Background: Trigeminal neuralgia (TN) is the most common neuropathic disorder in the maxillofacial region. The etiology and pathogenesis of TN have not been clearly determined to date, although there are many hypotheses. Objective: The goal of this study was to investigate the interactions between different types of cells in TN, particularly the impact and intrinsic mechanism of demyelination on the trigeminal ganglion, and to identify new important target genes and regulatory pathways in TN. Methods: TN rat models were prepared by trigeminal root compression, and trigeminal nerve tissues were isolated for spatial transcriptome sequencing. The gene expression matrix was reduced dimensionally by PCA and presented by UMAP. Gene function annotation was analyzed by Metascape. The progression of certain clusters and the developmental pseudotime were analyzed using the Monocle package. Modules of the gene coexpression network between different groups were analyzed based on WGCNA and assigned AddModuleScore values. The intercellular communication of genes in these networks via ligand‒receptor interactions was analyzed using CellPhoneDB analysis. Results: The results suggested that the trigeminal ganglion could affect Schwann cell demyelination and remyelination responses through many ligand‒receptor interactions, while the effect of Schwann cells on the trigeminal ganglion was much weaker. Additionally, ferroptosis may be involved in the demyelination of Schwann cells. Conclusions: This study provides spatial transcriptomics sequencing data on TN, reveals new markers, and redefines the relationship between the ganglion and myelin sheath, providing a theoretical basis and supporting data for future mechanistic research and drug development. Export

Trigeminal neuralgia (TN) is a chronic neuropathic pain disorder characterized by spontaneous and elicited paroxysms of electric‐shock‐like or stabbing pain in a region of the face. The epigenetic regulation of TN is still obscure. In current study, a rat TN model subject to carbamazepine (CBZ) treatment was established, and transcriptome‐ and genome‐scale profiling of H3K9ac and HDAC3 was performed by RNA‐seq and ChIP‐seq. We observed that H3K9ac levels in the trigeminal ganglion were lower in the TN rats compared with those in the control, and CBZ treatment led to recovery of H3K9ac levels. Further, we found that HDAC3 was overactivated, which interfered with H3K9 acetylation due to higher phosphorylation in TN compared with that in the control. Finally, the phosphokinase leucine‐rich repeat kinase 2 (LRRK2) was demonstrated to contribute to HDAC3 activity via the MAPK signaling pathway. Taken together, we identified a regulatory mechanism in which the phosphate groups transferred from activated ERK and LRRK2 to HDAC3 caused genome‐scale deacetylation at H3K9 and resulted in the silencing of a large number of genes in TN. The kinases or important enzymes within this regulatory axis may represent important targets for TN therapy and prevention.

Objective: Primary Trigeminal Neuralgia (PTN) is a common and refractory neurological disease. Conventional vascular compression theory could not completely explain the etiology and pathogenesis of PTN. This study used diffusion tensor imaging (DTI) to demonstrate the microstructural changes of root entry zone (REZ) region in PTN patients.Materials and methods: DTI sequences was performed on PTN patients and healthy controls (HCs). Clinical data included affected side, disease course and visual analogue scale (VAS) were collected. Quantitative DTI variables such as FA, MD, AD and RD of the root entry/Exit zone (REZ) were measured and compared in PTN/HCs, affected/unaffected side, and pre/post operation groups. The PCoA was established to conduct overall differences between PTN group and the HCs.Results: A total of 17 patients with PTN (mean age 59.29 ± 8.53; 5 men) and 34 HCs (mean age 57.70 ± 6.37; 10 men) were included. Lower FA value of the affected side of PTN group was observed compared to the unaffected side and the HCs (p = 0.001), whereas the values of MD, AD and RD were significantly increased (p < 0.001). Moreover, the decrease of FA value was recovered post operation. PCoA results of the comprehensive indexes can significantly distinguish PTN group from HCs (r = 0.500, p < 0.001).Conclusion: Quantitative variables derived from DTI in REZ had significantly different profiles between PTN patients and HCs, which were associated with VAS situation and the disease course of PTN. The comprehensive index established on DTI variables were of great potential to reveal the microstructure changes in PTN patients and predict the therapeutic effect.

Original Article Personalized tooth-supported digital guide plate used in the treatment of trigeminal neuralgia with balloon compression Wen-Bin Wei, Yi-Wen Wang, Zi-Xiang Han, Zhi-Yang Liu, Yue-Min Liu, Min-Jie Chen

Background: Trigeminal neuralgia is a typical kind of neuropathic pain featured with severe and recurrent pain attacks along the areas innervated by trigeminal nerve. Although mechanical injuries caused by vessels compression is highly related to the pathogenesis, the underlying molecular mechanism remains unclear. Methods: We constructed chronic constriction to infraorbital nerve (CCI) on Sprague Dawley rats, after which spontaneous pain and mechanical allodynia related behaviors were measured. Transcriptome of trigeminal ganglion (TG) affected by CCI were analyzed to select the related signaling pathway and genes. We examined the receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and domain-like receptor protein 3 (NLRP3) expression in the trigeminal ganglion by western blotting and RT-PCR; studied the location of RIPK1 and NLRP3 expression by performing immunofluorescence. Necrostatin-1, the specific antagonist of RIPK1, was administered to identify the effect of RIPK1 inhibition on NLRP3 expression. Results: We identified mechanical allodynia within the whisker pad area after CCI. RNA-sequencing indicated that NLRP3 levels in the trigeminal ganglion were higher in CCI groups compared to the control group and MAPK signaling pathway was up-regulated after CCI. We also identified an increase in overall reactivity of RIPK1 in trigeminal ganglia after the surgery. A significant proportion of RIPK1⁺ cells in the TG of CCI rats colocalized with the neuron cells. RT-PCR result shows the expression of NLRP3 also increased following RIPK1 activation. The results from immunofluorescence staining revealed that NLRP3 was upregulated in TG neuron cells. Also, when RIPK1 is inhibited by Nec-1, NLRP3 expression in neurons from CCI rats also decreased. Nec-1 can alleviate the demyelination of TG and mechanical allodynia after CCI. Compared to control group, RIPK1 expression is down-regulated after Nec-1 injection, followed by a decreasing in NLRP3 expression. Conclusions: This study demonstrates RIPK1 in TG neurons is activated when nerves are mechanically injuried, leading to the over-expression of NLRP3 inflammasome by activating MAPK signaling pathway. The subsequent cascade of inflammatory feedback and pain signal transmission led to the occurrence of trigeminal neuralgia.