Trigeminal nerve electrical stimulation attenuates early traumatic brain injury through the TLR4/NF-κB/NLRP3 signaling pathway mediated by orexin-A/OX1R system

Aging (Albany NY). 2024 May 6;16(9):7946-7960. doi: 10.18632/aging.205795. Epub 2024 May 6.

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.

Keywords: OX-A/OX1R; TLR4/NF-κB/NLRP3 pathway; inflammation; traumatic brain injury; trigeminal nerve electrical stimulation.

MeSH terms

  • Animals
  • Brain Injuries, Traumatic* / metabolism
  • Brain Injuries, Traumatic* / therapy
  • Disease Models, Animal
  • Electric Stimulation Therapy / methods
  • Male
  • NF-kappa B* / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein* / metabolism
  • Orexin Receptors* / genetics
  • Orexin Receptors* / metabolism
  • Orexins / metabolism
  • Rats
  • Rats, Sprague-Dawley*
  • Signal Transduction*
  • Toll-Like Receptor 4* / genetics
  • Toll-Like Receptor 4* / metabolism
  • Trigeminal Nerve* / metabolism

Substances

  • Tlr4 protein, rat
  • Nlrp3 protein, rat
  • Hcrtr1 protein, rat