BDNF protection of auditory neurons from cisplatin involves changes in intracellular levels of both reactive oxygen species and glutathione.
Previous studies have shown that brain derived neurotrophic factor (BDNF) can protect auditory neurons from cisplatin toxicity in vitro. To explore the mechanism of BDNF mediated neuronal protection sequential confocal microscopic sampling of auditory neurons measured intracellular levels of reactive oxygen species (ROS) in response to withdrawal of BDNF supplementation, cisplatin exposure, and BDNF protection from cisplatin damage in normal and oxidative stress states. Additionally, we examined intraneuronal levels of the free radical scavenger glutathione (GSH) in response to withdrawal of BDNF. Withdrawal of BDNF resulted in increased production of ROS and decreased survival of auditory neurons. Levels of GSH within neurons increased after BDNF withdrawal, and this increase was shown to lag behind the production of ROS. Auditory neurons in cultures supplemented with BDNF and exposed to cisplatin showed significantly lower levels of ROS and increased survival compared to neurons in unprotected, cisplatin exposed cultures. Neurons treated with buthionine sulfoximine (an inhibitor of GSH synthesis), supplemented with BDNF, and exposed to cisplatin showed significantly higher intracellular levels of ROS compared to the neurons in BDNF supplemented cultures exposed to cisplatin. These results suggest that intracellular levels of ROS play an important role in cisplatin induced cell death of auditory neurons and that production of ROS can be ameliorated through supplementation with BDNF. GSH appears to mediate BDNF protection of these neurons from cisplatin induced ROS and subsequent damage.
Gabaizadeh
R
R
Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Staecker
H
H
Liu
W
W
Van De Water
T R
TR
D000818:Animals; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors* / Q000633:toxicity; D001306:Auditory Pathways / Q000187:drug effects* / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000037:antagonists & inhibitors* / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism; D018613:Microscopy, Confocal; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013136:Spiral Ganglion / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D019208:Brain-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D019328:Buthionine Sulfoximine; D005978:Glutathione; D002945:Cisplatin