Blood—brain barrier opened by stimulation of the parasympathetic sphenopalatine ganglion: a new method for macromolecule delivery to the brain

Yarnitsky, David; Gross, Yossi; Lorian, Adi; Shalev, Alon; Lamensdorf, Itschak; Bornstein, Rinat; Shorer, Shy; Mayevsky, Avraham; Patel, Kaushik P.; Abbott, N. Joan; Mayhan, William G.

doi:10.3171/jns.2004.101.2.0303

Cited by 29 publications

(16 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, studies have shown that loss of direct noradrenergic input from the locus coeruleus results in increased BBB susceptibility to effects of acute hypertension, resulting in significantly increased permeability to 125 -I labeled albumin (57). Additionally, stimulation of the parasympathetic sphenopalatine ganglion has been found to induce BBB opening resulting in an increase in delivery of chemotherapeutic agents (i.e., anti-HER2 monoclonal antibody, etoposide) to the brain (72). In contrast, in a rodent model of traumatic brain injury (TBI), vagal stimulation following TBI resulted in a decrease in BBB permeability to FITC-dextran as compared to animals with TBI alone (73).…”

Section: Components Of the Nvumentioning

confidence: 99%

“…For example, electrical stimulation of postganglionic parasympathetic fibers of the sphenopalatine ganglion (SPG) has been shown to increase BBB permeability to FITC-dextran, implying an increase in BBB permeability (72). Delivery of etoposide and HER2 monoclonal, both chemotherapeutic agents, was also improved by the use of electrical stimulation of postganglionic parasympathetic fibers of the SPG (72). Stimulation of the SPG has also been found to induce reperfusion and BBB protection in a rodent stroke model (362).…”

Section: Blood-brain Barrier Opening Via Ultrasound and Electrical Stmentioning

confidence: 99%

See 1 more Smart Citation

Transporters at CNS Barrier Sites: Obstacles or Opportunities for Drug Delivery?

Sanchez-Covarrubias¹,

Slosky²,

Thompson³

et al. 2014

CPD

203

137

View full text Add to dashboard Cite

The blood-brain barrier (BBB) and blood-cerebrospinal fluid (BCSF) barriers are critical determinants of CNS homeostasis. Additionally, the BBB and BCSF barriers are formidable obstacles to effective CNS drug delivery. These brain barrier sites express putative influx and efflux transporters that precisely control permeation of circulating solutes including drugs. The study of transporters has enabled a shift away from “brute force” approaches to delivering drugs by physically circumventing brain barriers towards chemical approaches that can target specific compounds of the BBB and/or BCSF barrier. However, our understanding of transporters at the BBB and BCSF barriers has primarily focused on understanding efflux transporters that efficiently prevent drugs from attaining therapeutic concentrations in the CNS. Recently, through the characterization of multiple endogenously expressed uptake transporters, this paradigm has shifted to the study of brain transporter targets that can facilitate drug delivery (i.e., influx transporters). Additionally, signaling pathways and trafficking mechanisms have been identified for several endogenous BBB/BCSF transporters, thereby offering even more opportunities to understand how transporters can be exploited for optimization of CNS drug delivery. This review presents an overview of the BBB and BCSF barrier as well as the many families of transporters functionally expressed at these barrier sites. Furthermore, we present an overview of various strategies that have been designed and utilized to deliver therapeutic agents to the brain with a particular emphasis on those approaches that directly target endogenous BBB/BCSF barrier transporters.

show abstract

Section: Components Of the Nvumentioning

confidence: 99%

Section: Blood-brain Barrier Opening Via Ultrasound and Electrical Stmentioning

confidence: 99%

Transporters at CNS Barrier Sites: Obstacles or Opportunities for Drug Delivery?

Sanchez-Covarrubias¹,

Slosky²,

Thompson³

et al. 2014

CPD

203

137

View full text Add to dashboard Cite

show abstract

“…The authors attributed this to a compensatory mechanism in order to maintain a constant supply of nutrients to the brain during variations in cerebral blood flow. Yarnitsky et al, 2004 showed that stimulation of parasympathetic nerve fibers arising from the sphenopalatine ganglion, resulted in a reversible increase in BBB permeability, with enhanced entry of macromolecules such as FITC-dextran, Evans blue dye-albumin and the chemotherapeutic agents anti-HER2 mAb and etoposide into the brain. Using a neuropathic pain model of peripheral chronic nerve lesion, Gordh and Sharma, 2006, demonstrated a loss of blood-spinal cord barrier integrity, with increased permeability and activation of astrocytes in the spinal cord.…”

