scholarly journals Unravelling a novel mechanism for the up-regulation of connexin43 gap junctions between cells derived from the blood-brain barrier

2017 ◽  
Vol 595 (8) ◽  
pp. 2411-2412
Author(s):  
Juan C. Sáez
Keyword(s):  
Gap Junctions ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Blood Brain ◽  
Connexin43 Gap Junctions

scholarly journals Inhibition of Gap Junctions Sensitizes Primary Glioblastoma Cells for Temozolomide

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 858 ◽  
Author(s):  
Anna-Laura Potthoff ◽  
Dieter Henrik Heiland ◽  
Bernd O. Evert ◽  
Filipe Rodrigues Almeida ◽  
Simon P. Behringer ◽  
...  
Keyword(s):  
Gap Junctions ◽  
Gap Junction ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Glioblastoma Cells ◽  
Primary Glioblastoma ◽  
Blood Brain ◽  
Elevated Activity ◽  
Essential Contribution ◽  
Gap Junction Inhibitor

Gap junctions have recently been shown to interconnect glioblastoma cells to a multicellular syncytial network, thereby allowing intercellular communication over long distances as well as enabling glioblastoma cells to form routes for brain microinvasion. Against this backdrop gap junction-targeted therapies might provide for an essential contribution to isolate cancer cells within the brain, thus increasing the tumor cells’ vulnerability to the standard chemotherapeutic agent temozolomide. By utilizing INI-0602—a novel gap junction inhibitor optimized for crossing the blood brain barrier—in an oncological setting, the present study was aimed at evaluating the potential of gap junction-targeted therapy on primary human glioblastoma cell populations. Pharmacological inhibition of gap junctions profoundly sensitized primary glioblastoma cells to temozolomide-mediated cell death. On the molecular level, gap junction inhibition was associated with elevated activity of the JNK signaling pathway. With the use of a novel gap junction inhibitor capable of crossing the blood–brain barrier—thus constituting an auspicious drug for clinical applicability—these results may constitute a promising new therapeutic strategy in the field of current translational glioblastoma research.

scholarly journals A circadian clock in the blood-brain barrier regulates xenobiotic efflux from the brain

2017 ◽  
Author(s):  
Shirley L. Zhang ◽  
Zhifeng Yue ◽  
Denice M. Arnold ◽  
Amita Sehgal
Keyword(s):  
Gap Junctions ◽  
Blood Brain Barrier ◽  
Time Of Day ◽  
Brain Barrier ◽  
Circadian Regulation ◽  
List Type ◽  
Intracellular Magnesium ◽  
Therapeutic Implications ◽  
Blood Brain ◽  
The Central Nervous System

HighlightsThe Drosophila BBB displays a circadian rhythm of permeabilityCyclic efflux driven by a clock in the BBB underlies the permeability rhythmCircadian control is non-cell-autonomous via gap junction regulation of [Mg2+]iAn anti-seizure drug is more effective when administered at nightSummaryEndogenous circadian rhythms are thought to modulate responses to external factors, but mechanisms that confer time-of-day differences in organismal responses to environmental insults / therapeutic treatments are poorly understood. Using a xenobiotic, we find that permeability of the Drosophila “blood”-brain barrier (BBB) is higher at night. The permeability rhythm is driven by circadian regulation of efflux and depends upon a molecular clock in the perineurial glia of the BBB, although efflux transporters are restricted to subperineurial glia (SPG). We show that transmission of circadian signals across the layers requires gap junctions, which are expressed cyclically. Specifically, during nighttime gap junctions reduce intracellular magnesium ([Mg2+]i), a positive regulator of efflux, in SPG. Consistent with lower nighttime efflux, nighttime administration of the anti-epileptic phenytoin is more effective at treating a Drosophila seizure model. These findings identify a novel mechanism of circadian regulation and have therapeutic implications for drugs targeted to the central nervous system.

