Transcriptome profiling of long noncoding RNAs and mRNAs in spinal cord of a rat model of paclitaxel-induced peripheral neuropathy identifies potential mechanisms mediating neuroinflammation and pain

Abstract

Background Paclitaxel is a widely prescribed chemotherapy drug for treating solid tumors. However, paclitaxel-induced peripheral neuropathy (PIPN) is a common adverse effect during paclitaxel treatment, which results in sensory abnormalities and neuropathic pain among patients. Unfortunately, the mechanisms underlying PIPN still remain poorly understood. Long noncoding RNAs (lncRNAs) are novel and promising targets for chronic pain treatment, but their involvement in PIPN still remains unexplored. Methods We established a rat PIPN model by repetitive paclitaxel application. Immunostaining, RNA sequencing (RNA-Seq) and bioinformatics analysis were performed to study glia cell activation and explore lncRNA/mRNA expression profiles in spinal cord dorsal horn (SCDH) of PIPN model rats. qPCR and protein assay were used for further validation. Results PIPN model rats developed long-lasting mechanical and thermal pain hypersensitivities in hind paws, accompanied with astrocyte and microglia activation in SCDH. RNA-Seq identified a total of 814 differentially expressed mRNAs (DEmRNA) (including 467 upregulated and 347 downregulated) and 412 DElncRNAs (including 145 upregulated and 267 downregulated) in SCDH of PIPN model rats vs. control rats. Functional analysis of DEmRNAs and DElncRNAs identified that the most significantly enriched pathways include immune/inflammatory responses and neurotrophin signaling pathways, which are all important mechanisms mediating neuroinflammation, central sensitization, and chronic pain. We further compared our dataset with other published datasets of neuropathic pain and identified a core set of immune response-related genes extensively involved in PIPN and other neuropathic pain conditions. Lastly, a competing RNA network analysis of DElncRNAs and DEmRNAs was performed to identify potential regulatory networks of lncRNAs on mRNA through miRNA sponging. Conclusions Our study provided the transcriptome profiling of DElncRNAs and DEmRNAs and uncovered immune and inflammatory responses were predominant biological events in SCDH of the rat PIPN model. Thus, our study may help to identify promising genes or signaling pathways for PIPN therapeutics.

Neuroimmune Consequences of eIF4E Phosphorylation on Chemotherapy-Induced Peripheral Neuropathy

“…The number of ATF3 + neurons were significantly higher in the DRG of paclitaxel-treated animals indicating damage; however, there were no sex-based or genotype differences observed (Figure 6 and Table 5). The increase is similar to previously published literature, albeit at a later time point (59,60), thus we conclude that this higher dose does not comparatively alter DRG neurons at day 10 after our regimen. (61)(62)(63).…”

Expression Profiling of Contralateral Dorsal Root Ganglia of a Rat Model of Complex Regional Pain Syndrome Type-i Uncovers Potential Mechanisms Involved in Mirror-image Painexpression Profiling of Contralateral Dorsal Root Ganglia of a Rat Model of Complex Regional Pain Syndrome Type-i Uncovers Potential Mechanisms Involved in Mirror-image Pain

“…For positive control, in one of our recent studies, we stained DRGs with ATF3 from paclitaxel-treated rats, a rat model for chemotherapy-induced peripheral neuropathy and well known for its peripheral neuropathy. We found the number of ATF3 positively expressed neurons was signi cantly increased in DRG of paclitaxel-treated rats vs. control rats [32]. Therefore, the above results indicated no neuronal damage occurred in bilateral DRG neurons of the CPIP model rats.…”

LncRNA HOXA-AS2 regulates microglial polarization via recruitment of PRC2 and epigenetic modification of PGC-1α expression

“…Increasing evidence has shown that lncRNAs are involved in multiple biological and pathological processes, including neurodegenerative disease [ 18 , 19 ]. LncRNAs can regulate microglia/macrophage polarization and innate immune responses [ 20 , 21 ]. A recent study demonstrated that lncRNA Tug1 could regulate PGC-1α expression in mitochondrial bioenergetics [ 22 ].…”