Transcriptome Profiles of IncRNA and mRNA Highlight the Role of Ferroptosis in Chronic Neuropathic Pain With Memory Impairment

Abstract

Background: Chronic neuropathic pain is commonly associated with memory loss, which increases the risk of dementia, lowers life quality and spending. On the other hand, the molecular processes are unknown, and effective therapies have yet to be discovered. Long non-coding RNAs (lncRNAs) are emerging potential therapeutic targets for chronic pain, but their role in chronic pain-induced memory impairment is unknown.Methods: We established a CCI-induced memory impairment rat model. To investigate and validate the gene expression alterations in the hippocampus of CCI-induced memory impairment, we used RNA-Seq, bioinformatics analysis, qRT-PCR, western blot, immunostaining, Nissl staining, and Diaminobenzidine-enhanced Perls’ stain.Results: CCI rats displayed long-term memory deficits in the Y maze and novel objective recognition tests, and chronic mechanical and thermal pain hypersensitivity in the hind paws. We found a total of 179 differentially expressed mRNAs (DEmRNAs) (81 downregulated and 98 upregulated) and 191 differentially expressed long noncoding RNAs (DElncRNAs) (87 downregulated and 105 upregulated) between the hippocampus CA1 of CCI-induced memory impairment model and the sham control, using RNA-Seq expression profiles. The most enriched pathways involving oxidation and iron metabolism were explored using a route and function pathway analysis of DEmRNAs and DElncRNAs. We also discovered that ATF3 was considerably overexpressed in the hippocampal CA1 area, and gene markers of ferroptosis, such as GPX4, SLC7A11, SLC1A5, and PTGS2, were dysregulated in the CCI-induced memory impairment paradigm. Furthermore, in the hippocampus CA1 of CCI-induced memory impairment, lipid peroxidation and iron overload were considerably enhanced. Fer-1 treatment reversed ferroptosis damage of CCI with memory impairment model. Finally, in CCI-induced memory impairment, a competing RNA network analysis of DElncRNAs and DEmRNAs was performed to investigate the putative regulatory link of DElncRNAs on DEmRNAs via miRNA sponging.Conclusion: Using RNA-Seq, we created a genome-wide profile of the whole hippocampus of a rat model of CCI-induced memory impairment. In the hippocampus, pathways and function analyses revealed numerous intriguing genes and pathways involved in ferroptosis and memory impairment in response to chronic pain stress. As a result, our research may aid in the identification of potential and effective treatments for CCI-induced memory impairment.

Ferroptosis Regulated by 5-HT3a Receptor via Calcium/Calmodulin Signaling Contributes to Neuropathic Pain in Brachial Plexus Avulsion Rat Model

“…Lipid peroxidation is a chain reaction process that involves the oxidative degradation of lipids in cell membranes and is a key mechanism implicated in the development of ferroptosis [29]. Dysregulation of GPX4 and ACSL4 expression, along with iron accumulation, can ultimately lead to lipid peroxidation [27].…”

Schwann cell-derived extracellular vesicles promote memory impairment associated with chronic neuropathic pain

“…Substantial evidence from clinical and experimental research suggests that chronic pain often coexists with memory impairment [ 3 , 4 ]. Peripheral nerve injury has been linked to abnormalities in short-term hippocampal working and recognition memory deficits and long-term potentiation deficits associated with spatial learning and memory disorders [ 5 ]. Persistent pain accelerates memory loss, affects daily activities, and decreases patient quality of life; for example, the relative risk of inability to manage finances independently is 11.8% greater [ 6 ].…”

“…However, current pain therapies are frequently ineffective for CNP. Moreover, neither effective nor ineffective of these therapies typically do not specifically target the rehabilitation of pain-related memory impairment [ 5 ]. Therefore, new strategies targeting the prevention or treatment of CNP-related memory impairment are urgently needed.…”

The multifaceted roles of activating transcription factor 3 (ATF3) in inflammatory responses – Potential target to regulate neuroinflammation in acute brain injury

“…[2][3][4] ATF3 is emerging as a master regulator of inflammation in multiple pathophysiological processes such as cardiovascular disease, dementia, and ischemia/reperfusion-induced damage. 1,[5][6][7][8][9][10][11][12][13][14][15] Neuroinflammation is one of the key pathological features of a wide range of acute brain injuries (ABIs), [16][17][18][19] which mainly include stroke and traumatic brain injury (TBI). 20,21 Neuroinflammation plays a pivotal role in ischemic brain injury during the acute phase of ABI, with excessive immune cell activation and the release of inflammatory mediators.…”

“…2–4 ATF3 is emerging as a master regulator of inflammation in multiple pathophysiological processes such as cardiovascular disease, dementia, and ischemia/reperfusion-induced damage. 1,5–15…”