Bolus injection of hypertonic solutions for cerebral edema in rats: Challenge of homeostasis of healthy brain

Jiang, Wei; Cao, Wanjun; Zhang, Yu-Kai; Wei, Xiao-Yan; Kuang, Fang

doi:10.1016/j.neulet.2011.12.045

Cited by 7 publications

(6 citation statements)

References 25 publications

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“…No signs of neurodegeneration were observed in rat brains harvested on the third day after a single NG291 dose or 1 h after the third dose of NG291 administered once per day for 3 days. NG291 did not elicit the common inflammation associated with BBB disruption, as observed in various studies (Sandoval and Witt, 2008;Jiang et al, 2012;Chen et al, 2016). Taking these results together, NG291 is capable of increasing BBB permeability without contributing to the risks associated with BBB disruption.…”

Section: Discussionsupporting

confidence: 72%

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The Bradykinin B2 Receptor Agonist (NG291) Causes Rapid Onset of Transient Blood–Brain Barrier Disruption Without Evidence of Early Brain Injury

et al. 2021

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Background: The blood–brain barrier (BBB) describes the brain’s highly specialized capillaries, which form a dynamic interface that maintains central nervous system (CNS) homeostasis. The BBB supports the CNS, in part, by preventing the entry of potentially harmful circulating molecules into the brain. However, this specialized function is challenging for the development of CNS therapeutics. Several strategies to facilitate drug delivery into the brain parenchyma via disruption of the BBB have been proposed. Bradykinin has proven effective in disrupting mechanisms across the blood–tumor barrier. Unfortunately, bradykinin has limited therapeutic value because of its short half-life and the undesirable biological activity elicited by its active metabolites.Objective: To evaluate NG291, a stable bradykinin analog, with selective agonist activity on the bradykinin-B2 receptor and its ability to disrupt the BBB transiently.Methods: Sprague Dawley rats and CD-1 mice were subjected to NG291 treatment (either 50 or 100 μg/kg, intravenously). Time and dose-dependent BBB disruption were evaluated by histological analysis of Evans blue (EB) extravasation. Transcellular and paracellular BBB leakage were assessed by infiltration of 99mTc-albumin (66.5 KDa) and 14C-sucrose (340 Da) radiolabeled probes into the brains of CD-1 mice treated with NG291. NG291 influence on P-glycoprotein (P-gp) efflux pump activity was evaluated by quantifying the brain accumulation of 3H-verapamil, a known P-gp substrate, in CD-1 mice.Results: NG291-mediated BBB disruption was localized, dose-dependent, and reversible as measured by EB extravasation. 99mTc-albumin leakage was significantly increased by 50 μg/kg of NG291, whereas 100 μg/kg of NG291 significantly augmented both 14C-sucrose and 99mTc-albumin leakage. NG291 enhanced P-gp efflux transporter activity and was unable to increase brain uptake of the P-gp substrate pralidoxime. NG291 did not evoke significant short-term neurotoxicity, as it did not increase brain water content, the number of Fluoro-Jade C positive cells, or astrocyte activation.Conclusion: Our findings strongly suggest that NG291 increases BBB permeability by two different mechanisms in a dose-dependent manner and increases P-gp efflux transport. This increased permeability may facilitate the penetration into the brain of therapeutic candidates that are not P-gp substrates.

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Section: Discussionsupporting

confidence: 72%

“…We showed that NG291 does not increase the brain water content in male or female rats. This result suggests that NG291-mediated BBB disruption is subtle compared to the results obtained with hyperosmotic mannitol injections ( Jiang et al, 2012 ; Weidman et al, 2016 ). Vasogenic edema is not achieved by NG291-mediated BBB disruption.…”

Section: Discussionmentioning

confidence: 82%

The Bradykinin B2 Receptor Agonist (NG291) Causes Rapid Onset of Transient Blood–Brain Barrier Disruption Without Evidence of Early Brain Injury

et al. 2021

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“…Some considerable defects limit the application of classic methods to regulate BBB permeability in the clinic. For example, the specific injection location (via internal carotid) of the hypertonic solutions has a high risk of breaking healthy brain homeostasis . The mechanism of BBB regulation relying on the osmotic pressure is of poor specificity.…”

Section: Discussionmentioning

confidence: 99%

Targeted Regulation of Blood–Brain Barrier for Enhanced Therapeutic Efficiency of Hypoxia-Modifier Nanoparticles and Immune Checkpoint Blockade Antibodies for Glioblastoma

