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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 58:B394-B399 (2003)
© 2003 The Gerontological Society of America

Dietary Restriction Does Not Protect the Nigrostriatal Dopaminergic Pathway of Older Animals From Low-Dose MPTP-Induced Neurotoxicity

William W. Morgan1, Arlan G. Richardson,2,3 and James F. Nelson2

Departments of 1 Cellular and Structural Biology
2 Physiology, The University of Texas Health Science Center, San Antonio.
3 The Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio.


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
To determine whether reduced caloric intake affects the susceptibility of nigrostriatal dopamine (DA) neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity, 1-year-old male C57BL6 mice were offered food ad libitum or were given only 60% of the normal dietary intake. After 3 months, both groups were treated with low cumulative doses of 0, 10, 15, or 20 mg/kg MPTP. One week later, the striata were collected and DA, dihydroxyphenylalanine (DOPAC), and norepinephrine (NE) were measured. Treatment with MPTP had no effect on striatal NE but produced a dose-related depletion of DA and DOPAC in both the ad libitum-fed and the dietary-restricted mice. The MPTP-induced depletions of DA and DOPAC were not ameliorated in the dietary-restricted versus the ad libitum-fed mice. Baseline DA levels and those observed after treatment with the 15-mg/kg dose of MPTP were lower in the dietary-restricted mice compared with the ad libitum-fed mice. Overall, these results suggest that, at least in 1-year-old mice, dietary restriction for 3 months does not protect nigral DA nerve terminals from low toxic dosages of MPTP.

Dietary restriction has been shown to extend the life span of a number of widely divergent species (1,2). Reduced caloric intake is also known to augment oxidative defense mechanisms (3,4) and to delay the aging-related accumulation of oxidative damage in cellular lipids (5), proteins (6), and DNA (7). Dietary restriction also may be protective against the effects of aging as well as injury on the function of the brain. For example, this perturbation retarded the age-related increase in glial fibrillary acidic protein in the brain of rats (8) and enhanced the performance of aged mice in tasks related to learning and memory (9). Dietary restriction also increased the resistance of neurons in the brain to excitotoxins (10) and reduced the volume of brain damage as well as the magnitude of the behavioral deficits associated with experimentally induced focal ischemia in rats (11). Dietary restriction also reduced the sensitivity of hippocampal neurons to centrally administered kainate in mice expressing a mutant form of presenilin-1 (12). By contrast, dietary restriction did not alter either the time of onset or the rate of progression of the degeneration of anterior horn cells in a transgenic mouse model of familial amyotrophic lateral sclerosis (13).

Recent data also suggest that dietary restriction can reduce the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on the nigrostriatal dopaminergic pathway in mice (14). However, the investigators in that study did not directly measure the effects of this neurotoxin on the levels of dopamine (DA), the neurotransmitter for the nigrostriatal neurons. To further assess the effects of dietary restriction on MPTP-induced toxicity, we recently measured and compared the levels of norepinephrine (NE), DA, and the metabolite of DA, dihydroxyphenylacetic acid (DOPAC) in the striata of food-restricted mice versus mice provided with food ad libitum. In contrast to the earlier report, we observed that dietary restriction had no ameliorative effect on the ability of even low doses of MPTP to markedly reduce DA and DOPAC levels in the mouse striatum.


   METHODS
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Treatment of Mice
Male C57BL6 mice (Jackson Laboratory, Bar Harbor, ME) were housed in groups of 2 in microisolator-topped cages and maintained pathogen free in an Association for Assessment and Accreditation of Laboratory Animal Care-accredited facility maintaining strict adherence to the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals. All protocols involving the use of animals were reviewed and approved by the Institutional Animal Care and Use Committee located at the Audie Murphy Veterans Administration Hospital. The animals were maintained in an animal room with controlled temperature and were exposed to a 12:12 light–dark lighting regimen with the lights on daily from 6:00 AM to 6:00 PM. The animals had access to food ad libitum until the initiation of dietary restriction and were 1 year of age when the experiment was begun. At this time, the mice were randomly assigned to a dietary-restricted group or to a group provided with food ad libitum. The food provided was Harlan Teklad LM-485 Mouse/Rat Diet (Harlan Teklad, Madison, WI). The dietary-restricted animals were provided daily with 60% of the average food consumed by the ad libitum animals and were maintained on food resriction for 3 months. Food was provided to the dietary-restricted animals at 3:00 PM daily, and the mice remained on the dietary restriction regimen until sacrifice.

