Minimal penetration of lipopolysaccharide across the murine blood–brain barrier

Abstract

LPS given peripherally or into the brain induces a neuroinflammatory response. How peripheral LPS induces its effects on brain is not clear, but one mechanism is that LPS crosses the blood-brain barrier (BBB). Alternatively, LPS acts outside the BBB by stimulating afferent nerves, acting at circumventricular organs, and altering BBB permeabilities and functions. Here, we labeled LPS with radioactive iodine (I-LPS) and co-injected it with radioactively labeled albumin (I-Alb) which acted as a vascular space marker. Measurable amounts of I-LPS associated with the BBB, most reversibly bound to brain endothelia. Brain endothelia also sequestered small amounts of I-LPS and about 0.025% of an intravenously injected dose of I-LPS crossed the BBB to enter the CNS. Disruption of the BBB with repeated injections of LPS did not enhance I-LPS uptake. Based on dose-response curves in the literature of the amounts of LPS needed to stimulate brain neuroimmune events, it is unlikely that enough peripherally administered LPS enters the CNS to invoke those events except possibly at the highest doses used and for the most sensitive brain functions. I-LPS injected into the lateral ventricle of the brain entered the circulation with the reabsorption of cerebrospinal fluid (bulk flow) as previously described. In conclusion, brain uptake of circulating I-LPS is so low that most effects of peripherally administered LPS are likely mediated through LPS receptors located outside the BBB.

Immune stress up regulates <i>TLR4</i> and <i>Tollip</i> gene expression in the hypothalamus of ewes

“…On the other hand, a new study carried out on rats injected with radioactive-iodine-labeled LPS (I-LPS) suggests that some measurable amount of LPS crosses the BBB (Banks and Robinson, 2010). The results of these studies could have been affected by insufficiently sensitive LPS detection methods.…”

“…On the other hand, in vivo studies performed on rats showed that peripherally injected LPS previously labeled with radioactive iodine 125 crossed the BBB. The brain uptake of circulating LPS was found to be low but measurable (Banks and Robinson, 2010).…”

Mouse brain plasmalogens are targets for hypochlorous acid-mediated modification in vitro and in vivo

“…This treatment regimen causes progressive loss of neurons in the substantia nigra in male mice [47]. Under normal conditions peripheral LPS passage across the blood-brain barrier is low [48] and therefore does not induce brain inflammation directly. However, systemic LPS induces hepatic TNFα synthesis and secretion and subsequent TNFα-receptor-dependent signal transduction to the brain, where TNFα synthesis is further amplified [49].…”

Contributions of central and systemic inflammation to the pathophysiology of Parkinson's disease

“…Likewise, another report provides evidence that nigral injection of VEGF to mice disrupted the BBB permeability and induced dopaminergic neuronal death in the ventral mesencephalon (VM) (Chen et al, 2008a). Acute systemic injection of LPS to rats either directly or indirectly can also cause functional breakdown of the BBB resulting in granulocyte infiltration and activation of parenchymal microglia (Banks and Robinson, 2010;Perry, 2004) which contribute to the degeneration of dopaminergic neurons in the SNpc (Brochard et al, 2009;Dutta et al, 2008).…”