present study was to investigate the possible beneficial effects of resveratrol in mice subjected to vinyl cyclohexene dieposide (VCD) -induced testicular toxicity. MATERIAL AND METHODS: A total of thirty- six Swiss albino male mice aged 28-days were used in the present study. The study was composed of two stages where mice which received or did not receive VCD (320 mg/kg/day) were administered resveratrol. The animals were assigned into control and resveratrol-treated groups in the first stage and into groups of VCD- and VCD+resveratrol-treated groups in the second stage. At the end of the experiments, relative testicular weight (TW/BW) and dry/wet weight of testis (TDW/TWW) were calculated. Histological analysis by hematoxylin and eosin (H&E) staining and immunohistochemical staining by BAX and Bcl-2 were performed. Serum testosterone, LH and FSH levels were measured by a commercially available ELISA kit. RESULTS: Resveratrol caused a dose-dependent increase in TW/BW and decrease in TDW/TWW (p<0.05). Resveratrol at a dose of 20 mg/kg resulted in an improvement in testosterone, LH and FSH levels in mice with VCD-induced testicular toxicity (p<0.001). Resveratrol also improved apoptotic index and epithelial cell height of testicular seminipherous tubuli significantly after VCD exposure (p<0.001). CONCLUSION: Results of the present study suggest that resveratrol can be used as a protective and/or therapeutic agent particularly for cases with male infertility caused by testicular toxicity.