MPTP Regimen and Tissue Collection
At the end of 3 months on caloric restriction, groups of 5–8 randomly selected dietary-restricted and ad libitum-fed mice were treated with 0, 2, 3, or 4 doses of 6.1 mg/kg MPTP HCl (5 mg/kg of the free base). Therefore, the cumulative doses of the free base of MPTP administered to these various groups were 0, 10, 15, or 20 mg/kg, respectively. The subcutaneous administrations of the drug were given on the dorsum of the back at intervals of 2 hours and in 0.2 mL of 0.9% saline. The handling and administration of the MPTP and the subsequent housing of the treated animals followed recommended guidelines (15).

The mice were sacrificed 1 week following treatment with MPTP. The striata of each animal were dissected using anatomically defined landmarks (16), placed in separate 1.5 mL plastic centrifuge tubes, frozen immediately on dry ice, and stored at -80°C.

Catecholamine Analysis
One striatum from each animal was homogenized in cold (4°C) 0.1 N perchloric acid (HClO4) containing 1 mM sodium metabisulfite (Na2S2O5) and 100 nM dihydroxybenzylamine (DHBA). The latter compound was used as an internal standard. Norepinephrine, DA, and DOPAC in duplicate aliquots of each striatal sample were extracted with alumina (17) and subsequently analyzed by high performance liquid chromatography following a previously described procedure (18). Briefly, an Alltech Associates (Deerfield, IL) 5-micrometer, 15-centimeter reverse-phase column was used to resolve the catecholamines, which were analyzed using a Waters Corporation (Milford, MA) Model 464 electrochemical (EC) detector. The potential on the EC electrode was set at +0.7 volts, and the mobile phase was a 75 mM phosphate buffer (pH 2.5) containing 25 micromolar (µM) EDTA (ethylenediaminetetraacetic acid), 2.3 mM octane sulfonate, and 5% acetonitrile. Protein concentration was determined in duplicate aliquots of each homogenate (19), and the concentration of each catecholamine was ultimately expressed as picomoles per milligram of protein.

Statistical Analysis
To satisfy the assumption of an equality of variances among the treatment groups, a log base 10 transformation was performed on the DA data before further statistical analysis. In a separate analysis, the DA levels observed in both the MPTP-treated dietary-restricted and the ad libitum-fed mice were expressed as a percent of control, i.e., the mean level of DA observed in the corresponding group of dietary-restricted or ad libitum-fed mice that did not receive MPTP. These normalized data were also treated with a log base 10 transformation before further statistical analysis. All statistical evaluations of the DOPAC and NE data were performed on nontransformed data. The statistical significance of differences observed in the parameters measured in dietary-restricted versus ad libitum-fed mice were analyzed by a two-way analysis of variance (ANOVA) using a general linear model (Minitab Statistical Software for Windows, Version 13; Minitab Inc., State College, PA). Statistically significant main effects as well as interaction effects were further resolved with a one-way ANOVA and Student-Newman-Keuls (SNK) tests using a Graphpad-Prism Software Package (Version 3; San Diego, CA).


   RESULTS
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 Abstract
 Methods
 Results
Discussion
 References
 
After maintenance on dietary restriction for 3 months, the food-restricted mice weighed significantly less (, degrees of freedom among [v1] = 1, degrees of freedom error [v2] = 43; ) than the mice provided with food ad libitum (Figure 1). The comparatively low doses of MPTP administered in this study produced no overt evidence of acute toxicity, e.g., hypothermia or akinesia, in either the ad libitum-fed or the dietary-restricted mice. However, 1 week following treatment with MPTP, a marked and dose-related decrease in DA levels was evident in the striata of both the ad libitum-fed mice and the mice maintained on dietary restriction (Figure 2). This effect of MPTP was highly significant statistically when analyzed using a two-way ANOVA (). The MPTP-induced reduction in striatal DA was highly significant statistically (SNK, ) beginning with the lowest cumulative dosage (10 mg/kg, free base) of the drug. When compared with the low 10 mg/kg dosage, treatment with the highest cumulative dosage of MPTP (20 mg/kg, free base) resulted in significantly greater (SNK, ) reduction of DA in the striata of both the ad libitum-fed and the dietary-restricted-animals.



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  		Figure 1. Comparison of the body weights (g) of ad libitum-fed versus dietary-restricted male mice. The dietary-restricted mice were maintained on a diet providing 60% of the caloric intake of that of the ad libitum-fed mice for 3 months before the measurement of body weights. Statistical significance was determined by a one-way analysis of variance.

