Neuronal Nitric Oxide Synthase is a Key Factor in Doxorubicin-Induced Toxicity to Rat-Isolated Cortical Neurons

Abstract

Doxorubicin (DOX) is neurotoxic to serum-free cultures of rat cortical neurons in a biphasic concentration manner. For concentrations up to 0.5 μM, cell death follows an apoptotic pattern, while for higher concentrations apoptosis is inhibited and necrosis becomes dominant. Considering the potential toxic effects of DOX resulting from its redox-cycling, in this study we investigated the generation of reactive species and subsequent oxidative stress effects, formation of quinoproteins, activation of NF-kB, depletion of energy levels and consequent cell death in cultures of primary rat cortical cells challenged with this antitumour drug. The influence of neuronal nitric oxide synthase (nNOS) on DOX-induced neuronal cell damage was subsequently evaluated. The exposure of rat cortical primary cell cultures to DOX resulted in a significant generation of ROS/RNS, activation of NF-kB, depletion of GSH levels, depletion of ATP, and cell death, in a concentration biphasic manner. Doxorubicin also significantly increased protein-bound quinone products in neurons in a concentration-dependent manner. Inhibition of nNOS decreased neuronal cell death induced by DOX in a significant way, at the first phase of the biphasic curve. In conclusion, this study shows, for the first time, a clear involvement of nNOS and subsequent ROS/RNS generation as crucial signalling mediators of DOX-induced neurotoxicity on isolated cortical neurons. Inhibition of ROS/RNS formation, modulation of NOS isoforms and modulation of NF-kB activation could be of beneficial in preventing damage in the CNS caused by DOX.

Effects of histidine andn-acetylcysteine on experimental lesions induced by doxorubicin in sciatic nerve of rats

“…Long-term bortezomib administration produced small-fiber neuropathy (Meregalli et al, 2010). The mechanisms of DOX-induced neurotoxicity and subsequent neuropathic pain are not completely understood, but recent evidences indicate that generation of reactive oxygen species (ROS) involved (Lopez et al, 2011;Pal et al, 2012). The decreased and increased plasma levels of MDA and TAC, respectively, observed in the present study, may be associated to the involvement of oxidative stress in DOX-induced peripheral neuropathy.…”

Doxorubicin and cyclophosphamide induce cognitive dysfunction and activate the ERK and AKT signaling pathways

“…Doxorubicin has been shown by others to increase oxidative stress and induce DNA damage [29], therefore we have initially evaluated these pathways with respect to their contributions to chemotherapy-induced cognitive dysfunction. As a first step, we have measured activation of ERK1/2 and Akt pathways in doxorubicin and cyclophosphamide treated intact and OVX Sprague-Dawley rats that have not been subjected to any behavioral assays.…”

Mitochondria-targeted vitamin E analogs inhibit breast cancer cell energy metabolism and promote cell death

“…It is well known that redox-based chemotherapeutics induce depletion of intracellular ATP levels via increased oxidative stress [43]. Unfortunately, these drugs also cause toxic side effects through oxidative mechanism of activation [44].…”