Localization of cellular retinol-binding protein and retinol-binding protein in cells comprising the blood-brain barrier of rat and human.

Abstract

Brain is not generally recognized as an organ that requires vitamin A, perhaps because no obvious histologic lesions have been observed in severely vitamin A-deficient animals. However, brain tissue does contain cellular vitamin A-binding proteins and a nuclear receptor protein for retinoic acid. In the present study, immunohistochemical techniques were used to determine the cell-specific location of cellular retinol-binding protein in human and rat brain tissue. Cellular retinol-binding protein was localized specifically within the endothelial cells of the brain microvasculature and within the cuboidal epithelial cells of the choroid plexus, two primary sites of the mammalian blood-brain barrier. In addition, autoradiographic procedures demonstrated binding sites for serum retinol-binding protein in the choroidal epithelium. These observations suggest that a significant movement of retinol across the blood-brain barrier may occur.The mammalian brain is secluded in a specialized environment created by a series of selective membranes at the blood-brain interface. The passive entry of many biomolecules into neutral tissue is prevented by tight junctions that exist between the endothelial cells of the cerebral microvasculature. An additional barrier between the blood and the cerebrospinal fluid (CSF) is formed by tight junctions between adjacent epithelial cells of the choroid plexus. Saturable, facilitative transport processes for monosaccharides, amino acids, fatty acids, and various vitamins exist within the cells comprising these barrier sites to control the passage of these nutrients into neural tissue. The presence of a mechanism for the transport of vitamin A across neural capillaries and/or choroidal epithelium is not presently recognized.Retinol (vitamin A alcohol) is delivered to target tissues as a complex with serum retinol-binding protein (RBP) (1). A putative plasma membrane receptor on target cells binds RBP and internalizes the retinol (1). A cytoplasmic protein termed cellular retinol-binding protein (CRBP) may then transport the internalized retinol through the aqueous milieu of the cytoplasm to intracellular sites of action or metabolism (2). Studies of the retina (3) and testes (4, 5) have demonstrated high levels of CRBP in some of the cells that form the blood-retina and blood-testis barriers, suggesting a role for CRBP in the transcellular movement of retinol across these blood-organ barriers. CRBP is present in human (6) and rat (7,8) 4265The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Retinoic acid is detected at relatively high levels in the CNS of adult rats

“…It seems likely that vitamin A plays a role in neurological functions of adult animals, since retinoid-binding proteins have been identified in the adult brain and spinal cord. Both cellular ROL-binding protein and ROL-binding protein have been identified in cells comprising the blood-brain barrier, suggesting a mechanism by which vitamin A may enter the brain (17). The nuclear retinoid receptors RAR and RXR have been characterized in the adult brain (4).…”

“…RA is synthesized in crude adult rabbit brain homogenates (8) and was detected in specific areas in the brain of songbirds (6), suggesting that RA is not only required for the proper development of the CNS but continues to play a role in the adult CNS as well. Biochemical apparati, such as retinoid receptors and cellular retinoid-binding proteins, that are required for retinoid signaling are present in adult brain (4,17,31). Impaired dopamine signaling and impaired locomotion were observed in mutant mice in which a combination of RAR-␤ and RXR-␤ or -␥ was ablated, suggesting a possible function for RA in the adult mouse brain (12).…”

The role of extrahepatic retinol binding protein in the mobilization of retinoid stores

“…These include kidney, adipose, lacrimal gland, retinal pigment epithelium, testes, and brain (2). It is believed that the synthesis of RBP in extrahepatic tissues serves either to recycle retinol to liver (22)(23)(24)(25) or to facilitate the uptake of retinol by tissues with blood tissue barriers (testes, eyes, and brain) (26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38). However, neither of these possibilities has been tested experimentally.…”

Retinoids and Opioids: Factors in the Development of HIV-Related Neurological Disease

“…For example, vitamin A deficient children were found to have lower naive and higher memory T cell percentages in blood, and these numbers were reversed by treatment with vitamin A [35] . In other human studies, vitamin A deficiency resulted in decreased cellmediated immune function [36,37] and antibody responses [36] and in lower numbers of CD4+ lymphocytes, all which also normalized following vitamin A administration [30,35,38].…”