Recent Developments in Understanding Barrier Mechanisms in the Developing Brain: Drugs and Drug Transporters in Pregnancy, Susceptibility or Protection in the Fetal Brain?

2019 ◽  
Vol 59 (1) ◽  
pp. 487-505 ◽  
Author(s):  
Norman R. Saunders ◽  
Katarzyna M. Dziegielewska ◽  
Kjeld Møllgård ◽  
Mark D. Habgood
Keyword(s):  
Fetal Brain ◽  
Adult Brain ◽  
Brain Barrier ◽  
Normal Brain ◽  
Developmentally Regulated ◽  
Protective Mechanisms ◽  
Control Drug ◽  
Newborn Brain ◽  
Recent Developments ◽  
In Pregnancy

Efflux mechanisms situated in various brain barrier interfaces control drug entry into the adult brain; this review considers the effectiveness of these protective mechanisms in the embryo, fetus, and newborn brain. The longstanding belief that the blood-brain barrier is absent or immature in the fetus and newborn has led to many misleading statements with potential clinical implications. The immature brain is undoubtedly more vulnerable to damage by drugs and toxins; as is reviewed here, some developmentally regulated normal brain barrier mechanisms probably contribute to this vulnerability. We propose that the functional status of brain barrier efflux mechanisms should be investigated at different stages of brain development to provide a rational basis for the use of drugs in pregnancy and in newborns, especially in those prematurely born, where protection usually provided by the placenta is no longer present.

scholarly journals Gestational Hypoxia and Blood-Brain Barrier Permeability: Early Origins of Cerebrovascular Dysfunction Induced by Epigenetic Mechanisms

2021 ◽  
Vol 12 ◽  
Author(s):  
Emilio A. Herrera ◽  
Alejandro González-Candia
Keyword(s):  
Blood Brain Barrier ◽  
Neurovascular Unit ◽  
Fetal Brain ◽  
Brain Barrier ◽  
Normal Brain ◽  
Epigenetic Mechanisms ◽  
Blood Brain ◽  
Intrauterine Hypoxia ◽  
Bbb Permeability ◽  
The Brain

Fetal chronic hypoxia leads to intrauterine growth restriction (IUGR), which is likely to reduce oxygen delivery to the brain and induce long-term neurological impairments. These indicate a modulatory role for oxygen in cerebrovascular development. During intrauterine hypoxia, the fetal circulation suffers marked adaptations in the fetal cardiac output to maintain oxygen and nutrient delivery to vital organs, known as the “brain-sparing phenotype.” This is a well-characterized response; however, little is known about the postnatal course and outcomes of this fetal cerebrovascular adaptation. In addition, several neurodevelopmental disorders have their origins during gestation. Still, few studies have focused on how intrauterine fetal hypoxia modulates the normal brain development of the blood-brain barrier (BBB) in the IUGR neonate. The BBB is a cellular structure formed by the neurovascular unit (NVU) and is organized by a monolayer of endothelial and mural cells. The BBB regulates the entry of plasma cells and molecules from the systemic circulation to the brain. A highly selective permeability system achieves this through integral membrane proteins in brain endothelial cells. BBB breakdown and dysfunction in cerebrovascular diseases lead to leakage of blood components into the brain parenchyma, contributing to neurological deficits. The fetal brain circulation is particularly susceptible in IUGR and is proposed to be one of the main pathological processes deriving BBB disruption. In the last decade, several epigenetic mechanisms activated by IU hypoxia have been proposed to regulate the postnatal BBB permeability. However, few mechanistic studies about this topic are available, and little evidence shows controversy. Therefore, in this mini-review, we analyze the BBB permeability-associated epigenetic mechanisms in the brain exposed to chronic intrauterine hypoxia.

scholarly journals Increased Blood—Brain Barrier Transport of Protein-Bound Anticonvulsant Drugs in the Newborn

1983 ◽  
Vol 3 (3) ◽  
pp. 280-286 ◽  
Author(s):  
Eain M. Cornford ◽  
William M. Pardridge ◽  
Leon D. Braun ◽  
William H. Oldendorf
Keyword(s):  
Blood Brain Barrier ◽  
Transit Time ◽  
Plasma Protein ◽  
Adult Brain ◽  
Anticonvulsant Drugs ◽  
Neonatal Rat ◽  
Brain Barrier ◽  
Newborn Brain ◽  
Blood Brain ◽  
The Brain

