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Caloric Restriction Increases Neurotrophic Factor Levels SEE COMMENTARY and Attenuates Neurochemical and Behavioral Deficits in a Primate Model of Parkinson’S Disease

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Caloric Restriction Increases Neurotrophic Factor Levels SEE COMMENTARY and Attenuates Neurochemical and Behavioral Deficits in a Primate Model of Parkinson’S Disease Caloric restriction increases neurotrophic factor levels SEE COMMENTARY and attenuates neurochemical and behavioral deficits in a primate model of Parkinson’s disease Navin Maswood*, Jennifer Young†, Edward Tilmont†, Zhiming Zhang‡, Don M. Gash‡, Greg A. Gerhardt‡, Richard Grondin‡, George S. