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Ascorbic Acid (AA) 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.

Ascorbic Acid (AA)

Ascorbic acid is an antioxidant agent that modulates dopamine and glutamate concentrations to alter their re-uptake into the neuron. Overall, AA is well tolerated with possible side effects including nausea, vomiting, heartburn, abdominal cramps, fatigue, flushing, headache, insomnia and sleepiness. Diarrhea can occur with higher doses.

 

Scientific Rationale

The main mechanism by which AA is believed to exert its neuroprotective effects is through its antioxidant properties (i.e, scavenging free radicals generated from dopamine catabolism).1 However, it may modulate DA and glutamate concentrations by altering their uptake. In addition, AA has been shown to increase DA synthesis in cell culture.

1. Trends Neurosci. 2000;23:209-216. (for review, other references cited below)

Animal Model Data

RODENT: The ability of AA to prevent decreases in brain DA were determined in MPTP C57 black mice.1 Mice were given MPTP 30-mg/kg x 6 days, MPTP 15-mg/kg or 30-mg/kg x 1 day with AA (1000-mg/kg x 6 days, 500-mg/kg or 200-mg/kg x 1 day). None of the AA treatments were able to reduce decreases in DA concentrations following MPTP. Regardless of AA dose, DA concentrations decreased to a level comparable to that found in MPTP-vehicle treated mice. In this same model, tocopherol, cysteamine, indomethacin, and selenium, were also ineffective in attenuating decreases in DA secretion following MPTP administration.

Two studies evaluated MPTP administration and its effects on DA concentrations and oxidation status in young adult (3 month) and older adult rats (6 and 18 months).2,3 In the first, rats were given MPTP (35-52 mg/kg) which resulted in an increase in AA oxidation in the older, but not younger rats.2 The older rats experienced a higher fatality rate after MPTP administration (35% vs 0%). Because GSH levels were increased after MPTP administration in younger rats compared to the older animals, the investigators concluded that younger rats GSH oxidant capacity is more efficient and spares the AA-antioxidant capacity in that age group. In addition, the authors hypothesize that the decreased antioxidant capacity in the older rats resulted in the higher fatality rate observed in that age group. In the second study, rats were given 12-35 mg/kg.3 Like the previous study the mature rats had a lower baseline concentrations of AA and GSH. In the older group, MPTP administration resulted in a 70% (vs none in the younger rats) mortality rate, however unlike the previous study AA oxidation status remained unchanged. These conflicting results regarding AA oxidation following MPTP may be attributed to the differences in the mature rats ages (6 and 18 months) or it may be reflective of differences in dosing. However, one cannot rule out the possibility that AA oxidation in determining neurological outcome is not a sensitive indicator of susceptibility to MPTP-induced toxicity.

PRIMATE: AA (100 mg/kg before and after MPTP) was unable to prevent decreases in DA secretion following MPTP administration in common marmosets.4

OTHER: PC12 cells treated with DA are believed to be injured by a free radical-mediated mechanism. Vitamin C and E, N-acetyl-cysteine (NAC), and dithothreitol (DTT) were compared in there ability to restore PC12 cell proliferation and maintain viability as measured by [3H]-thymidine uptake, trypan blue and TUNEL staining.5 Although AA (0.1 mM) was able to significantly reduce decreases in cell proliferation following DA exposure (53%, vs control p<0.01), it was less effective than NAC (113% vs control p<0.01) and DTT (73% vs control p<0.01). Equal molar concentrations of thiol-containing antioxidants and AA (10 mM,) were able to reduce dopamine-melanin formation (autoxidation). In contrast to the thiol-containing antioxidants, AA was ineffective in preventing DNA fragmentation as detected by TUNEL staining. Vitamin E was ineffective as a neuroprotective agent in this model system.

The effects of AA on DA and 6OHDA have been determined in PC12 cells.6 Administration of 100 mM of AA was able to minimally decrease cell loss following exposure to low concentrations of DA (10-100 mM). At higher DA concentrations (300 mM) no protective effect was observed. Combined exposure of 6OHDA and AA, resulted in a significantly greater cell death when compared to 6OHDA treatment alone (10 and 30 mM, p<0.001). With higher concentrations of 6OHDA, (100-300 mM) no difference between AA and vehicle treated cells were observed. When the duration of exposure to DA before administration of AA was increased, cell death became more marked with intervals greater than 1-hour resulting in significant increases in DA induced cell death (vs. DA alone, p<0.001). This suggests that DA derived reactive oxidative increase with time and make AA less effective in preventing injury. The authors also suggest that under the higher oxidative conditions associated with the longer DA exposure, AA may have developed pro-oxidant properties that led to increased cell death. Use of both AA and glutathione, prevented in cell loss by DA and 6OHDA more than either agent when used alone.