Section: Introductionmentioning

confidence: 99%

Nociceptive inhibition prevents inflammatory pain induced changes in the blood–brain barrier

et al. 2008

View full text Add to dashboard Cite

Previous studies by our group have shown that peripheral inflammatory insult, using the λ-carrageenan inflammatory pain (CIP) model, induced alterations in the molecular and functional properties of the blood-brain barrier (BBB). The question remained whether these changes were mediated via an inflammatory and/or neuronal mechanism. In this study, we investigated the involvement of neuronal input from pain activity on alterations in BBB integrity by peripheral inhibition of nociceptive input. A perineural injection of 0.75% bupivacaine into the right hind leg prior to CIP was used for peripheral nerve block. Upon nerve block, there was a significant decrease in thermal allodynia induced by CIP, but no effect on edema formation 1 h post CIP. BBB permeability was increased 1 h post CIP treatment as determined by in situ brain perfusion of [ 14 C] sucrose; bupivacaine nerve block of CIP caused an attenuation of [ 14 C] sucrose permeability, back to saline control levels. Paralleling the changes in [ 14 C] sucrose permeability, we also report increased expression of three tight junction (TJ) proteins, zonula occluden-1 (ZO-1), occludin and claudin-5 with CIP. Upon bupivacaine nerve block, changes in expression were prevented. These data show that the λ-carrageenan induced changes in [ 14 C] sucrose permeability and protein expression of ZO-1, occludin and claudin-5 are prevented with inhibition of nociceptive input. Therefore, we suggest that nociceptive signaling is in part responsible for the alteration in BBB integrity under CIP.

show abstract

“…Parasympathetic innervation from the PPG acting directly or indirectly on nociceptive sensory fibres has also been suggested to participate in regulation of blood–brain barrier (BBB) permeability (Delépine & Aubineau, ; Yarnitsky et al . a , b ) and development of cluster headaches/migraine (Yarnitsky et al . ).…”

Section: Other Proposed Functions Of Parasympathetic Innervation To Cmentioning

confidence: 99%

“…This effect of PPG stimulation has been used clinically to deliver macromolecules through the BBB (Yarnitsky et al . a ). Hence the (over‐) stimulation of the parasympathetic innervation to the cerebral arteries may not only yield positive effects.…”

Section: Parasympathetic Targets With Clinical Relevance For the Cerementioning

confidence: 99%

Parasympathetic innervation of vertebrobasilar arteries: is this a potential clinical target?

Roloff

Tomiak-Baquero

Kasparov

et al. 2016

The Journal of Physiology

View full text Add to dashboard Cite

This review aims to summarise the contemporary evidence for the presence and function of the parasympathetic innervation of the cerebral circulation with emphasis on the vertebral and basilar arteries (the posterior cerebral circulation). We consider whether the parasympathetic innervation of blood vessels could be used as a means to increase cerebral blood flow. This may have clinical implications for pathologies associated with cerebral hypoperfusion such as stroke, dementia and hypertension. Relative to the anterior cerebral circulation little is known of the origins and neurochemical phenotypes of the parasympathetic innervation of the vertebrobasilar arteries. These vessels normally provide blood flow to the brainstem and cerebellum but can, via the Circle of Willis upon stenosis of the internal carotid arteries, supply blood to the anterior cerebral circulation too. We review the multiple types of parasympathetic fibres and their distinct transmitter mechanisms and how these vary with age, disease and species. We highlight the importance of parasympathetic fibres for mediating the vasodilatory response to sympathetic activation. Current trials are investigating the possibility of electrically stimulating the postganglionic parasympathetic ganglia to improve cerebal blood flow to reduce the penumbra following stroke. We conclude that although there are substantial gaps in our understanding of the origins of parasympathetic innervation of the vertebrobasilar arteries, activation of this system under some conditions might bring therapeutic benefits.

show abstract

Blood—brain barrier opened by stimulation of the parasympathetic sphenopalatine ganglion: a new method for macromolecule delivery to the brain

Abstract: Sphenopalatine ganglion activation demonstrates a promising potential for clinical use in the delivery of small and large molecules to the brain.

Cited by 29 publications

References 18 publications

Transporters at CNS Barrier Sites: Obstacles or Opportunities for Drug Delivery?

Transporters at CNS Barrier Sites: Obstacles or Opportunities for Drug Delivery?

Nociceptive inhibition prevents inflammatory pain induced changes in the blood–brain barrier

Parasympathetic innervation of vertebrobasilar arteries: is this a potential clinical target?

Contact Info

Product

Resources

About