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

Abstract

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, hot plate, 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.

Piceatannol ameliorates behavioural, biochemical and histological aspects in cisplatin‐induced peripheral neuropathy in rats

“…41 Furthermore, the difference in the dosing schedule may explain the disagreement in the behavioural results, because acute administration with cisplatin in our study and in the previously mentioned study by Ali et al resulted in hypoalgesia, 33 whereas the other aforementioned studies reported ensuing hyperalgesia with administration of repeated doses of cisplatin. 39,40 Our results of the locomotor activity and neuromuscular coordination tests are in agreement with previous works showing cisplatin-induced reduction in locomotor activity 42,43 and grip strength. 44,45 On the other hand, coadministration with PIC (10 mg/kg) attenuated the aforesaid cisplatin-induced behavioural changes in the hotplate, tail flick and writhing tests, in addition to the motor results in the locomotor activity and the neuromuscular coordination tests.…”

“…39 Likewise, a previous study showed no difference in the paw withdrawal latency between cisplatin and the control in the hotplate test; such variation from our results may be attributed to the lower cisplatin dose they used (3 mg/kg), administered once a week for 5 weeks. 40 Indeed, an earlier study resolved such inconsistency and reported that higher doses of cisplatin induced hypoalgesia, whereas lower doses produced hyperalgesia. 41 Furthermore, the difference in the dosing schedule may explain the disagreement in the behavioural results, because acute administration with cisplatin in our study and in the previously mentioned study by Ali et al resulted in hypoalgesia, 33 whereas the other aforementioned studies reported ensuing hyperalgesia with administration of repeated doses of cisplatin.…”

“…Our results are in agreement with several previous studies in experimental animals. [38][39][40]47,48 In addition, cisplatin was shown to induce myelin-forming Schwann cells cytotoxicity and to decrease the quantity of functioning mitochondria in neurons and Schwann cells in vitro. [49][50][51] The demyelination observed in the cisplatintreated group could lead to slow impulse conduction, explaining our behavioural and motor results.…”

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

“…Our results showed that L-NAME did not significantly potentiate the antiallodynic and neuroprotective effects of agmatine. 139 It was demonstrated that NOS inhibitors and NMDA receptor antagonists could increase the release of 5-HT by activating tryptophan hydroxylase. 140 It can be thought that the increase in serotonin could contribute the antinociceptive activity of agmatine.…”

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

“…The primary cultures of DRG were prepared as previously described [24]. Rats were purchased from Medical and Surgical Research Center of Eskisehir Osmangazi University.…”