Research Paper Volume 16, Issue 9 pp 7946—7960
Trigeminal nerve electrical stimulation attenuates early traumatic brain injury through the TLR4/NF-κB/NLRP3 signaling pathway mediated by orexin-A/OX1R system
- 1 Department of Rehabilitation Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi, P.R. China
Received: December 20, 2023 Accepted: April 9, 2024 Published: May 6, 2024
https://doi.org/10.18632/aging.205795How to Cite
Copyright: © 2024 Kang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Background: Traumatic brain injury (TBI) is a significant contributor to global mortality and disability, and emerging evidence indicates that trigeminal nerve electrical stimulation (TNS) is a promising therapeutic intervention for neurological impairment following TBI. However, the precise mechanisms underlying the neuroprotective effects of TNS in TBI are poorly understood. Thus, the objective of this study was to investigate the potential involvement of the orexin-A (OX-A)/orexin receptor 1 (OX1R) mediated TLR4/NF-κB/NLRP3 signaling pathway in the neuroprotective effects of TNS in rats with TBI.
Methods: Sprague-Dawley rats were randomly assigned to four groups: sham, TBI, TBI+TNS+SB334867, and TBI+TNS. TBI was induced using a modified Feeney’s method, and subsequent behavioral assessments were conducted to evaluate neurological function. The trigeminal nerve trunk was isolated, and TNS was administered following the establishment of the TBI model. The levels of neuroinflammation, brain tissue damage, and proteins associated with the OX1R/TLR4/NF-κB/NLRP3 signaling pathway were assessed using hematoxylin-eosin staining, Nissl staining, western blot analysis, quantitative real-time polymerase chain reaction, and immunofluorescence techniques.
Results: The findings of our study indicate that TNS effectively mitigated tissue damage, reduced brain edema, and alleviated neurological deficits in rats with TBI. Furthermore, TNS demonstrated the ability to attenuate neuroinflammation levels and inhibit the expression of proteins associated with the TLR4/NF-κB/NLRP3 signaling pathway. However, it is important to note that the aforementioned effects of TNS were reversible upon intracerebroventricular injection of an OX1R antagonist.
Conclusion: TNS may prevent brain damage and relieve neurological deficits after a TBI by inhibiting inflammation, possibly via the TLR4/NF-κB/NLRP3 signaling pathway mediated by OX-A/OX1R.
Abbreviations
TBI: Traumatic brain injury; TLR4: Toll-like receptor 4; NF-κB: Nuclear factor-κB; NLRP3: Nucleotide-binding domain-like receptor protein 3; IL-1β: Interleukin-1β; TNF-α: Tumor necrosis factor-α; IL-18: Interleukin-18; ASC: Apoptosis-associated speck-like protein; TNS: Trigeminal nerve electrical stimulation; OX-A: Orexin-A; OX1R: Orexin receptor 1; DMSO: Dimethyl sulfoxide; LORR: Loss of righting reflex test; mNSS: Modified neurological severity scale.