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Folate Information Summary

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A number of compounds were identified as candidates for further study by the Committee to Identify Neuroprotective Agents in Parkinson's (CINAPS). Of these compounds, Minocycline, Creatine , CoQ10 and GPI 1485 have been selected for testing in the Neuroprotection Clinical Trial.

FOLATE

Folate, also called folacin or folic acid, is a partner with B12 in DNA synthesis and in removal of homocysteine, which has shown to be toxic to neuronal cells. Without folate, B12 would be unable to complete many of its functions, and vice versa. Folate is the form found in foods, folic acid is the form in dietary supplements. One study using mice found that folic acid deficiency led to increased levels of homocysteine and symptoms of Parkinson's disease. Researchers speculate that homocysteine may damage DNA in the substantia nigra, the area of the brain affected in Parkinson's disease.

Scientific Rationale

Levodopa and DA are metabolized by COMT to 3-O-methyldopa.1 This conversion requires the methyl-donor S-adenosylmethionine (SAM). After SAM donates its methyl- group, it is converted to S-adenosylhomocysteine and then to homocysteine. Homocysteine, in addition to is harmful effects on the cardiovascular system, has been shown to be toxic to neuronal cells.2 SAM's formation is dependant on folic acid and inadequate folic acid supplementation may lead to hyperhomocysteinemia. Some patients with PD have been found to have elevations in plasma homocysteine concentrations.3-7 This has led to the hypothesis that patients with PD have depleted SAM concentrations or genetically induced impairment in metabolism through this pathway that ultimately leads to the accumulation of homocysteine. In this construct endogenous or exogenous sources of DA increase homocysteine concentrations.8 It is hypothesized that folic acid supplementation would help replenish SAM concentrations and prevent the accumulation of homocysteine. In vitro evidence also suggests that folic acid may induce or act as a cofactor for tyrosine hydroxylase and the synthesis of DA.9 However, this effect has not been consistently observed.

1. Postgrad Med J. 1986:62:113-23.
2. Brain Res Rev. 1993;18:293-14.
3. Exp Neurol. 1997;145:580-5.
4. J Neurol. 1998;245:811-2.
5. Neurology. 2000;55:437-40.
6. Clin Chem. 20001;47:1102-4.
7. Neurosci Lett. 308:54-6.
8. Life Sci. 2000;66:2277-88.9
9. CMAJ. 1972;106:145-6.

Animal Model Data

RODENT: In mice with folate deficiency induced by dietary depletion, MPTP-induced motor symptoms and neuronal damage are more severe than in mice without decreased plasma folate.1 It was also found that mice with decreased folate concentrations had a corresponding increase in plasma homocysteine levels. Interestingly, direct infusion of homocysteine concurrent with MPTP administration into the substantia niagra or striatum of non-folate-depleted mice resulted in a similar decrement of motor symptoms and neuronal injury as observed in the folate-depleted mice given MPTP.

In contrast, intrastriatal injections of folic acid have caused lesions in rats similar to that found after injection with kainic acid.2 These finding suggest that homocysteine is a likely mediator of neuronal injury, however the ability of folic acid to prevent such neuronal injury may be limited.

1. J Neurochem. 2002;80:101-10.
2. Brain Res. 1984;298:339-42.

Pharmacokinetics (including blood brain barrier (BBB) penetration)

Folic acid (100% from synthetic forms) is readily absorbed with a Tmax =30 to 60 minutes after oral ingestion.1 In food, its bioavailability decreases slightly and ranges from 85 to 100%. In doses ≤ 1mg folic acid is almost completely metabolized by hepatic enzymes, however higher doses circulate in the blood freely as folic acid. Folic acid is eliminated in the feces as metabolites (≤ 1 mg) and in the urine after its tubular maximum is exceeded. For example, the proportion of folic acid that is renally eliminated is approximately 50% after doses of 2.5 to 5 mg and increases to 90% after doses of 15 mg (Note RDA for most elderly adults = 0.4 mg/day). Folic acid enters the CSF via an active transport mechanism that creates a plasma to CSF ratio of approximately 1:3-4,2,3 with this ratio consistent across adult age groups.

1. AHFS. American American, Society of Health-System Pharmacists. Bethesda, MD. 2000.
2. Pharm Res. 1999;16:415-9.
3. J Neural Transm. 2001;108:93-9.

Safety/Tolerability in Humans

Folic acid tends to be well tolerated. However, adverse effects reported with folic acid intake include nausea, anorexia, abdominal distension, flatulence, taste perversion, alter sleep patterns, difficulty concentrating, irritability, depression, confusion. These effects are rare and tend to occur at higher doses (15 mg/day). Allergic reactions have also rarely been reported.1 Caution is warranted in administering folic acid in patients with anemia without ruling out the possibility of pernicious anemia. (disguising B-12 deficiency).

1. AHFS. American American, Society of Health-System, Pharmacists. Bethesda, MD. 2000.

Drug Interaction Potential

Folic acid decreases phenytoin levels, however in most individuals this is not clinically significant.1 Phenytoin, phenobarbital, para-salicylic acid, sulfasalazine, oral contraceptives, methotrexate, chloramphenicol, and trimethoprim may decrease concentrations and/or effects of folic acid.

1. AHFS. American, Society of Health-System, Pharmacists. Bethesda, MD. 2000.
2. Clin Neuropharmacol. 1999;22:268-72.

Clinical Trial/Epidemiological Evidence in Human PD

The effect of folic acid supplementation in PD was evaluated in an open-label, observational study. Eighteen patients with PD (with unspecified baseline symptom severity) were given 15 mg/day of folic acid for a period ranging from 14 to 182 days (mean = 45 days). No benefit was reported in 6 patients, a slight benefit was reported in 11 patients, and 1 patient reported worsening of symptoms. Three individuals reported side effects during the study that consisted of buzzing in the ears, jitteriness, and sleeplessness. Overall, this study is limited in that it was of a short duration, it lacked objective measures of efficacy, and it did not use a placebo-controlled design. Regardless, the available data do not support the use of folic acid as a neuroprotective agent in PD or as a symptomatic treatment for the disorder.

CMAJ. 1972;106:145-6.

Last updated September 09, 2008