Autoradiographic mapping of local cerebral permeability to bilirubin in immature rats: effects of hyperbilirubinemia.
Kernicterus is characterized by the accumulation of bilirubin mainly into subcortical brainstem nuclei. Inasmuch as premature infants are more susceptible to kernicterus, we hypothesized that the cerebral permeability to bilirubin could vary by cerebral region and with age. Therefore, in the present study, we measured the blood-to-brain transfer constant (Ki) of [3H]bilirubin in 6-8 rats at postnatal age 10 (P10) or 21 d (P21) in basal conditions and after a bilirubin perfusion to explore age-related and bilirubin-induced changes in the cerebral permeability to the dye. Blood-to-brain transfer of [3H]bilirubin was measured in 39 brain regions by quantitative autoradiography in 15-min experiments. Rats exposed to unlabeled bilirubin received a loading dose of 160 mg/kg over 15 min followed by a 90-min bilirubin perfusion at a speed of 64 mg/kg/h. At P10, cerebral permeability to bilirubin ranged from 0.07 to 0.12 microL/g/min, except in the auditory nerve, dentate nucleus, hypothalamus, and thalamus where it reached 0.41-0.47 microL/g/min. At P21, Ki of bilirubin was significantly lower than at P10 and ranged from 0.03-0.06 microL/g/min in most brain areas. In P10 bilirubin-exposed rats, permeability to bilirubin significantly increased over control levels in all brain regions but three. The largest increases (> 350%) were recorded in the sensory regions, most limbic areas, hypothalamus, and thalamus. At P21, hyperbilirubinemia induced increases in blood-to-brain transfer of bilirubin of 50-200% in 16 brain areas, except in the hippocampus, sensory-motor cortex, and thalamic nuclei where they reached 200-433%. Thus, it appears that the immature rat brain (P10) is very permeable to bilirubin. The increased permeability with preexposure to the dye, especially in brain regions which are affected in infants with kernicterus, could be related either to the large decrease in the value of the albumin:bilirubin ratio between control (15-16) and hyperbilirubinemic conditions (1.7-1.8) and/or to an increased permeability to bilirubin.
Roger
C
C
INSERM U 272, Université Henri Poincaré, Nancy, France.
Koziel
V
V
Vert
P
P
Nehlig
A
A
D000367:Age Factors; D000818:Animals; D001663:Bilirubin / Q000493:pharmacokinetics*; D001810:Blood Volume; D001921:Brain / Q000378:metabolism*; D005260:Female; D006932:Hyperbilirubinemia / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D001663:Bilirubin