Studies using rodent striatal synaptosomes are conflicting on the neuroprotective properties of AA. In rat synaptosomes, it has been shown that AA can be a pro-oxidant and its oxidative products can act to inhibit both DA and glutamate reuptake.7 Both of which result in increased excitotoxic cell death. In contrast, in mice synaptosomes, AA does not prevent [ 3H]-DA uptake, but it does act as a noncompetitive inhibitor of MPP-uptake.8 This suggest that AA may have some protective effects on striatal neurons. Some explanation of the discrepancy between the two experiments' results comes from another study examining the independent and combined effects on cell oxidant status and cell viability.9 Independently, exposure to either AA or DA resulted in increased radical formation, oxidation of methionine, H2O2 production, and decreased cell viability. However, combined administration was able to partially or completely reverse these adverse effects. These findings suggest that the relative concentrations of AA and DA (to one another) contribute to their overall effects on cell oxidation and viability.

Data also suggests that AA may have a stimulatory effect on DA synthesis.10 Neuroblastoma cells (SK-N-SH) incubated with AA (100-500 mM x 2hrs) show an increase in tyrosine hydroxylase activity leading to a production of DA. After longer exposure (5 days), AA (200 mM) induces this enzyme's transcription (3-fold) as detected by cDNA-PCR. The activity and mRNA concentrations of dopamine-b-hydroxylase remained unaffected after AA exposure, hence DA turnover was unaffected.

1. Neurosci Lett. 1986;69:192-197.
2. Pharmacol Biochem Behav. 1995;51:581-92.
3. Neurosci Lett. 1993:159:143-6.
4. J Neural Transm Park Dis Dement Sect. 1991;3:73-8.
5. Exp Neurol. 1996;141:32-9.
6. Neurosci Lett. 2000;296:81-4.
7. J Neurochem. 1997;69:1185-95.
8. Life Sci. 1988;42:2553-9.
9. Free Radic Biol Med. 1998;25:1013-20.
10. Neurosci Lett 1998;244:33-6.

Pharmacokinetics (including blood brain barrier (BBB) penetration)

AA's absorption decreases with higher does (>1.5 grams).1 Only 25% of AA is bound to plasma proteins. AA undergoes hepatic metabolism via oxidative pathways and metabolites are eliminated renally. When the renal threshold for AA is exceeded (>14 mg/mL), then AA (the parent compound) is eliminated in the urine. With low doses of AA little of the parent compound is eliminated renally. The pharmacokinetics of AA do not differ significantly with age. Oral AA supplementation (500 mg/day x 2 weeks, 1000 mg/day x 2weeks) was able to increase CSF concentrations significantly in healthy volunteers.2 After 4-weeks, plasma concentrations increased 50% and in CSF 28% (p<0.05). However, this did not result in a proportional increase in the CSF's antioxidant ability as judged by measuring free-radical trapping capacity.

1. AHFS. American American Society of Health-System Pharmacists. Bethesda, MD. 2000.
2. Free Radic Biol Med. 1996;21:211-7.

Safety/Tolerability in Humans

Overall, AA is well tolerated in doses < 1 gram.1 Possible side effects include; nausea, vomiting, heartburn, abdominal cramps, fatigue, flushing, headache, insomnia and sleepiness. Diarrhea can occur with higher doses. Rarely, AA can induce hypercalciuria.

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

Drug Interaction Potential

AA has a low drug interaction potential.1,2

1. AHFS. American American Society of Health-System Pharmacists. Bethesda, MD. 2000.
2. Biopharm Drug Dispos. 1984; 5:43-54.

Clinical Trial/Epidemiological Evidence in Human PD

The majority of studies focusing on PD and AA, have been retrospective case control studies, however there have been two that have examined AA prospectively and its effects on PD symptoms or the progression of PD symptoms.

