Expression of junctional proteins in choroid plexus epithelial cell lines: a comparative study

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TrkB-enhancer Facilitates Functional Recovery After Traumatic Brain Injury

Brain-derived neurotrophic factor (BDNF), a key player in regulating synaptic strength and learning, is dysregulated following traumatic brain injury (TBI), suggesting that stimulation of BDNF signaling pathways may facilitate functional recovery. This study investigates whether CN2097, a peptidomimetic ligand which targets the synaptic scaffold protein, postsynaptic density protein 95, to enhance downstream signaling of tropomyosin-related kinase B, a receptor for BDNF, can improve neurological function after TBI. Moderate to severe TBI elicits neuroinflammation and c-Jun-N-terminal kinase (JNK) activation, which is associated with memory deficits. Here we demonstrate that CN2097 significantly reduces the post-traumatic synthesis of proinflammatory mediators and inhibits the posttraumatic activation of JNK in a rodent model of TBI. The recordings of field excitatory post-synaptic potentials in the hippocampal CA1 subfield demonstrate that TBI inhibits the expression of long-term potentiation (LTP) evoked by high-frequency stimulation of Schaffer collaterals, and that CN2097 attenuates this LTP impairment. Lastly, we demonstrate that CN2097 significantly improves the complex auditory processing deficits, which are impaired after injury. The multifunctionality of CN2097 strongly suggests that CN2097 could be highly efficacious in targeting complex secondary injury processes resulting from neurotrauma

The Adhesion GPCR GPR125 is specifically expressed in the choroid plexus and is upregulated following brain injury

<p>Abstract</p> <p>Background</p> <p>GPR125 belongs to the family of <it>Adhesion </it>G protein-coupled receptors (GPCRs). A single copy of GPR125 was found in many vertebrate genomes. We also identified a <it>Drosophila </it>sequence, DmCG15744, which shares a common ancestor with the entire Group III of <it>Adhesio</it>n GPCRs, and also contains Ig, LRR and HBD domains which were observed in mammalian GPR125.</p> <p>Results</p> <p>We found specific expression of GPR125 in cells of the choroid plexus using <it>in situ </it>hybridization and protein-specific antibodies and combined <it>in situ</it>/immunohistochemistry co-localization using cytokeratin, a marker specific for epithelial cells. Induction of inflammation by LPS did not change GPR125 expression. However, GPR125 expression was transiently increased (almost 2-fold) at 4 h after traumatic brain injury (TBI) followed by a decrease (approximately 4-fold) from 2 days onwards in the choroid plexus as well as increased expression (2-fold) in the hippocampus that was delayed until 1 day after injury.</p> <p>Conclusion</p> <p>These findings suggest that GPR125 plays a functional role in choroidal and hippocampal response to injury.</p

The Involvement of Pial Microvessels in Leukocyte Invasion after Mild Traumatic Brain Injury.

The pathophysiological mechanisms underlying mild traumatic brain injury (mTBI) are not well understood, but likely involve neuroinflammation. Here the controlled cortical impact model of mTBI in rats was used to test this hypothesis. Mild TBI caused a rapid (within 6 h post-mTBI) upregulation of synthesis of TNF-α and IL-1β in the cerebral cortex and hippocampus, followed by an increase in production of neutrophil (CXCL1-3) and monocyte (CCL2) chemoattractants. While astrocytes were not a significant source of CXC chemokines, they highly expressed CCL2. An increase in production of CXC chemokines coincided with the influx of neutrophils into the injured brain. At 6 h post-mTBI, we observed a robust influx of CCL2-expressing neutrophils across pial microvessels into the subarachnoid space (SAS) near the injury site. Mild TBI was not accompanied by any significant influx of neutrophils into the brain parenchyma until 24 h after injury. This was associated with an early induction of expression of intercellular adhesion molecule 1 on the endothelium of the ipsilateral pial, but not intraparenchymal, microvessels. At 6 h post-mTBI, we also observed a robust influx of neutrophils into the ipsilateral cistern of velum interpositum (CVI), a slit-shaped cerebrospinal fluid space located above the 3rd ventricle with highly vascularized pia mater. From SAS and CVI, neutrophils appeared to move along the perivascular spaces to enter the brain parenchyma. The monocyte influx was not observed until 24 h post-mTBI, and these inflammatory cells predominantly entered the ipsilateral SAS and CVI, with a limited invasion of brain parenchyma. These observations indicate that the endothelium of pial microvessels responds to injury differently than that of intraparenchymal microvessels, which may be associated with the lack of astrocytic ensheathment of cerebrovascular endothelium in pial microvessels. These findings also suggest that neuroinflammation represents the potential therapeutic target in mTBI

Synergistic interactions between cytokines and AVP at the blood-CSF barrier result in increased chemokine production and augmented influx of leukocytes after brain injury.

