The Role of Gene Expression in the Lateral Hypothalamus on the Development of Allodynia after Cisplatin Treatment
Year: 2018
Type: article
Abstract: Advances in cancer treatment have led to an increase in cancer survivorship as the number of individuals living beyond cancer diagnosis and treatment rises each year. Yet, as this number rises, so does the number of people who live with the side-effects of cancer treatment. Chemotherapy-induced peripheral neuropathy (CIPN) is a common side-effect of neurotoxic chemotherapeutic drugs that is characterized by sensations of numbness and tingling that begin in the distal extremities and can develop into chronic neuropathic pain. There are no recommended preventative measures for CIPN and the only recommended treatment is the serotonin-norepinephrine reuptake inhibitor, duloxetine, which does not offer relief to all patients. The lateral hypothalamus (LH) is part of a descending system that modulates pain in the spinal cord dorsal horn. The chemotherapeutic drug cisplatin accumulates in the dorsal root ganglion of the primary afferent neuron and promotes abnormal pain signaling that may disrupt the genome of LH cells, via the spinohypothalamic ascending tract, contributing to the development of painful CIPN. This dissertation study investigated the role of the LH in the development of cisplatin-related mechanical allodynia, a sign of neuropathic pain. The goal was to detect changes in LH-derived gene expression and examine the association of these changes with development and persistence of mechanical allodynia in different strains of mice. Results of nocifensive behavioral von Frey testing have shown that different strains of mice (C57BL/6J, BALB/cJ, DBA/2J, A/J, FVB/NJ, and CD-1) develop allodynia at different rates post cisplatin treatment. Based on these results, the two strains that represented the highest (C57BL/6J) and lowest (A/J) responders to allodynia development were selected for further gene expression and protein analysis. Analysis of microarray data from the LH transcriptome of C57BL/6J and A/J mice showed very few gene expression changes within each strain after cisplatin treatment, but we discovered 1311 differentially expressed genes (DEGs) between the strains prior to treatment. Using Ingenuity Pathway Analysis (IPA) to characterize these DEGs, we discovered that the top biological pathways affected by the DEGs included “Synaptic Long-Term Potentiation” and “Neuropathic Pain Signaling in Dorsal Horn Neurons.” Using IPA, we identified nine genes with documented function in pain development for further target gene expression validation with quantitative real-time polymerase chain reaction (qPCR). The results of the qPCR were used to verify the gene expression direction in seven of the DEGs. Western blot confirmed two of the genes were present at the protein level. The results of this pre-clinical study are suggestive that the gene expression profile prior to cisplatin treatment may predispose the development of painful CIPN in mice. These pre-clinical findings may ultimately guide precision health by using gene expression profiles to predict patients at risk for painful CIPN and identify patients who will benefit from preventative measures.
Author: Monica A. Wagner
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2924470780