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Spinal neuronal ferroptosis aggravates peripheral nerve injury-induced neuropathic pain via modulating competing endogenous RNA axis

ABSTRACT: Peripheral nerve injury-induced neuropathic pain presents a significant clinical challenge and the pathogenesis remains unclear. Recent findings have implicated spinal neuronal ferroptosis in the modulation of neuropathic pain progression, but the molecular mechanism is inadequately understood. This work constructed competitive endogenous RNA (ceRNA) regulatory network in neuronal ferroptosis model through total transcriptome sequencing. Bioinformatic analyses elucidated the biological roles and signaling pathways of differentially expressed genes associated with neuronal ferroptosis. In vitro experiments substantiated the involvement of two critical regulatory axes, namely lncRNA-Sh3bp5l/miR-92b-5p/Pgd and lncRNA-Scrn2/miR-133a-3p/Srxn1, in the regulation of neuronal ferroptosis. The knockdown of PGD and SRXN1 was observed to significantly inhibit the ferroptosis phenotype. Utilizing an in vivo chronic constriction injury (CCI) pain model, we demonstrated that the expression of ceRNA-mediated downstream targets, PGD and SRXN1, was localized within spinal neurons. Furthermore, lncRNA-Sh3bp5l and lncRNA-Scrn2 were found to be upregulated in the ipsilateral spinal cord following CCI injury, accompanied by increased levels of PGD and SRXN1. In brief, this study explored the key ceRNA axis that regulates spinal neuronal ferroptosis, which might serve as the potential therapeutic targets for neuropathic pain.

ORGANISM(S): Mus musculus

PROVIDER: GSE285467 | GEO | 2024/12/30

REPOSITORIES: GEO

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Project description:Not all patients with nerve injury develop neuropathic pain. The extent of nerve damage and age at the time of injury are two of the few risk factors identified to date. In addition, preclinical studies show that neuropathic pain variance is heritable. To define such factors further, we performed a large-scale gene profiling experiment which plotted global expression changes in the rat dorsal root ganglion in three peripheral neuropathic pain models. This resulted in the discovery that the potassium channel alpha subunit KCNS1, involved in neuronal excitability, is constitutively expressed in sensory neurons and markedly downregulated following nerve injury. KCNS1 was then characterized by an unbiased network analysis as a putative pain gene, a result confirmed by single nucleotide polymorphism association studies in humans. A common amino acid changing allele, the 'valine risk allele', was significantly associated with higher pain scores in five of six independent patient cohorts assayed (total of 1359 subjects). Risk allele prevalence is high, with 18-22% of the population homozygous, and an additional 50% heterozygous. At lower levels of nerve damage (lumbar back pain with disc herniation) association with greater pain outcome in homozygote patients is P = 0.003, increasing to P = 0.0001 for higher levels of nerve injury (limb amputation). The combined P-value for pain association in all six cohorts tested is 1.14 E-08. The risk profile of this marker is additive: two copies confer the most, one intermediate and none the least risk. Relative degrees of enhanced risk vary between cohorts, but for patients with lumbar back pain, they range between 2- and 3-fold. Although work still remains to define the potential role of this protein in the pathogenic process, here we present the KCNS1 allele rs734784 as one of the first prognostic indicators of chronic pain risk. Screening for this allele could help define those individuals prone to a transition to persistent pain, and thus requiring therapeutic strategies or lifestyle changes that minimize nerve injury. Microarrays were run on mRNA extracted from adult rat L4 and L5 DRGs cells after 3,7,21,40 hours after three different sciatic nerve lesions [Spared Nerve Injury (SNI); Chronic Constriction Injury (CCI); Spinal Nerve Ligation (Ch) with Sham controls (SH)].

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Spinal neuronal ferroptosis aggravates peripheral nerve injury-induced neuropathic pain via modulating competing endogenous RNA axis

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