Several lines of evidence indicate that the blood-cerebrospinal fluid barrier (BCSFB), which primarily resides in the choroid plexus (CP), plays a significant pathophysiological role not only in neuroinflammatory diseases, such as multiple sclerosis, but also in traumatic brain injury (TBI). Here we investigated how arginine vasopressin (AVP) regulates function of the BCSFB in the context of post-traumatic neuroinflammation. It has previously been shown that AVP exacerbates various forms of brain injury, but the mechanisms underlying this AVP action are poorly understood. Type 1A AVP receptor is highly expressed on the CP epithelium and the CP synthesizes AVP. Using the controlled cortical impact model of TBI, we demonstrated decreased post-traumatic production of proinflammatory mediators by the CP and reduced influx of inflammatory cells across the BCSFB in AVP-deficient Brattleboro rats when compared with Long-Evans rats, a parental strain for Brattleboro rats. Arginine vasopressin was also found to play an important role in post-traumatic activation of c-Jun N-terminal kinase (JNK) in the CP. In the CP epithelial cell cultures, AVP augmented the tumor necrosis factor-α- and interleukin-1β-dependent increase in synthesis of proinflammatory mediators, including neutrophil chemoattractants, an action largely dependent on the JNK signaling pathway. Under in vivo conditions, a selective JNK inhibitor decreased the post-traumatic production of neutrophil chemoattractants by the CP and reduced the influx of neutrophils across the BCSFB. These results provide evidence for the synergistic interactions between proinflammatory cytokines and AVP, a ligand for G protein-coupled receptors, and support a pathophysiological role of AVP in post-traumatic neuroinflammation

Expression of cell adhesion molecules in the injured brain after mTBI.

<p>In these experiments, the depth of brain deformation was set at 1 mm, and the images shown were acquired at 6 h post-mTBI. (A, B) Double immunostaining of injured brains with anti-P-selectin (SELP) antibody and an antibody to von Willebrand factor (vWF), a marker for endothelial cells. Note that SELP is expressed both ipsilaterally and contralaterally (Ipsi/Contra) on the endothelium of pial (arrows) and intraparenchymal microvessels. SELP was not expressed in the intact rat brain (data not shown). SAS and CVI are the subarachnoid space and the cistern of velum interpositum, respectively. (C, D) Double immunostaining of injured brains with anti-intercellular adhesion molecule 1 (ICAM1) antibody and an antibody to vWF. Note that ICAM1 is expressed on the endothelium of the ipsilateral pial (arrows), but not intraparenchymal, microvessels. ICAM1 is also not expressed on the endothelium of the contralateral pial microvessels. Bars: panels A–D, 50 μm.</p

Changes in mRNA levels of proinflammatory mediators in the cerebral cortex and hippocampus at 6 and 24 h after mTBI as assessed by real-time RT-PCR.

<p>In these experiments, the depth of brain deformation was set at 1.5 mm. The production of proinflammatory mediators in the ipsilateral (I-Cx) versus contralateral (C-Cx) cortex, and the ipsilateral (I-Hip) versus contralateral (C-Hip) hippocampus is shown. Peptidylprolyl isomerase A (PPIA)/cyclophilin A was used for the normalization of the data. The F and the corresponding <i>p</i> values for each proinflammatory mediator are indicated. *<i>p</i><0.05, **<i>p</i><0.01 for the ipsilateral versus contralateral Cx or Hip. ^†<i>p</i><0.05, ^††<i>p</i><0.01 for the difference in expression of proinflammatory mediators at 6 versus 24 h post-mTBI. (<i>n</i> = 4–6 rats per group)</p

The influx of monocytes into the injured brain after mTBI.

<p>In these experiments, the depth of brain deformation was set at 1 mm, and the images shown were acquired at 24 h post-mTBI. Double immunostaining of injured brains was performed with anti-CD68 antibody, a monocyte marker, and an antibody to von Willebrand factor (vWF), a marker for endothelial cells. (A, B) Similar to severe TBI, in mTBI, monocytes did not appear in the injured brain until 24 h after the impact. However, only a small number of monocytes invaded the injured brain parenchyma at 24 h post-mTBI. Note that at this time point after injury, these inflammatory cells were predominantly located close to intraparenchymal blood microvessels. (C, D) In contrast to brain parenchyma, a large number of monocytes crossed the pial microvessels and invaded the subarachnoid space (SAS) near the injury site. Note that some of these monocytes appeared to subsequently move along the perivascular space to enter the brain parenchyma (arrows). (E–G) An influx of monocytes into the ipsilateral cistern of velum interpositum (CVI) also occurred at 24 h post-mTBI. Bars: panels A, B, E, 100 μm; panels C, D, F, G, 50 μm.</p

The quest for a better insight into physiology of fluids and barriers of the brain: the exemplary career of Joseph D. Fenstermacher.

International audienceIn June 2014 Dr. Joseph D. Fenstermacher celebrated his 80th birthday, which was honored by the symposium held in New London, NH, USA. This review discusses Fenstermacher's contribution to the field of fluids and barriers of the CNS. Specifically, his fundamental work on diffusion of molecules within the brain extracellular space and the research on properties of the blood-brain barrier in health and disease are described. Fenstermacher's early research on cerebrospinal fluid dynamics and the regulation of cerebral blood flow is also reviewed, followed by the discussion of his more recent work involving the use of magnetic resonance imaging