The extraction of heroin, caffeine, diphenylhydantoin, and phenobarbital has been measured in the newborn, suckling, and adult brain. Anticonvulsant drugs such as diphenylhydantoin and phenobarbital are bound by plasma protein, and it is generally believed that only the fraction of drug that is free (dialyzable) in vitro is available for transport through the blood-brain barrier in vivo. In both the adult and neonatal rat or rabbit, lipid-mediated transport of free phenytoin occurs. In addition, a fraction of the drug that enters the capillary bound to plasma protein also gains access to the brain. A greater amount of protein-bound drug permeates the newborn brain, and this is ascribed to a longer capillary transit time in the neonate. With regard to phenobarbital, the total (i.e., both free and protein-bound) plasma drug enters the newborn brain. In contrast, no protein-bound phenobarbital permeates the adult brain, and it is only the free drug fraction that gains access to the brain. Since the blood—brain barrier permeability—surface area product for the two anticonvulsants is unchanged in newborn and older animals, the age-related differences in brain uptake of protein-bound drugs can be attributed to developmental changes in cerebral blood flow and capillary transit time. The increased transport of protein-bound drugs in the newborn may cause increased concentrations (i.e., brain:plasma ratios) of these anticonvulsants in the neonatal brain.

Fetal Brain Activity in Pregnancy of Women with Type 1 Diabetes Mellitus

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 1402-P
Author(s):  
ELLEN FEHLERT ◽  
FRANZISKA SCHLEGER ◽  
KATARZYNA LINDER ◽  
MARTIN HENI ◽  
HANS-ULRICH HAERING ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Type 1 Diabetes Mellitus ◽  
Brain Activity ◽  
Fetal Brain ◽  
In Pregnancy

Radiotherapy for Brain Tumors: Current Practice and Future Directions

2020 ◽  
Vol 16 (3) ◽  
pp. 182-195
Author(s):  
Sarah Baker ◽  
Natalie Logie ◽  
Kim Paulson ◽  
Adele Duimering ◽  
Albert Murtha
Keyword(s):  
Brain Tumors ◽  
Treatment Strategies ◽  
Brain Parenchyma ◽  
Benign Tumors ◽  
Tumor Control ◽  
Normal Brain ◽  
Neurocognitive Deficits ◽  
Close Proximity ◽  
Recent Developments ◽  
High Level

Radiotherapy is an important component of the treatment for primary and metastatic brain tumors. Due to the close proximity of critical structures and normal brain parenchyma, Central Nervous System (CNS) radiotherapy is associated with adverse effects such as neurocognitive deficits, which must be weighed against the benefit of improved tumor control. Advanced radiotherapy technology may help to mitigate toxicity risks, although there is a paucity of high-level evidence to support its use. Recent advances have been made in the treatment for gliomas, meningiomas, benign tumors, and metastases, although outcomes remain poor for many high grade tumors. This review highlights recent developments in CNS radiotherapy, discusses common treatment toxicities, critically reviews advanced radiotherapy technologies, and highlights promising treatment strategies to improve clinical outcomes in the future.

scholarly journals Transfer of rhodamine-123 into the brain and cerebrospinal fluid of fetal, neonatal and adult rats

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Liam M. Koehn ◽  
Katarzyna M. Dziegielewska ◽  
Mark D. Habgood ◽  
Yifan Huang ◽  
Norman R. Saunders
Keyword(s):  
Cerebrospinal Fluid ◽  
Fetal Brain ◽  
Maternal Blood ◽  
Adult Brain ◽  
Rhodamine 123 ◽  
Patient Specific ◽  
Adult Rats ◽  
Blood Brain ◽  
The Brain ◽  
Brain Barriers

Abstract Background Adenosine triphosphate binding cassette transporters such as P-glycoprotein (PGP) play an important role in drug pharmacokinetics by actively effluxing their substrates at barrier interfaces, including the blood-brain, blood-cerebrospinal fluid (CSF) and placental barriers. For a molecule to access the brain during fetal stages it must bypass efflux transporters at both the placental barrier and brain barriers themselves. Following birth, placental protection is no longer present and brain barriers remain the major line of defense. Understanding developmental differences that exist in the transfer of PGP substrates into the brain is important for ensuring that medication regimes are safe and appropriate for all patients. Methods In the present study PGP substrate rhodamine-123 (R123) was injected intraperitoneally into E19 dams, postnatal (P4, P14) and adult rats. Naturally fluorescent properties of R123 were utilized to measure its concentration in blood-plasma, CSF and brain by spectrofluorimetry (Clariostar). Statistical differences in R123 transfer (concentration ratios between tissue and plasma ratios) were determined using Kruskal-Wallis tests with Dunn’s corrections. Results Following maternal injection the transfer of R123 across the E19 placenta from maternal blood to fetal blood was around 20 %. Of the R123 that reached fetal circulation 43 % transferred into brain and 38 % into CSF. The transfer of R123 from blood to brain and CSF was lower in postnatal pups and decreased with age (brain: 43 % at P4, 22 % at P14 and 9 % in adults; CSF: 8 % at P4, 8 % at P14 and 1 % in adults). Transfer from maternal blood across placental and brain barriers into fetal brain was approximately 9 %, similar to the transfer across adult blood-brain barriers (also 9 %). Following birth when placental protection was no longer present, transfer of R123 from blood into the newborn brain was significantly higher than into adult brain (3 fold, p < 0.05). Conclusions Administration of a PGP substrate to infant rats resulted in a higher transfer into the brain than equivalent doses at later stages of life or equivalent maternal doses during gestation. Toxicological testing of PGP substrate drugs should consider the possibility of these patient specific differences in safety analysis.

