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Brain Uptake of Folate Forms in the Presence of Folate Receptor Alpha Antibodies in Young Rats: Folate and Antibody
Natasha Bobrowski-Khoury1, Jeffrey M Sequeira2, Edward V Quadros2
1School of Graduate Studies, SUNY Downstate Health Sciences University, Brooklyn, NY 11203, USA.
Insights
Folate receptor alpha antibodies block brain folate transport in rats, causing deficits. Levofolinate effectively restored folate levels in the brain, suggesting its potential for treating cerebral folate deficiency in autism spectrum disorder.
Area of Science:
- Neuroscience
- Developmental Biology
- Immunology
Background:
- Folate receptor alpha antibodies (FRαAb) exposure during gestation in rats leads to placental and fetal accumulation.
- FRαAb blocks folate transport to the fetal brain, causing behavioral deficits preventable by folinic acid.
- Cerebral folate deficiency (CFD) is linked to autism spectrum disorders (ASD) via folate receptor autoimmune disorders.
Purpose of the Study:
- To evaluate folate transport to the brain in young rat pups.
- To determine the effect of FRαAb on brain folate transport.
- To identify an effective folate form for restoring cerebral folate status in the presence of FRαAb.
Main Methods:
- Intraperitoneal injection of FRαAb in a rat model.
- Oral administration of different folate forms (folic acid, D,L-folinic acid, levofolinate).
- Analysis of folate distribution in brain tissues (cerebrum, cerebellum) using biotin-tagged folic acid and measuring folate concentrations.
Main Results:
- FRαAb localizes to the choroid plexus and brain blood vessels.
- All tested folate forms (folic acid, D,L-folinic acid, levofolinate) are converted to methylfolate or absorbed as L-methylfolate and distributed to the brain.
- Levofolinate demonstrated significantly higher folate concentration in the cerebrum and cerebellum, both with and without FRαAb.
Conclusions:
- The rat model results support the investigation of levofolinate for treating CFD in children with ASD.
- Levofolinate appears to be efficiently transported to the brain and effective in restoring cerebral folate status.
- Understanding FRαAb's impact on folate transport is crucial for developing targeted therapies for CFD associated with ASD.
Abstract:
In a rat model, following exposure to rat folate receptor alpha antibodies (FRαAb) during gestation, FRαAb accumulates in the placenta and the fetus and blocks folate transport to the fetal brain and produces behavioral deficits in the offspring. These deficits could be prevented with folinic acid. Therefore, we sought to evaluate folate transport to the brain in young rat pups and determine what effect FRαAb has on this process, to better understand the folate receptor autoimmune disorder associated with cerebral folate deficiency (CFD) in autism spectrum disorders (ASD). When injected intraperitoneally (IP), FRαAb localizes to the choroid plexus and blood vessels including the capillaries throughout the brain parenchyma. Biotin-tagged folic acid shows distribution in the white matter tracts in the cerebrum and cerebellum. Since these antibodies can block folate transport to the brain, we orally administered various folate forms to identify the form that is better-absorbed and transported to the brain and is most effective in restoring cerebral folate status in the presence of FRαAb. The three forms of folate, namely folic acid, D,L-folinic acid and levofolinate, are converted to methylfolate while L-methylfolate is absorbed as such and all are efficiently distributed to the brain. However, significantly higher folate concentration is seen in the cerebrum and cerebellum with levofolinate in the presence or absence of FRαAb. Our results in the rat model support testing levofolinate to treat CFD in children with ASD.
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