 


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  		Figure 2. Comparison of dopamine (DA) levels (pmol/mg protein) in ad libitum-fed (dark bars) versus dietary-restricted (DR) male C57BL6 mice (clear bars) 1 week following treatment with cumulative dosages of 0, 10, 15, or 20 mg/kg MPTP (free base). The dietary restriction paradigm was outlined in the caption to
Figure 1. The mice were on the restricted diet for 3 months before treatment with MPTP and were maintained on dietary restriction until sacrifice. Statistical significance was determined by a two-way analysis of variance followed by Student-Newman-Keuls tests. A = statistically different () from ad libitum-fed mice not given MPTP; B = statistically different () from corresponding group of ad libitum or dietary-restricted mice not treated with MPTP; C = statistically different () from ad libitum-fed mice treated with 15 mg/kg MPTP; D = statistically different () from either ad libitum-fed or dietary-restricted mice treated with 10 mg/kg MPTP

 
The two-way ANOVA also resolved a statistically significant main effect on DA levels in the ad libitum-fed versus the dietary-restricted male mice (). Graphically, striatal DA levels in the dietary-restricted mice that did not receive MPTP or those that received cumulative dosages of 10, 15, or 20 mg/kg MPTP were consistently lower than those observed in the corresponding groups of ad libitum-fed animals (Figure 2). However, only the reductions of DA in the dietary-restricted mice that were not treated with MPTP or treated with the cumulative dose of 15 mg/kg MPTP were statistically significant relative to the comparably treated groups of ad libitum-fed animals (SNK, ).

To determine whether the significantly lower baseline levels of DA observed in the dietary-restricted mice that were not treated with MPTP could explain the lower levels of this parameter observed in the dietary-restricted versus the ad libitum mice treated with each of the 3 different cumulative dosages of MPTP, the striatal DA levels for both the MPTP-treated dietary-restricted mice and the ad libitum-fed mice were normalized as a percent of their corresponding controls. Following this mathematical manipulation, no statistically significant differences were observed in the normalized DA values from the dietary-restricted versus the ad libitum-fed mice treated with the same cumulative dosage of MPTP (data not shown).

There were no statistically significant differences in striatal weights in the dietary-restricted () versus the ad libitum mice (). In addition, no significant differences in total protein levels were observed in the dietary-restricted () compared with the ad libitum-fed mice ().

Treatment with MPTP also produced a marked decrease in DOPAC levels in the striata of both the ad libitum-fed mice and the mice maintained on dietary restriction (Figure 3). This effect of MPTP was highly significant statistically when analyzed using a two-way ANOVA (). Although there was a trend toward greater reductions in DOPAC in the striata of the dietary-restricted animals that received cumulative dosages of 15 or 20 mg/kg MPTP, these apparent reductions were not different statistically from the corresponding MPTP-treated groups of ad libitum-fed mice. Therefore, statistically, DOPAC levels were maximally reduced in both the ad libitum and the dietary-restricted animals following the administration of the 10-mg/kg cumulative dosage of MPTP. Striatal DOPAC levels also were comparable in the ad libitum-fed versus the dietary-restricted mice that did not receive MPTP.



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  		Figure 3. Comparison of dihydroxyphenylacetic acid (DOPAC) levels (pmol/mg protein) in ad libitum-fed (dark bars) versus dietary-restricted (DR) male C57BL6 mice (clear bars) 1 week following treatment with cumulative dosages of 0, 10, 15, or 20 mg/kg MPTP (free base). The dietary restriction paradigm was outlined in the caption to
Figure 1. Statistical analyses were performed as outlined in the caption to
Figure 2. A = statistically different () from the corresponding group of ad libitum-fed or dietary-restricted mice not treated with MPTP

 
Treatment with MPTP had no statistically significant effects on NE levels in the striata of either the mice provided with food ad libitum or the mice maintained on the dietary restriction regimen (data not shown).


   DISCUSSION
Top
 Abstract
 Methods
 Results
 Discussion
References
 
The reduction of dietary caloric intake is a widely recognized method for extending the life span of a variety of different types of organisms (2). In addition to its beneficial effects on life span, dietary restriction also has been shown to significantly improve the ability of organisms to resist environmental stressors (20). For example, rats exposed to a restricted caloric intake also showed an ameliorated weight loss in response to surgery (21). Dietary restriction also reduced the sensitivity of rats to toxic drugs (22) and enhanced the ability of rats to survive an acute increase in environmental temperature (23).

Recent evidence suggests that this experimental manipulation also can protect the brain from injury induced by ischemic insult (11) or excitotoxicity (10). Observations such as these prompted us to investigate whether dietary restriction could also shield the dopaminergic nigrostriatal pathway in the mouse brain from damage produced by the selective neurotoxin MPTP. The possibility for such an ameliorative effect is supported by the consensus that the neurotoxicity induced by MPTP is due in part to the generation of reactive oxygen species (24,25) and the observation that the dietary restriction can augment mechanisms related to antioxidant defense (26).