scholarly journals Insulin and insulinlike growth factor 1 (IGF-1) receptors during central nervous system development: expression of two immunologically distinct IGF-1 receptor beta subunits.

1989 ◽  
Vol 9 (7) ◽  
pp. 2806-2817 ◽  
Author(s):  
R S Garofalo ◽  
O M Rosen
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
System Development ◽  
Fetal Brain ◽  
Nervous System Development ◽  
Adult Brain ◽  
Beta Subunit ◽  
Tyrosine Kinase Domain ◽  
Beta Subunits ◽  
Insulinlike Growth Factor

Insulin and insulinlike growth factor 1 (IGF-1) receptors are present in brain, yet their function remains obscure. Expression of these tyrosine kinase-bearing growth factor receptors during rat brain development was examined by using three antipeptide antibodies directed against epitopes in the beta subunits (AbP2, AbP4, and AbP5). All three antibodies recognized both insulin and IGF-1 receptors. Membranes were prepared from fetal brains (14 to 21 days of gestation), neonatal brain (postnatal day 1), and adult brain. Immunoblot analyses using AbP4 and AbP5 revealed a 92-kilodalton (kDa) protein that corresponded to the beta subunit of the insulin and IGF-1 receptors. Densitometric scanning of immunoblots indicated that receptor proteins were 4- to 10-fold more abundant in fetal brain membranes than in membranes from adult brain. Expression was highest during 16 to 18 days of gestation and declined thereafter to the relatively low level found in adult brain. Immunoblot analyses with AbP2 as well as ligand-activated receptor autophosphorylation revealed an additional protein of 97 kDa. This protein was phosphorylated in response to IGF-1 and was not directly recognized by AbP4 or AbP5. The covalent association of the 97-kDa protein with the 92-kDa beta subunit was indicated by the ability of AbP4 and AbP5 to immunoprecipitate both proteins under nonreducing conditions but only the 92-kDa protein after reduction. In contrast, AbP2 immunoprecipitated both proteins regardless of their association. This immunospecificity remained unchanged after deglycosylation of the isolated proteins. Two-dimensional tryptic phosphopeptide analysis showed that the 92- and 97-kDa subunits of the IGF-1 receptor are related but distinct proteins. Taken together, the data suggest that the 92- and 97-kDa subunits differ in primary amino acid sequence. Thus, two distinct beta subunits may be present in a single IGF-1 receptor in brain. These subunits have in common an epitope recognized by an antibody to the tyrosine kinase domain (AbP2) but differ in regions thought to be important in receptor kinase regulation and signal transduction.

scholarly journals Importance of Adult Dmbx1 in Long-Lasting Orexigenic Effect of Agouti-Related Peptide

Endocrinology ◽  
2016 ◽  
Vol 157 (1) ◽  
pp. 245-257 ◽  
Author(s):  
Seiichiro Hirono ◽  
Eun Young Lee ◽  
Shunsuke Kuribayashi ◽  
Takahiro Fukuda ◽  
Naokatsu Saeki ◽  
...  
Keyword(s):  
Mouse Strain ◽  
Energy Homeostasis ◽  
Expression Patterns ◽  
Critical Role ◽  
Fetal Brain ◽  
Cre Recombinase ◽  
Calcitonin Gene Related Peptide ◽  
Adult Brain ◽  
Related Peptide ◽  
Calcitonin Gene

