The impact of hypoxia on blood-brain, blood-CSF, and CSF-brain barriers

Abstract

The blood-brain barrier (BBB), blood-cerebrospinal fluid (CSF) barrier (BCSFB), and CSF-brain barriers (CSFBB) are highly regulated barriers in the central nervous system comprising complex multicellular structures that separate nerves and glia from blood and CSF, respectively. Barrier damage has been implicated in the pathophysiology of diverse hypoxia-related neurological conditions, including stroke, multiple sclerosis, hydrocephalus, and high-altitude cerebral edema. Much is known about the damage to the BBB in response to hypoxia, but much less is known about the BCSFB and CSFBB. Yet, it is known that these other barriers are implicated in damage after hypoxia or inflammation. In the 1950s, it was shown that the rate of radionucleated human serum albumin passage from plasma to CSF was five times higher during hypoxic than normoxic conditions in dogs, due to BCSFB disruption. Severe hypoxia due to administration of the bacterial toxin lipopolysaccharide is associated with disruption of the CSFBB. This review discusses the anatomy of the BBB, BCSFB, and CSFBB and the impact of hypoxia and associated inflammation on the regulation of those barriers.

Keywords: blood-brain barrier; blood-cerebrospinal fluid barrier; cerebrospinal fluid-brain barrier; hypoxia.

Figure 1.

Schematic of the blood-brain barrier (BBB) neurovascular unit, choroid plexus blood-cerebrospinal fluid (CSF) barrier (BCSFB), and ependymal CSF-brain barrier (CSFBB). At the BBB, paracellular transport of molecules is limited by tight junctions connecting the endothelial cells. The choroid plexus, within the ventricles, comprises a fenestrated capillary enveloped in a layer of ependymal cells held together by tight junctions that prevent paracellular transport but facilitates transcellular transport of water, oxygen, and micronutrients between the blood and CSF. The mature ependymal CSFBB, composed of adherens and gap junctions, is considered a partial barrier, as it has selective permeability to water, CSF proteins, and exogenous tracers.

Figure 2.

Sodium fluorescein (NaFl) leakage as a marker of blood-brain barrier (BBB) disruption in room temperature (RT) and high ambient temperature (HAT) hypoxic animals. Sections from control rats injected with NaFl showed no leakage in the brain tissue of the frontal (top) and parietal (bottom) cortexes. In contrast, sections from the brain of 1 or 2 days of RT-hypoxic rats showed moderate monofocal leakages in the frontal and parietal cortexes. Sections from the brain of 1 or 2 days of HAT plus hypoxia showed multiple focal regions of NaFl in the brain tissue. (Modified from Ref. 24).

Figure 3.

Voxel-based analysis of the periventricular area in the brains of rats exposed to hypobaric hypoxia, i.e., 1/2 atm, equivalent to ∼10% O₂ at sea level (A), normobaric hypoxia with 8% O₂ (B), and 1 mg/kg lipopolysaccharide (C). Voxels with statistically increased signal after Gd administration are hyperintense. Major enhancement in the periventricular was observed in the brains of rats exposed to lipopolysaccharide and normobaric hypoxic conditions. [Modified from Nathoo et al. (4) with permission from Springer Nature.].