Blood-Brain Barrier Abnormalities in Vulnerable Brain Regions during Thiamine Deficiency

Abstract

Experimental thiamine deficiency (TD) is a classical model of metabolic encephalopathy and selective cell loss in the brain resulting from a generalized, low-grade oxidative deficit. Late stages of TD are characterized by hemorrhages in the brain indicating a disruption of the blood-brain barrier (BBB). However, the relation of the breakdown of the BBB to selective cell loss in TD is not understood. The current studies examined the BBB at different stages of TD using immunoglobulin G (IgG) as an indicator of BBB integrity. Adult rats received thiamine-deficient diet ad libitum and daily injections of the thiamine antagonist pyrithiamine. IgG immunoreactivity increased in the inferior colliculus and inferior olive as early as 10 days after the initiation of TD and prior to the onset of cell death and hemorrhage. After 11 or 12 days, IgG immunoreactivity increased in multiple vulnerable regions. On Day 13, intense IgG immunoreactivity was found in regions of tissue damage and hemorrhage such as the thalamus, inferior colliculus, mammillary body, medial geniculate nucleus, medial vestibular nucleus, and inferior olive. Nonvulnerable regions displayed little or no IgG immunoreactivity. Immunoblotting analysis confirmed the presence of IgG in vulnerable areas such as the thalamus and inferior colliculus but not in preserved regions such as the cortex. Preliminary electron microscopy of capillary endothelia in areas of IgG accumulation in the thalamus at Day 13 revealed perivascular edema and intact interendothelial tight junctions. Thus, TD leads to a breakdown of the BBB in vulnerable regions prior to or coinciding with hemorrhage and cell loss. These results are important in understanding the pathophysiology of TD and perhaps other neurodegenerative disorders associated with oxidative stress.