Focal astrocyte loss is followed by microvascular damage, with subsequent repair of the blood‐brain barrier in the apparent absence of direct astrocytic contact

Abstract

Blood-brain barrier (BBB) breakdown is a feature of cerebral ischaemia, multiple sclerosis, and other neurodegenerative diseases, yet the relationship between astrocytes and the BBB integrity remains unclear. We present a simple in vivo model in which primary astrocyte loss is followed by microvascular damage, using the metabolic toxin 3-chloropropanediol (S-alpha-chlorohydrin). This model is uncomplicated by trauma, ischaemia, or primary immune involvement, permitting the study of the role of astrocytes in vascular endothelium integrity, maintenance of the BBB, and neuronal function. Male Fisher F344 rats given 3-chloropropanediol show astrocytic damage and death at 4-24 h in symmetrical brainstem and midbrain nuclear lesions, while neurons show morphological changes at 24-48 h. Fluorescent 10 kDa dextran tracers show the BBB leaking from 24 h, progressing to petechial haemorrhage after 48-72 h, with apparent repair after 6 days. BBB breakdown, but not the earlier astrocytic death, is accompanied by a delayed increase in blood flow in the inferior colliculus. An ED1 inflammatory response develops well after astrocyte loss, suggesting that inflammation may not be a factor in starting BBB breakdown. This model demonstrates that the BBB can self-repair despite the apparent absence of direct astrocytic-endothelial contact. The temporal separation of pathological events allows pharmacological intervention, and the mild reversible ataxia permits long-term survival studies of repair mechanisms.

Astrocytes Are an Early Target in Osmotic Demyelination Syndrome

“…In these experiments, we also showed that the BBB dysfunction occurred concurrently with the earliest morphologic evidence of astrocyte death. Two potential explanations could account for these findings: (1) astrocyte death could induce dysfunction of the BBB, which has been shown in other models 11,52 or (2) the BBB dysfunction itself could induce damage to astrocytes. The second hypothesis is not supported by other models of BBB damage including osmotic disruption by mannitol infusion or stroke, where no astrocyte death occurs despite a dramatic BBB rupture.…”

Mild ischemia produces hippocampal neuronal death in stroke-prone spontaneously hypertensive rats

“…Cultured cells derived from newborn SHRSPs indicated astrocytic dysfunction in these animals (Yamagata et al, 1997). Astrocytes are important components of the BBB that support endothelial cells (Abbott et al, 2006), and astrocytic degeneration induces microvascular damage and greatly increases the permeability of the BBB (Willis and et al, 2004). Therefore, in SHRSPs, astrocytes may not function adequately to support the functioning of the BBB, and this may partly contribute to the high incidence of DND in these animals, because the permeability of the BBB in SHRSPs increased greatly due to 2-VO at 6 and 24 h after ischemia-reperfusion (Abraham et al, 2000).…”

Effect of Exercise Prior or After Ischemia on the Density of Neurons and Astrocytes in the Brain of Rats

“…The most abundant glial cells in the central nervous system (Abbott, 2002;Goudstein and Betz, 1986) are the astrocytes, covering 90% of the cerebrovascular surface (Willis et al, 2004). These cells participate in the regulation of free neurotransmitters, immune response, repair of the extracellular matrix, control of the cerebrovascular barrier and trophic support (Eddleston and Mucke, 1993).…”