All vertebrates started out with a glial blood‐brain barrier 4–500 million years ago

Abstract

All extant vertebrates have a blood-brain barrier (BBB), a specialized layer of cells that controls molecular traffic between blood and brain, and contributes to the regulation (homeostasis) of the brain microenvironment. Such homeostasis is critical for the stable function of synapses and neural networks. The barrier is formed by vascular endothelial cells in most groups, but by perivascular glial cells (astrocytes) in elasmobranch fish (sharks, skates, and rays). It has been unclear which is the ancestral form, but this information is important, as it could offer insights into the roles of the endothelium and perivascular glia in the modern mammalian BBB. We have used electron microscopic techniques to examine three further ancient fish groups, with intravascular horseradish peroxidase as permeability tracer. We find that in bichir and lungfish the barrier is formed by brain endothelial cells, while in sturgeon it is formed by a complex perivascular glial sheath, but with no detectable tight junctions. From their BBB pattern, and position on the vertebrate family tree, we conclude that the ancestral vertebrate had a glial BBB. This means that an endothelial barrier would have arisen independently several times during evolution, and implies that an endothelial barrier gave strong selective advantage. The selective advantage may derive partly from greater separation of function between endothelium and astrocytic glia. There are important implications for the development, physiology, and pathology of the mammalian BBB, and for the roles of endothelium and glia in CNS barrier layers.

The Grasshopper: A Novel Model for Assessing Vertebrate Brain Uptake

“…Recently, we presented an insect-based BBB screening model that uses an intact whole brain under controlled in vitro-like exposure conditions (Nielsen et al, 2011). As in vertebrates, the protection of the insect CNS requires a tight brain barrier containing influx and efflux transporter proteins, which control elements entering the brain (Banerjee and Bhat, 2007;Bundgaard and Abbott, 2008;Stork et al, 2008;DeSalvo et al, 2011). The insect brain barrier consists of glia cells, which are the most abundant cell type in the vertebrate CNS.…”

Functions of lipid raft membrane microdomains at the blood–brain barrier

“…Intercellular junctional complexes between brain endothelial cells (BECs), namely tight junctions (TJs) and adherens junctions (AJ), provide endothelial polarity in addition to high transendothelial electrical resistance (TEER) and restrictive permeability [5]. Pericytes and perivascular astrocytes, through complex communications and signaling events with BECs, induce BBB properties and promote TJ maintenance, specialized transporter expression, and immune quiescence of BECs [4,[6][7][8][9][10][11][12][13]. In the current review, we make use of the term BBB to include molecular and functional events, which occur at the level of the highly specialized capillaries and of postcapillary venules of the CNS.…”

Transport Mechanisms of Nucleosides and Nucleoside Analogues ReverseTranscriptase Inhibitors in the Brain

“…To control the brain microenvironment, the endothelial blood-brain barriers (BBB) exists in all vertebrates, except for a few fish species (Bundgaard and Abbott, 2008). The BBB and the blood-cerebrospinal fluid barrier (BCSFB) are formed by brain endothelial cells (BECs) and choroid plexus (CP) epithelial cells, respectively (for a review see Redzic, 2011).…”

“…Potentially, all those nucleoside analogues could be used for the neuro-HIV treatment; however, their effect on HIV replication in the brain largely depends on its ability to enter the CNS and concentrations that they can achieve in the brain ECF and in the cytoplasm. Transport across the BBB largely depends on physico-chemical characteristics of a drug (polarity, lipophilicity, molecular weight) (for the role of lipophilicity in the BBB passage see Abbott et al, 2008 andAbbott et al, 2010). Based upon their measured CSF concentrations and therapeutic effects, these anti-HIV nucleosides are classified either as high CNS penetrating drugs (zidovudine and abacavir), intermediate CNS penetrating drugs (stavudine, lamivudine and emitricitabine) or low CNS penetrating drugs (zalcitabine and didanosine) (Letendre et al, 2008).The first drug that was approved for AIDS was zidovudine.…”