Region-specific disruption of the blood-brain barrier following repeated inflammatory dural stimulation in a rat model of chronic trigeminal allodynia

Fried, Nathan T.; Maxwell, Christina R.; Elliott, Melanie B.; Oshinsky, Michael L.

doi:10.1177/0333102417703764

Cited by 44 publications

(42 citation statements)

References 59 publications

(81 reference statements)

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“…Therefore, changes in permeability at the brainstem, an important target area for headache therapeutics, may be particularly relevant for drug delivery during headache. Although studies done in an inflammation induced model of headache showed changes in BBB permeability in the brainstem, namely the TNC ( Fried et al, 2017 ), our studies revealed that cortical KCl injection did not increase paracellular permeability in the brainstem as measured by 14 C-sucrose. This suggests the possibility of model-specific alterations in BBB permeability.…”

Section: Discussioncontrasting

confidence: 69%

“…In conditions such as TBI and ischemic stroke, the integrity of the BBB is altered following injury ( Prakash and Carmichael, 2015 ), although this loss of integrity is most often associated with trauma within the CNS rather than with CSD or headache. Additionally, in studies examining primary headache disorders, where no obvious CNS trauma exists, CSD and increased BBB permeability have been shown to occur in some instances (i.e., migraine with aura; Leira et al, 2007 ; Charles and Baca, 2013 ; Fried et al, 2017 ). The data presented here represent the first study examining, concurrently, the temporal occurrence of CSD, nociceptive behaviors, and BBB leak in a CSD-induced model of episodic headache.…”

Section: Discussionmentioning

confidence: 99%

“…Separately, it has also been shown that KCl-induced CSD elicits nociceptive behaviors in rats; however, BBB permeability was not measured ( Fioravanti et al, 2011 ). Additionally, examination of BBB permeability in a dural inflammation model of headache showed a site-specific increase in BBB permeability in the trigeminal nucleus caudalis (TNC), a brain region involved in transmission of nociceptive stimuli from the trigeminal afferents ( Fried et al, 2017 ). A few clinical studies have also attempted to study BBB changes in response to primary headache disorders such as migraine but have produced conflicting results.…”

Section: Introductionmentioning

confidence: 99%

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Loss of Blood-Brain Barrier Integrity in a KCl-Induced Model of Episodic Headache Enhances CNS Drug Delivery

Cottier

Galloway

Calabrese

et al. 2018

eNeuro

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Cortical spreading depression (CSD) in the CNS is suggested as a common mechanism contributing to headache. Despite strong evidence for CNS involvement in headache disorders, drug development for headache disorders remains focused on peripheral targets. Difficulty in delivering drugs across the blood-brain barrier (BBB) may partially account for this disparity. It is known, however, that BBB permeability is increased during several CNS pathologies. In this study, we investigated BBB changes in response to KCl-induced CSD events and subsequent allodynia in rats. Cortical KCl injection in awake, freely moving rats produced facial allodynia with peak intensity between 1.5 and 3 h and CSD induction within 0.5–2 h postinjection. Brain perfusion of 14C-sucrose as a marker of BBB paracellular permeability revealed increased leak in the cortex, but not brainstem, beginning 0.5 h post-KCl injection and resolving within 6 h; no changes in tight junction (TJ) proteins occludin or claudin-5 expression were observed. Acute pretreatment with topiramate to inhibit CSD did not prevent the increased BBB paracellular permeability. CNS delivery of the abortive anti-migraine agent sumatriptan was increased in the cortex 1.5 h post-KCl injection. Surprisingly, sumatriptan uptake was also increased in the brainstem following CSD induction, suggesting regulation of active transport mechanisms at the BBB. Together, these results demonstrate the ability of CSD events to produce transient, time-dependent changes in BBB permeability when allodynia is present and to mediate access of clinically relevant therapeutics (i.e., sumatriptan) to the CNS.

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Section: Discussioncontrasting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Loss of Blood-Brain Barrier Integrity in a KCl-Induced Model of Episodic Headache Enhances CNS Drug Delivery

Cottier

Galloway

Calabrese

et al. 2018

eNeuro

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“…Attentionally, we chose peripheral administration intervention to suppress IL-18 bioactivity before each IS dural infusion, by considering the particularity of our animal models. Western blot analysis verified the blockade of IL-18 in the medullary dorsal horn, which could be explained by blood-brain barrier (BBB) breakdown due to repeated IS dural stimulation [27] . Glial activation occupied a key position in the BBB modulation [28,29] .…”

Section: Discussionmentioning

confidence: 76%

Involvement of Interleukin-18-Mediated Microglia/Astrocyte Interaction in Experimental Models of Migraine

