Novel Oto-Protection Strategy in Cisplatin Induced Ototoxicity

It has been almost forty years since cisplatin was introduced in clinical practice as a potent and promising anti-neoplastic drug. Since then, the usage of cisplatin for treating a variety of cancers in both children and young adults has increased. Ototoxicity is one of the dose limiting side effects of cisplatin. Currently, there is not a single good otoprotecting drug against cisplatin ototoxicity in clinical practice. We planed to study the effect of noise stress against cisplatin ototoxicity alone and in combination with two other thiol based otoprotectors, namely L-NAC and D-MET, at very low dosages which had shown otoprotection against cisplatin ototoxicity. Although these two otoprotectors have shown promising results in animal studies at high dosages, there is concern that high dose of L-NAC and D-MET could have negative effects on chemotherapy, leading to reduced chemotherapeutic efficacy. In an attempt to avoid this negative chemotherapeutic effect, studies have been conducted administrating the otoprotecting drug at varying times and space. The underlined hypothesis of this thesis is that a tolerable stress before an intolerable cisplatin insult could better prepare the hair cells for the intolerable cisplatin insult. Above all, an acute noise stress alone could potentially activate antioxidant enzymes, heat shock proteins, glucocorticoids, and stress activated protein kinases that could protect the hair cells from cisplatin toxicity. We used noise stress to enhance the otoprotective effects of L-NAC and D-MET. Moreover, we were interested in studying the effect of noise stress alone. Results of our studies have demonstrated that the noise stress technique maximizes the otoprotecting efficacy of 275 mg/kg L-NAC and 300 mg/kg D-MET, where 300 mg/kg D-MET + noise stress being the best among all treated groups. More interestingly, we found that noise stress alone showed better results against cisplatin ototoxicity when compared with the cisplatin only group. Both Hematoxylin and Eosin staining and TRITC-conjugated phalloidin staining were essentially consistent with the ABR findings. Even minor otoprotection by an acute noise stress could change the current course of drug-only otoprotection approach against cisplatin ototoxicity. In clinic, this would let us use certain frequencies of sound by a headphone before or after the cisplatin treatment to protect at least the speech perception frequencies of patients.