Electroacupuncture of the trigeminal nerve causes N-methyl-D-aspartate receptors to mediate blood-brain barrier opening and induces neuronal excitatory changes

Abstract

The blood-brain barrier (BBB) is an important structure for maintaining environmental stability in the central nervous system (CNS). Our previous study showed that specific parameters of electroacupuncture (EA) at the head points Shuigou (GV26) and Baihui (GV20) can open the BBB; however, the mechanism by which stimulation of body surface acupuncture points on the head results in peripheral stimulation and affects the status of the central BBB and the neuronal excitatory changes has not been elucidated. We used laser spectroscopy, the In Vivo Imaging System (IVIS), immunofluorescence and immunoblotting to verified the role of the trigeminal nerve in BBB opening during EA, and we applied the central N-methyl-D-aspartate (NMDA) receptors blocker MK-801 to verify the mediating role of NMDA receptors in EA-induced BBB opening. Next, electroencephalogram (EEG) and in vivo calcium imaging techniques were applied to verify the possible electrical patterns of BBB opening promoted by different intensities of EA stimulation. The results showed that the trigeminal nerve plays an important role in the alteration of BBB permeability promoted by EA stimulation of the head acupoints. Brain NMDA receptors play a mediating role in promoting BBB permeability during EA of the trigeminal nerve, which may affect the expression of the TJ protein occludin, and thus alter BBB permeability. The analysis of the electrical mechanism showed that there was no significant change in the rhythm of local field potentials (LFP) in different brain regions across frequency bands immediately after EA of the trigeminal nerve at different intensities. However, the local primary somatosensory (S1BF) area corresponding to the trigeminal nerve showed a transient reduction in the delta rhythm of LFP with no change in the high-frequency band, and the action potential (spike) with short inter spike interval (ISI) varied with EA intensity. Meanwhile, EA of the trigeminal nerve resulted in rhythmic changes in calcium waves in the S1BF region, which were influenced by different EA intensities. This study provides a research perspective and a technical approach to further explore the mechanism of EA-induced BBB opening and its potential clinical applications.

Trigeminal nerve stimulation: a current state-of-the-art review

“…TNS has a bimodal effect on blood–brain barrier (BBB) permeability. In healthy animals, electroacupuncture TNS (EA-TNS) applied at the infraorbital nerve resulted in increased BBB permeability, as indicated by increased Evans-Blue perfusion (Gong et al 2022 ). In a rat model of TBI, however, the application of TNS at the anterior ethmoidal nerve resulted in decreased BBB permeability (Chiluwal et al 2017 ).…”

“…This potentially results in the prevention of a self-reinforcing cycle of glutamatergic kainite and NMDA receptor overactivation and further glutamate release, thus affecting CSD propagation (Nash, Powell, White, et al 2023 ). EA-TNS in healthy conditions, however, increases NMDA receptor expression (Gong et al 2022 ). This increases glutamate expression and transmission in the S1 cortex, resulting in decreased occludin expression and increased BBB permeability.…”

“…The application of TNS in healthy and TBI conditions results in two distinctly opposing effects on the BBB (Gong et al 2022 ; Chiluwal et al 2017 ). In healthy conditions, TNS results in the increase of BBB permeability via the downregulation of occludin (Gong et al 2022 ).…”

“…Systemically, it modulates the autonomic nervous system (ANS), induces peripheral vasoconstriction, decreases systemic inflammation, and modulates cardiac performance (Degiorgio et al 2011 ; Borges and Casselman 2010 ; Shankland 2000 ; Walker 1990 ). Clinical and pre-clinical assessments in healthy conditions illustrate TNS’ widespread effects and the underlying mechanisms, forming the basis of its application in pathological conditions (Gong et al 2022 ; Li et al 2021a , b ; Just et al 2010 ; Weber et al 2003 ; Suzuki et al 1990 ). Clinically, TNS has been primarily applied to chronic brain disorders.…”

Electroacupuncture stimulation enhances the permeability of the blood-brain barrier: A systematic review and meta-analysis of preclinical evidence and possible mechanisms

“…As an illustration, electroacupuncture has the capacity to activate the sensory distribution region associated with the trigeminal nerve, thereby triggering the release of neurotransmitters like glutamate. This process leads to heightened neural activity within the cerebral cortex and elicits the opening effect of the blood-brain barrier [ 7 ]. On the other hand, electroacupuncture affects glial membrane barrier tight junction proteins.…”