Gong

Lin

et al. 2020

Preprint

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Background: The exact molecular mechanisms of migraine were not fully understood. Emerging evidence indicated that inflammation had a significant role in pathophysiological mechanisms of migraine. The present study aimed to investigate the involvement of Interleukin-18-Mediated Microglia/Astrocyte Interaction in the development of hyperpathia or allodynia induced by migraine. Methods: Experimental rat model of migraine was established by repetitive inflammatory soup (IS) dural infusions. The expression of Interleukin-18 (IL-18) and IL-18 receptor (IL-18R) was examined by quantitative real-time polymerase chain reaction or Western blot. The expression of activated microglia and astrocytes was examined by Western blot or immunofluorescence. The expression of nuclear factor-kappa B (NF-κB) was examined by Western blot. TAK-242 and anti-IL-18 antibody were used to inhibit the activation of toll-like receptor 4 (TLR4) and IL-18 pathway, respectively. Results: IS dural infusions elicited microglial activation and astrocytic activation. Meanwhile, IS dural infusions induced the upregulation of IL-18 and IL-18R in microglia and astrocytes, respectively. Blocking the IL-18 signaling pathway attenuated nociceptive behavior. Meanwhile, blocking IL-18 signaling also suppressed astrocytic activation, as well as activation of NF-κB. And IL-18 dural infusions induced nociceptive behavior and glia activation. Conclusions: IL-18, a product of microglial toll-like receptor 4 (TLR4) activation, acted on IL-18R expressed in astrocyte, and subsequently stimulated activation of NF-κB, leading to the astrocytic activation. Together, the present results suggest that IL-18-mediated microglia/astrocyte interactions in the medullary dorsal horn may participate in the development of hyperpathia or allodynia induced by migraine.

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“…The IS was formulated with histamine, serotonin, and bradykinin of 2 mM each, and prostaglandin E2 (PGE2) of 0.2 mM in 0.9% sterile saline, with a pH of 7.0 ( Figure 1). [31][32][33] A total of six researchers participated in the experiment procedure and were denoted as follows: 1) person in charge of grouping; animal feeder; animal, saline and IS transmitter; 2) electroacupuncture executor; 3) modelmaker; 4) behavioral text; 5) electrophysiological recorder and experienced histopathologist; and 6) data analyst and statistician. Researchers 3, 4, 5, and 6 were blinded to the grouping situation of the rats.…”

Section: Experimental Designmentioning

confidence: 99%

<p>Prophylactic Electroacupuncture on the Upper Cervical Segments Decreases Neuronal Discharges of the Trigeminocervical Complex in Migraine-Affected Rats: An in vivo Extracellular Electrophysiological Experiment</p>

Liu

Zhao

et al. 2020

JPR

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Purpose: This rat experiment aims to demonstrate the efficacy of electrical acupuncture in preventing migraine attacks by stimulating the acupoint GB20. Introduction: Migraine, which takes 2ed at level four causes of GBD's disease hierarchy, becomes a public health issue. It is important for physicians to supplement their knowledge of its treatment and consider alternative methods of therapy, such as acupuncture. However, the neurobiological and pathophysiological mechanisms of this prophylactic effect were unclear. The trigeminocervical complex is thought to be an important relay station in migraine pathophysiology as the key nuclei of the trigeminovascular system and the brainstem descending pain modulation system. Methods: There were six groups involved in this study: control, model, electroacupuncture, non-acupoint electroacupuncture, saline+electroacupuncture and saline+non-acupoint electroacupuncture. We injected saline or inflammatory soup into dura mater to induce control or migraine in the rats. The mechanical pain threshold and the single-cell extraneural neurophysiology of the C1 spinal dorsal horn neurons in the trigeminocervical complex were detected. Results: Pre-electroacupuncture could significantly increase the mechanical pain threshold of the periorbital region receptive field of the trigeminal nerve and decrease the discharges of neurons in the trigeminocervical complex. Acupuncture also reversed the abnormal skin pain response of the periorbital region receptive field of the trigeminal nerve caused by lowintensity stimulation. Discussion: We believe that our study makes a significant contribution to the literature because it is the first of its kind to use GB20 to provide relief from migraine attacks and mechanical cephalic cutaneous hypersensitivity by regulating the neuronal discharge from trigeminocervical complex.

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Region-specific disruption of the blood-brain barrier following repeated inflammatory dural stimulation in a rat model of chronic trigeminal allodynia

Cited by 44 publications

References 59 publications

Loss of Blood-Brain Barrier Integrity in a KCl-Induced Model of Episodic Headache Enhances CNS Drug Delivery

Loss of Blood-Brain Barrier Integrity in a KCl-Induced Model of Episodic Headache Enhances CNS Drug Delivery

Involvement of Interleukin-18-Mediated Microglia/Astrocyte Interaction in Experimental Models of Migraine

<p>Prophylactic Electroacupuncture on the Upper Cervical Segments Decreases Neuronal Discharges of the Trigeminocervical Complex in Migraine-Affected Rats: An in vivo Extracellular Electrophysiological Experiment</p>

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