Abstract Dmbx1 is a brain-specific homeodomain transcription factor expressed primarily during embryogenesis, and its systemic disruption (Dmbx1−/−) in the ICR mouse strain resulted in leanness associated with impaired long-lasting orexigenic effect of agouti-related peptide (AgRP). Because spatial and temporal expression patterns of Dmbx1 change dramatically during embryogenesis, it remains unknown when and where Dmbx1 plays a critical role in energy homeostasis. In the present study, the physiological roles of Dmbx1 were examined by its conditional disruption (Dmbx1loxP/loxP) in the C57BL/6 mouse strain. Although Dmbx1 disruption in fetal brain resulted in neonatal lethality, its disruption by synapsin promoter-driven Cre recombinase, which eliminated Dmbx1 expression postnatally, exempted the mice (Syn-Cre;Dmbx1loxP/loxP mice) from lethality. Syn-Cre;Dmbx1loxP/loxP mice show mild leanness and impaired long-lasting orexigenic action of AgRP, demonstrating the physiological relevance of Dmbx1 in the adult. Visualization of Dmbx1-expressing neurons in adult brain using the mice harboring tamoxifen-inducible Cre recombinase in the Dmbx1 locus (Dmbx1CreERT2/+ mice) revealed Dmbx1 expression in small numbers of neurons in restricted regions, including the lateral parabrachial nucleus (LPB). Notably, c-Fos expression in LPB was increased at 48 hours after AgRP administration in Dmbx1loxP/loxP mice but not in Syn-Cre;Dmbx1loxP/loxP mice. These c-Fos-positive neurons in LPB did not coincide with neurons expressing Dmbx1 or melanocortin 4 receptor but did coincide with those expressing calcitonin gene-related peptide. Accordingly, Dmbx1 in the adult LPB is required for the long-lasting orexigenic effect of AgRP via the neural circuitry involving calcitonin gene-related peptide neurons.

Identification of a novel neuronal C-SRC exon expressed in human brain

1990 ◽  
Vol 10 (5) ◽  
pp. 2035-2040
Author(s):  
J M Pyper ◽  
J B Bolen
Keyword(s):  
Amino Acids ◽  
Human Brain ◽  
Phosphorylation Site ◽  
Fetal Brain ◽  
Serine Residue ◽  
Developmentally Regulated ◽  
Site Analysis ◽  
Rna Transcripts ◽  
Splicing Pattern ◽  
Src Gene

Neuronal cells are known to express at least two different forms of the C-SRC proto-oncogene as a consequence of alternative splicing events which add an 18-nucleotide exon (the NI exon) between C-SRC exons 3 and 4. Here we report that a second neuronal exon of C-SRC is also present between C-SRC exons 3 and 4. This neuronal exon (the NII exon) of C-SRC was isolated from human adult and fetal brain-derived cDNAs and contains 33 nucleotides capable of encoding 11 amino acids (Gln-Thr-Trp-Phe-Thr-Phe-Arg-Trp-Leu-Gln-Arg). The human NI exon was located approximately 390 nucleotides from the end of C-SRC exon 3, whereas the NII exon was approximately 1,000 nucleotides from the beginning of C-SRC exon 4. Analysis of human brain RNA revealed that the NII exon is utilized primarily in conjunction with the NI exon to yield transcripts capable of encoding C-SRC products possessing 17 additional amino acids. These splicing events, which occur between the NI and NII exons, are predicted to alter the sixth amino acid encoded by the NI exon from an arginine to a serine residue, producing a potentially novel phosphorylation site. Analysis of the different C-SRC RNA transcripts revealed that the level of C-SRC RNA containing both NI and NII exons is similar in adult and fetal brain tissue, whereas the level of C-SRC RNA containing only the NI exon or the nonneuronal form of C-SRC RNAs is significantly higher in fetal brain tissues. These results indicate that the expression and splicing pattern of the C-SRC gene are developmentally regulated in the human brain.

Regulation of N-myc gene expression: use of an adenovirus vector to demonstrate posttranscriptional control

1990 ◽  
Vol 10 (12) ◽  
pp. 6700-6708
Author(s):  
L E Babiss ◽  
J M Friedman
Keyword(s):  
Recombinant Adenovirus ◽  
Wilms Tumor ◽  
Fetal Brain ◽  
Adenovirus Vector ◽  
Cell Types ◽  
Adult Brain ◽  
Posttranscriptional Control ◽  
Equivalent Rate ◽  
Myc Gene ◽  
Recombinant Adenovirus Vector

We present evidence that differences in the levels of N-myc mRNA among different cell types are the result of posttranscriptional control. First, we noted that while steady-state mouse N-myc mRNA could be detected only in fetal mouse brain, it was transcribed at an equivalent rate in adult brain, liver, spleen, and placenta and in fetal brain. Similarly, the human N-myc gene was transcribed at an equivalent rate in HeLa cells, which do not accumulate this RNA in the cytoplasm, and cell lines G401 (a Wilms tumor-derived cell line) and SKNMc (established from a primitive neuroepithelioma), which do express N-myc RNA. As expected, the N-myc promoter functioned at equivalent rates, as demonstrated by the level of a reporter gene, when introduced into these cell types by using a recombinant adenovirus vector. The suggestion that posttranscriptional mechanisms control the level of this RNA was supported by the observation that sequences in the N-myc third exon specifically decreased the level of E1A mRNA when these sequences were placed downstream of the E1A promoter in a recombinant adenovirus. Finally, we further localized these sequences to a 600-bp fragment of the third exon by introducing various subclones of this sequence downstream of the E1A promoter in both viral and plasmid vectors.

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