Folates blood-brain barrier

Because folic acid and many of its analogs are hydrophilic, they cross the blood—brain barrier poorly and require specific transport mechanisms to enter mammalian cells. Three inward folate transport systems are found on mammalian cells (I) a folate receptor, which has high (fffin-ity for folic acid but much reduced ability to transport methotrexate and other analogs (2) the reduced folate transporter, the majortransitproteinfor methotrexate, raltitrexed, pemetrexed, and most... 

New folate antagonists have been identified that are better substrates for the reduced folate carrier and appear to have significant advantages in clinical chemotherapy (see pemetrexed below). In efforts to bypass the obligatory membrane transport system and to facilitate penetration of the blood—brain barrier, lipid-soluble folate antagonists also have been synthesized. Trime-trexate (NEVTREXIN) has modest antitumor activity, primarily in combination with leucovorin rescue. However, it is beneficial in the treatment Pneumocystis jiroveci pneumonia, where leucovorin provides differential rescue of the host but not the parasite. 

Normally, there is an active transport of folate across the blood-brain barrier. The concentration of 5-methyl tetrahydrofolate (5-MTHF) in the cerebrospinal fluid is three times higher than in the serum. The epithelial cells of the choroid plexus, which produce cerebrospinal fluid, have folate receptors, which are part of an active transport system (Figure 30.1). 

Folate transport across the blood-brain barrier. The active transport of folate into the brain takes place in the epithelial cells of the choroid plexus. 5-Methyl tetrahydrafolate (5-MTHF), the main form of folate in serum, is bound to the high affinity folate receptors on the epithehal cells and transported into the cells. Endosomes and transport proteins are involved in the intracellular transfer. Finally, the reduced folate carriers on the brush border deliver 5-MTHF into the CSF. This folate transport system is energy dependent and saturable. It stabilizes cerebrospinal folate concentration whether the serum folate is low or high. Thus, the transport system has an important homeostatic function for brain folate. Likewise, vitamins Bi, B2, Be, B7 and B12 have specialized transport systems into the CSF. 

Low cerebrospinal fluid (CSF) levels of vitamin B12 and folate in dementia patients with normal serum levels have been demonstrated in a number of studies. Hence, CSF vitamin B and folate may be more sensitive indicators of their deficiencies at tissue level. This can be due to formation of inactive vitamin analogues at tissue level which are not detected by current analytical methods and disturbed transport of vitamin across the blood-brain barrier. 

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