Identification of Novel Regulators of Zalcitabine-Induced Neuropathic Pain.
Antón L MartínezJosé BreaEduardo DomínguezMaría J VarelaMarta CimadevilaCatarina AllegueRaquel CruzXavier MonroyManuel MerlosJavier BurgueñoÁngel CarracedoMaria Isabel LozaPublished in: ACS chemical neuroscience (2021)
Neuropathic pain is one of the foremost adverse effects that worsens quality of life for patients undergoing an antiretroviral treatment. Currently, there are no effective analgesics for relieving it; thus, there is an urgent need to develop novel treatments for neuropathic pain. Previously, we described and validated F11 cells as a model of DRG (dorsal root ganglia) neurons. In the current work, we employed F11 cells to identify regulators of antiretroviral-induced neuropathic pain combining functional and transcriptomic analysis. The antiretroviral zalcitabine (ddC) increased the excitability of differentiated F11 cells associated with calcium signaling without morphological changes in the neuronal phenotype, mimicking the observed increase of painful signaling in patients suffering from antiretroviral-induced neuropathic pain. Employing RNA sequencing, we observed that zalcitabine treatment upregulated genes related with oxidative stress and calcium homeostasis. The functional impact of the transcriptomic changes was explored, finding that the exposure to zalcitabine significantly increased intracellular oxidative stress and reduced store-operated calcium entry (SOCE). Because the functional and transcriptomic evidence points toward fundamental changes in calcium signaling and oxidative stress upon zalcitabine exposure, we identified that NAD(P)H quinone dehydrogenase and the sarcoplasmic/endoplasmic reticulum calcium ATPase 3 were involved in zalcitabine-induced hyperexcitability of F11 cells. Overexpression of those genes increases the calcium-elicited hyperexcitability response and reduces SOCE, as well as increases intracellular ROS levels. These data do not only mimic the effects of zalcitabine but also highlight the relevance of oxidative stress and of calcium-mediated signaling in antiretroviral-induced hyperexcitability of sensory neurons, shedding light on new therapeutic targets for antiviral-induced neuropathic pain.
Keyphrases
- neuropathic pain
- spinal cord
- diabetic rats
- spinal cord injury
- oxidative stress
- induced apoptosis
- high glucose
- hiv infected
- human immunodeficiency virus
- patients undergoing
- hiv aids
- cell cycle arrest
- dna damage
- hiv positive
- hiv infected patients
- signaling pathway
- endoplasmic reticulum
- cell proliferation
- ischemia reperfusion injury
- single cell
- endothelial cells
- chronic kidney disease
- cell death
- machine learning
- end stage renal disease
- working memory
- electronic health record
- deep learning
- dna methylation
- pi k akt
- artificial intelligence
- reactive oxygen species
- bioinformatics analysis
- big data