Intercellular junctions in the central nervous system of insects

1977 ◽  
Vol 26 (1) ◽  
pp. 175-199
Author(s):  
N.J. Lane ◽  
H.L. Skaer ◽  
L.S. Swales
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Gap Junctions ◽  
Tight Junctions ◽  
Blood Brain Barrier ◽  
Intercellular Junctions ◽  
Brain Barrier ◽  
Insect Species ◽  
Blood Brain ◽  
The Central Nervous System

The intercellular junctional complexes in the central nervous system (CNS) from a variety of insect species have been examined by thin-sectioning and freeze-fracturing techniques. Of particular concern has been the fine-structural basis of the blood-brain barrier observed to be present in the outer perineurial layer around the avascular insect CNS. The basis of this has been found in the form of tight junctions (zonulae occludentes) present both in sections and in replicas of the perineurium. In the latter, they appear as one or two simple linear ridges, lying parallel to the outer surface, which occasionally display overlapping. The complex geometry of the interdigitating perineurial cells apparently permits such a relatively simple series of ridges to function as a barrier, since tracers are found not to penetrate beyond this level into the underlying nervous tissue. Such evidence is supported by microprobe X-ray analysis of lanthanum-incubated tissues, the perineurium compared with the glia-ensheathed axons showing the presence and absence of lanthanum, respectively. Possible physiological mechanisms that could operate ‘in vitro’ to maintain the blood-brain barrier are also considered. Other intercellular junctions such as desmosomes, septate junctions and gap junctions are found in the perineurial layer too, the last exhibiting EF particle plaques and PF pits. Glia-glia junctions also occur in some insect species; they include desmosomes, inverted gap junctions and occasional tight junctions. Septate, gap and tight junctions are also found on the membranes of tracheoles penetrating the CNS. Short, ridge-like elaborations and other particle arrays are found on the PF on the axon surfaces and the significance of these structures is discussed.

scholarly journals Reorganization of Gap Junctions after Focused Ultrasound Blood–Brain Barrier Opening in the Rat Brain

2010 ◽  
Vol 30 (7) ◽  
pp. 1394-1402 ◽  
Author(s):  
Angelika Alonso ◽  
Eileen Reinz ◽  
Jürgen W Jenne ◽  
Marc Fatar ◽  
Hannah Schmidt-Glenewinkel ◽  
...  
Keyword(s):  
Gap Junctions ◽  
Blood Brain Barrier ◽  
Cellular Response ◽  
Connexin 43 ◽  
Brain Barrier ◽  
Ultrasound Exposure ◽  
Connexin 36 ◽  
Blood Brain ◽  
Gap Junctional ◽  
Bbb Opening

Ultrasound-induced opening of the blood–brain barrier (BBB) is an emerging technique for targeted drug delivery to the central nervous system. Gap junctions allow transfer of information between adjacent cells and are responsible for tissue homeostasis. We examined the effect of ultrasound-induced BBB opening on the structure of gap junctions in cortical neurons, expressing Connexin 36, and astrocytes, expressing Connexin 43, after focused 1-MHz ultrasound exposure at 1.25 MPa of one hemisphere together with intravenous microbubble (Optison, Oslo, Norway) application. Quantification of immunofluorescence signals revealed that, compared with noninsonicated hemispheres, small-sized Connexin 43 and 36 gap-junctional plaques were markedly reduced in areas with BBB breakdown after 3 to 6 hours (34.02±6.04% versus 66.49±2.16%, P=0.02 for Connexin 43; 33.80±1.24% versus 36.77±3.43%, P=0.07 for Connexin 36). Complementing this finding, we found significant increases in large-sized gap-junctional plaques (5.76±0.96% versus 1.02±0.84%, P=0.05 for Connexin 43; 5.62±0.22% versus 4.65±0.80%, P=0.02 for Connexin 36). This effect was reversible at 24 hours after ultrasound exposure. Western blot analyses did not show any change in the total connexin amount. These results indicate that ultrasound-induced BBB opening leads to a reorganization of gap-junctional plaques in both neurons and astrocytes. The plaque-size increase may be a cellular response to imbalances in extracellular homeostasis after BBB leakage.

Conformationally Constrained Peptide Drugs Targeted at the Blood-Brain Barrier

1995 ◽  
Author(s):  
Thomas P. Davis ◽  
Thomas J. Abbruscato ◽  
Elizabeth Brownson ◽  
Victor J. Hruby
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Peptide Drugs ◽  
Conformationally Constrained ◽  
Blood Brain
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