The ability of high-dose antioxidants to prevent the progression of PD symptoms was evaluated in a small open-label study.1 Patients (n=15) with onset of PD within 4 years were given a-tocopherol (3200 U/day) and AA (3000 mg/day) and followed until levodopa therapy was warranted. Patients could receive anticholinergics and amantadine over the course of the study. A historical control population was used for comparison. Mean age at onset for both group was 50.7± 2.3 years. Patients were divided into those with onset of symptoms before (n=11) and after (n=4) 53 years of age. In patients with PD onset before 53 years of age, the duration of symptoms before the levodopa was required was 71± 6.5 months. For those with symptoms after 53 years of age, the duration was 63.3 ± 3.9 months. Comparison to historical controls showed that antioxidants delayed the need for levodopa (because of worsening of PD symptoms) by 2.5-3 years. Although this design and outcome measures are limited, the results suggest a positive role for antioxidants (not only AA) in the prevention of the progression of PD. In another study, the affects of AA on on-off fluctuations was determined in a randomized, placebo-controlled, crossover study. Six PD patients with severe on-off fluctuations were enrolled. Although AA use resulted in a minor improvement in patient functioning, it did not result in a significant improvement in severity of motor symptoms or in patient self-assessment of symptom improvement.2

Three large case-control studies examining AA effects and the development of PD have been performed (as summarized below). Overall, their results do not consistently show a neuroprotective or disease modifying effect in individuals at risk for PD. However, the studies are markedly limited, in that they rely on historical report of dietary intake over the course of prolonged periods of time. In addition, only rough estimates of quantities are assessed. This means that total exposure to AA cannot be adequately determined.

The link between dietary intake and PD was assessed in 380 PD patients and 342 case-matched controls (38 patients failed to complete the food questionnaires, so some controls were used twice).3 The study took place at 9 German Neurological Centers who used a standard dietary questionnaire in which food intake and frequency was estimated. Questionnaires were completed after the patients had developed PD and historical recall of food intakes were reported. The study specifically compared the intake of micronutrients (including AA), fat, protein, carbohydrate intake and the development of PD. The mean age of PD patients (56.2 ± 6.7 years) and the control groups were similar (56.1 ± 6.9). In the PD patients, the average duration of symptoms was 3.7 ± 1.8 years. After consideration of covariants, the dietary factor associated with PD was higher carbohydrate intake (OR=2.74, 95%CI=1.30-6.07, ptrend =0.02). This was particularly true for patients with an increased intake of monosaccharides and disaccharides. There was only a weak inverse association between PD and AA (OR=0.6, 95%CI=0.33-1.09, ptrend =0.04).

In another similar study (Netherland-Rotterdam Study), 5342 patients (ages 55 to 95 years) were evaluated for symptoms of PD and antioxidant intake.4 Dietary intake was assessed using a semi-quantitative food history questionnaire. Among the total population only 31 had PD (Hoehn And Yahr stages 1 to 3) for a median duration of 2.8 years. Among the antioxidants evaluated (Vitamin E, AA, β-carotene, flavonoids), only increased Vitamin E intake was inversely associated with the development of PD (for every 10 mg/day increase in Vitamin E intake, OR=0.5, 95%CI= 0.2-0.9). AA intake did not correlate with the development of PD.

I n a third study performed in the U.S., 157 patients (103 PD patients, 138 age-matched controls) were asked about their adult dietary history using a standard questionnaire.5 Specifically, the history included average intake of various foods during the patients' lives after the age of 18 years. In the study, the median age of both groups was 72 years. The duration of PD symptom duration was not provided. Among the foods and micronutrients evaluated, there was no association between fruits, breads/cereals, dairy products, meat, non-alcoholic beverages, vitamin A or vitamin E intake and the development of PD. AA intake was only slightly associated with a decreased risk of PD. This decrease in risk was only found in the patients with the highest quartile of consumption (OR=0.75, 95%CI=0.32-1.77). Increased animal fat intake however was associated with an increased risk of PD. Similar findings regarding animal fat and antioxidant intake have been shown in smaller studies.6,7 Other information suggests that AA intake may increase the risk for developing PD.8

1. Am J Clin Nutr. 1991;53:380S-2S.
2. Adv Neurol. 1983;37:51-60.
3. Neurology. 1996:47:644-50.
4. Arch Neurol. 1997;54:762-5.
5. Mov Disord. 1999;14:21-7.
6. Ann Neurol. 1996;39:89-94
7. Neuroepidemiology. 2001;20:118-24.
8. Mov Disord. 1997;12:190-6.

Last updated June 23, 2008