Choroid plexus (ChP), the brain structure primarily responsible for cerebrospinal fluid production, contains a robust circadian clock, whose role remains to be elucidated. The aim of our study was to [1] identify rhythmically controlled cellular processes in the mouse ChP and [2] assess the role and nature of signals derived from the master clock in the suprachiasmatic nuclei (SCN) that control ChP rhythms. To accomplish this goal, we used various mouse models (WT, mPer2Luc, ChP-specific Bmal1 knockout) and combined multiple experimental approaches, including surgical lesion of the SCN (SCNx), time-resolved transcriptomics, and single cell luminescence microscopy. In ChP of control (Ctrl) mice collected every 4 h over 2 circadian cycles in darkness, we found that the ChP clock regulates many processes, including the cerebrospinal fluid circadian secretome, precisely times endoplasmic reticulum stress response, and controls genes involved in neurodegenerative diseases (Alzheimer's disease, Huntington's disease, and frontotemporal dementia). In ChP of SCNx mice, the rhythmicity detected in vivo and ex vivo was severely dampened to a comparable extent as in mice with ChP-specific Bmal1 knockout, and the dampened cellular rhythms were restored by daily injections of dexamethasone in mice. Our data demonstrate that the ChP clock controls tissue-specific gene expression and is strongly dependent on the presence of a functional connection with the SCN. The results may contribute to the search for a novel link between ChP clock disruption and impaired brain health.
- MeSH
- cirkadiánní hodiny * fyziologie MeSH
- cirkadiánní rytmus fyziologie MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši MeSH
- nucleus suprachiasmaticus * metabolismus fyziologie MeSH
- plexus chorioideus * metabolismus fyziologie MeSH
- transkripční faktory ARNTL metabolismus genetika MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The response of the blood-brain barrier (BBB) following a stroke, including subarachnoid hemorrhage (SAH), has been studied extensively. The main components of this reaction are endothelial cells, pericytes, and astrocytes that affect microglia, neurons, and vascular smooth muscle cells. SAH induces alterations in individual BBB cells, leading to brain homeostasis disruption. Recent experiments have uncovered many pathophysiological cascades affecting the BBB following SAH. Targeting some of these pathways is important for restoring brain function following SAH. BBB injury occurs immediately after SAH and has long-lasting consequences, but most changes in the pathophysiological cascades occur in the first few days following SAH. These changes determine the development of early brain injury as well as delayed cerebral ischemia. SAH-induced neuroprotection also plays an important role and weakens the negative impact of SAH. Supporting some of these beneficial cascades while attenuating the major pathophysiological pathways might be decisive in inhibiting the negative impact of bleeding in the subarachnoid space. In this review, we attempt a comprehensive overview of the current knowledge on the molecular and cellular changes in the BBB following SAH and their possible modulation by various drugs and substances.
The choroid plexus (CP) forming the blood-cerebrospinal fluid (B-CSF) barrier is among the least studied structures of the central nervous system (CNS) despite its clinical importance. The CP is an epithelio-endothelial convolute comprising a highly vascularized stroma with fenestrated capillaries and a continuous lining of epithelial cells joined by apical tight junctions (TJs) that are crucial in forming the B-CSF barrier. Integrity of the CP is critical for maintaining brain homeostasis and B-CSF barrier permeability. Recent experimental and clinical research has uncovered the significance of the CP in the pathophysiology of various diseases affecting the CNS. The CP is involved in penetration of various pathogens into the CNS, as well as the development of neurodegenerative (e.g., Alzheimer´s disease) and autoimmune diseases (e.g., multiple sclerosis). Moreover, the CP was shown to be important for restoring brain homeostasis following stroke and trauma. In addition, new diagnostic methods and treatment of CP papilloma and carcinoma have recently been developed. This review describes and summarizes the current state of knowledge with regard to the roles of the CP and B-CSF barrier in the pathophysiology of various types of CNS diseases and sets up the foundation for further avenues of research.
- MeSH
- homeostáza fyziologie MeSH
- lidé MeSH
- mozkomíšní mok metabolismus MeSH
- nemoci centrálního nervového systému * imunologie metabolismus patofyziologie MeSH
- plexus chorioideus anatomie a histologie fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
BACKGROUND: Chemokines and cytokines in cerebrospinal fluid (CSF) and serum have been extensively studied in adults with neuroborreliosis (NB), whereas there are limited data about the pediatric population. In adults, T helper type 1 (Th1) and Th17-related cytokines were observed during acute NB. In children, the Th2 response is thought to moderate the disease course. The aim of this study was to determine the chemokine-cytokine profile in children with acute NB displaying Borrelia-related peripheral facial nerve palsy (PFNP). METHODS: Luminex multiple bead technology was used for the detection of twelve cytokines and chemokines in the CSF and serum of three groups: 1) children with Borrelia-related PFNP (BPFNP); 2) children with non-borrelial "idiopathic" PFNP (NIPFNP); and 3) age-related controls. RESULTS: In BPFNP, cytokines-chemokines related to a non-specific pro-inflammatory activity and specific Th1/Th17 responses were detected in CSF, and elevated IL-7 and IL-10 levels were observed in serum and CSF compared to NIPFNP and to controls. In NIPFNP, CSF findings were similar to controls; however, higher levels of IL-7 and MCP-1 were observed in serum. Higher IL-8, IL-15 and MCP-1 levels were detected in CSF compared to serum in all groups. MCP-1 and IL-8 levels in CSF were strikingly higher in BPFNP compared to the other two groups, while IL-15 levels in CSF showed no difference. In addition, in controls, increased IL-4 level was found in CSF compared to serum. CONCLUSION: The chemokine-cytokine profile in the CSF of children with acute NB was similar to previous studies in adults. Our data suggests that higher levels of IL-4, IL-15 and MCP-1 levels in CSF compared to serum in controls might represent a potentially protective cytokine milieu in the CNS compartment.
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Oligoclonal IgG bands in cerebrospinal fluid that are absent in serum indicate intrathecal IgG synthesis and are a sensitive marker of CNS inflammatory diseases, in particular multiple sclerosis. It may be of interest to determine whether these bands are predominantly IgGκ or IgGλ. METHODS: We have used Hevylite™ antibodies and developed a technique for detection of oligoclonal IgGκ and IgGλ bands by means of isoelectric focusing followed by immunoblotting. The same technique was used for oligoclonal free κ and free λ detection. Among several techniques tested, affinity immunoblotting appears to be the most sensitive; it can detect less than 1 ng of IgGκ or IgGλ paraprotein. We compared oligoclonal IgG profiles with those of oligoclonal IgGκ and IgGλ. There was good agreement concerning the presence or absence of intrathecal synthesis. We observed the ratios between oligoclonal IgGκ and IgGλ bands, and they did not always match the ratios between free κ and free λ bands. We were also able to detect antigen-specific CSF-restricted oligoclonal IgGκ and IgGλ bands in neuroborreliosis. It remains to be determined subsequently by a clinically-oriented prospective study, whether predominant IgGκ/IgGλ or free κ/free λ can be observed more frequently in particular diseases with oligoclonal IgG synthesis. DISCUSSION: Very sensitive detection of oligoclonal IgGκ and IgGλ bands in cerebrospinal fluid with Hevylite antibodies is feasible; detection of antigen-specific IgGκ or IgGλ is possible as well. In particular situations, e.g. when difficulties arise in distinguishing between oligoclonal and monoclonal pattern, the test may be of considerable clinical value.
- Publikační typ
- časopisecké články MeSH