In the current study, measurements of the levels of DA and DOPAC in the striatum were used to assess the neurotoxicity of MPTP to the nigrostriatal dopaminergic pathway. The striatum is known to be the site of termination of the nerve ending of nigral DA neurons, and the levels of DA and DOPAC in the striatum have been widely used as indices of the integrity and functionality of the nigrostriatal dopaminergic pathway (27–29). If dietary restriction were protective against the selective neurotoxic effects of MPTP on the nigrostriatal pathway, then there should be less depletion of one or both of these parameters in the striatum of dietary-restricted mice compared with ad libitum-fed mice. However, in the current study, there was no evidence for such an amelioration of the effects of MPTP on these parameters in the dietary-restricted versus the ad libitum-fed mice. It is concluded, therefore, that dietary restriction does not protect nigral DA neurons from the neurotoxic effects of MPTP.

This conclusion is inconsistent with that reached in a previous study by Duan and Mattson (14) where a significant protective effect against MPTP-induced toxicity to the nigrostriatal dopaminergic pathway was reported in dietary-restricted mice. The underlying reasons for the divergence of the conclusions of the 2 studies are unclear. The dichotomy is not due to differences in sex or strain, as male C57BL6 mice were utilized in both studies. The difference in results also is unlikely to be attributable to differences in the dietary restriction regimen. In both studies, the animals were maintained on dietary restriction for 3 months; and although Duan and Mattson produced dietary restriction using an alternate-day schedule, this regimen is reported to result in a comparable reduction in caloric intake to that employed in the current study (30).

It seems unlikely that the cumulative doses of MPTP used in our study were too toxic to permit the demonstration of a protective effect of dietary restriction. In fact, in order to increase the likelihood of observing ameliorative effects of dietary restriction, we purposely administered quite low cumulative doses of MPTP compared with those routinely administered to C57BL6 mice to affect toxicity to the nigrostriatal DA pathway (31,32). In our study, the significantly greater reduction in DA levels produced by the 20 mg/kg as compared with the 10-mg/kg dosage of MPTP clearly shows that at least our lowest cumulative dose was not maximally toxic to the nigral dopamine neurons. In any case, this supposition cannot explain the opposite conclusions that were reached; even the highest cumulative dose of MPTP that we administered (20 mg/kg) was one-fourth of the cumulative dose used by Duan and Mattson (80 mg/kg).

A major difference in our current study versus the previous investigation of the effects of dietary restriction on the MPTP-induced toxicity involved the methods used to assess the integrity of the nigrostriatal dopaminergic pathway. While we quantified the levels of striatal DA and DOPAC, Duan and Mattson (14) performed counts of tyrosine hydroxylase (TH) immunopositive neurons in the substantia nigra. These investigators reported that there were significantly fewer TH neurons lost in dietary-restricted versus ad libitum-fed mice following treatment with MPTP. It is conceivable, therefore, that dietary restriction may be more effective in protecting dopaminergic cell bodies, compared to nerve terminals, from the neurotoxic effects of MPTP. On the other hand, since Duan and Mattson did not appear to have calibrated their counting method, it cannot be certain that their approach accurately estimated the effects of MPTP on the numbers of nigral DA neurons or the ability of dietary restriction to ameliorate this toxic effect (33).

It was recently observed that the neurotoxicity of MPTP to nigral DA cells bodies is reduced in mice homozygous for a knockout of the inducible nitric oxide synthase gene (34). At the same time, there was no corresponding ameliorative effect of this mutation on the toxicity of MPTP to nigral DA nerve terminals in the striatum. These collective observations suggest that at least some of the mechanisms involved in MPTP-induced toxicity are different for nigral cell bodies versus nerve terminals. If this is true, then it is also possible that dietary restriction may ameliorate some of these mechanisms and not others. Since our study focused on toxicity to nerve terminals, while Duan and Mattson focused on toxicity to nigral cell bodies, the possibility of a differential effectiveness of dietary restriction to ameliorate some mechanisms related to MPTP toxicity but not others may in part explain the dichotomous outcomes of our 2 studies. The possibility that dietary restriction protects nigral DA neurons but not nerve terminals from MPTP neurotoxicity seems worthy of further investigation.