Meng

Wang

Ya-ping

et al. 2021

ACS Appl. Mater. Interfaces

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Glioblastoma is the most destructive type of brain cancer. The blood−brain barrier (BBB) is a tremendous obstacle that hinders therapeutic agents, such as chemical drugs and antibodies, from reaching glioblastoma tissues. Meanwhile, the abnormal microenvironment of glioblastoma extremely restricts the expected therapeutic effects of accumulated drugs. Therefore, in the present study, BBB-regulating nanovesicles (BRN) are developed to achieve targeted and controlled BBB regulation, carrying adenosine 2A receptor (A 2A R) agonists and perfluorocarbon (PF). The red-blood-cell membrane (RBCM) is included on the outside to avoid the premature release of therapeutic agents. In the presence of ultrasonication (US), A 2A R agonists are released and induce effects on both F-actin and tight junctions of endothelial cells. Subsequently, BBB permeability is temporarily increased and enables small molecules and nanoparticles to enter brain parenchymal tissues. The high affinity between manganese dioxide and temozolomide (TMZ) is utilized to form multifunctional nanoparticles to ameliorate the hypoxic microenvironment, which yields improved glioblastoma inhibition combined with radiotherapy. Moreover, with the aid of targeted BBB regulation, programmed death ligand-1 (PD-L1) antibody induces a tumor-specific immune response. Taken together, the findings suggest that synergistic combination may have the potential in amplifying the therapeutic efficacies of clinical drugs and immune checkpoint blockade antibodies to overcome the therapeutic resistance of glioblastoma.

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“…Further, the neuroprotective action of several (food) antioxidants has been explained by the adjustment of AQP4 channel functions (260)(261)(262)(263)(264). Notably, the antiedematous effect of well-known osmolar drugs such as hypertonic saline and mannitol has been recently linked to modulation of AQP4-water channel permeability (265,266). Finally, the idea of repurposing some of these wellknown drugs like acetazolamide (267)(268)(269) or levetiracetam (270) was based on their presumed or proven effect on AQP4 channels.…”

Section: Discussion: Aqp4 As a Target For Therapeutical Approachesmentioning

confidence: 99%

Cerebral Microcirculation, Perivascular Unit, and Glymphatic System: Role of Aquaporin-4 as the Gatekeeper for Water Homeostasis

et al. 2021

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In the past, water homeostasis of the brain was understood as a certain quantitative equilibrium of water content between intravascular, interstitial, and intracellular spaces governed mostly by hydrostatic effects i.e., strictly by physical laws. The recent achievements in molecular bioscience have led to substantial changes in this regard. Some new concepts elaborate the idea that all compartments involved in cerebral fluid homeostasis create a functional continuum with an active and precise regulation of fluid exchange between them rather than only serving as separate fluid receptacles with mere passive diffusion mechanisms, based on hydrostatic pressure. According to these concepts, aquaporin-4 (AQP4) plays the central role in cerebral fluid homeostasis, acting as a water channel protein. The AQP4 not only enables water permeability through the blood-brain barrier but also regulates water exchange between perivascular spaces and the rest of the glymphatic system, described as pan-cerebral fluid pathway interlacing macroscopic cerebrospinal fluid (CSF) spaces with the interstitial fluid of brain tissue. With regards to this, AQP4 makes water shift strongly dependent on active processes including changes in cerebral microcirculation and autoregulation of brain vessels capacity. In this paper, the role of the AQP4 as the gatekeeper, regulating the water exchange between intracellular space, glymphatic system (including the so-called neurovascular units), and intravascular compartment is reviewed. In addition, the new concepts of brain edema as a misbalance in water homeostasis are critically appraised based on the newly described role of AQP4 for fluid permeation. Finally, the relevance of these hypotheses for clinical conditions (including brain trauma and stroke) and for both new and old therapy concepts are analyzed.

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Bolus injection of hypertonic solutions for cerebral edema in rats: Challenge of homeostasis of healthy brain

Cited by 7 publications

References 25 publications

The Bradykinin B2 Receptor Agonist (NG291) Causes Rapid Onset of Transient Blood–Brain Barrier Disruption Without Evidence of Early Brain Injury

The Bradykinin B2 Receptor Agonist (NG291) Causes Rapid Onset of Transient Blood–Brain Barrier Disruption Without Evidence of Early Brain Injury

Targeted Regulation of Blood–Brain Barrier for Enhanced Therapeutic Efficiency of Hypoxia-Modifier Nanoparticles and Immune Checkpoint Blockade Antibodies for Glioblastoma

Cerebral Microcirculation, Perivascular Unit, and Glymphatic System: Role of Aquaporin-4 as the Gatekeeper for Water Homeostasis

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