Duan and Mattson also observed that dietary restriction prevented the action of MPTP treatment to reduce the level of TH protein in the striatum (14). Interestingly, the MPTP regimen employed in their study produced only a very modest decrease in TH protein even in the ad libitum-fed animals. This latter observation is somewhat surprising given their report that the numbers of TH immunopositive neurons in the substantia nigra were reduced by more than one-third. Further, striatal TH enzymatic activity has been shown to be precipitously reduced in C57BL6 mice treated with much more modest doses of MPTP (18). Perhaps, in comparison to TH protein level, TH enzymatic activity or catecholamine levels provide better indices of magnitude of the damage of MPTP to the nigrostriatal pathway.

A potentially important difference in the design of the 2 studies is that Duan and Mattson used mice that were 4 months old at the start of dietary restriction while our animals were 1 year old. The results of an earlier study indicate that dietary restriction can reduce the development of cancer and increase both the average and maximal life span of mice, whether the restriction paradigm is initiated in young mice (3–6 weeks of age) or middle-aged mice (12–13 months of age) (35). However, it is still possible that the age of onset of dietary restriction may affect other parameters differently. Therefore, it would be interesting in a future study to directly test whether the age of the animals affects the ability of dietary restriction to protect against the neurotoxic effects of MPTP on nigral DA neurons.

In addition, it is well established that nigral DA neurons in 2-month-old mice are more resistant to the neurotoxic effects of MPTP compared with those in 8–12 month-old mice (36–38). Although a further increase in sensitivity to MPTP was reported between 10 and 16 months, this increase was quite small compared with that observed between 2 and 10 months (39). The age-related difference in susceptibility is believed to be largely due to an increase in monoamine oxidase B activity that occurs in C57BL6 mice primarily between the ages of 2 and 10 months (39,40). Therefore, it could be argued that the younger mice used in the study of Duan and Mattson were so much less sensitive to the neurotoxic effects of MPTP that a protective effect of dietary restriction could be resolved in their study but not in our study, which involved the use of older animals. However, the potential importance of this factor appears to be somewhat negated by the aforementioned use of 4- to 8-fold lower dosages of MPTP in our study. In addition, the mice used in the study of Duan and Mattson were 4 months old at the start of dietary restriction, but they were 7 months old at the time of treatment with MPTP. Others have shown that C57BL6 mice of this age are already markedly more sensitive to MPTP than 2-month-old mice (37).

In the current study, MPTP was administered to the mice subcutaneously while Duan and Mattson administered this neurotoxin intraperitoneally. Although it seems remote, there is a possibility that the different kinetics of the absorption and half-life of the drug in the circulation due to these different routes of administration may have influenced the different outcomes observed.

In our study, striatal DA levels were slightly but significantly lower in the dietary-restricted mice compared with the ad libitum-fed mice. It is unlikely that this observation is due to a reduction in brain tissue size in the dietary-restricted animals, as both the striatal weights and striatal total protein levels were not significantly different in the dietary-restricted mice versus the ad libitum-fed mice. The reduction in the baseline levels of this parameter is the probable explanation for the reduced levels of DA, which is graphically evident in the dietary-restricted versus the ad libitum-fed mice treated with each of the cumulative dosages of MPTP. This latter conclusion is supported by the observation that the normalization of the DA levels in all of the MPTP-treated animals as a percent of control eliminated any significant differences observed between dietary-restricted and ad libitum-fed mice given the same cumulative dosage of MPTP.

The reduced levels of DA in the dietary-restricted mice, which were not treated with MPTP, without an associated reduction in DOPAC levels may reflect an increase in the metabolism and perhaps the utilization of striatal DA in response to dietary restriction. To our knowledge, these are the first data to suggest that dietary restriction may affect the metabolism of nigral DA and perhaps alter the activity of the nigrostriatal pathway. However, the understanding of the mechanism and the physiological importance, if any, for this reduction in striatal DA in the dietary-restricted mice must await further study.

In summary, the results of this study indicate that, at least in 1-year-old male mice, maintenance on a restricted caloric intake for 3 months does not reduce the sensitivity of striatal DA nerve terminals to the neurotoxic effects of MPTP.


   Acknowledgments
 
This work was supported in part by a grant from the Merit Review Medical Research Program of the Department of Veterans Affairs and by U. S. Public Health Service Grant AG14932 from the National Institute on Aging. We also especially wish to acknowledge Elisa Figueroa and Heather A. Kiel, who performed the tissue collection as well as the catecholamine assays, and Vivian Diaz, who supervised the care and treatment of the animals.

Address correspondence to William W. Morgan, PhD, Department of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900. E-mail: morgan{at}uthscsa.edu


   Footnotes
 
Decision Editor: John A. Faulkner, PhD

Received December 16, 2002

Accepted February 18, 2003


   References
Top
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 Methods
 Results
 Discussion
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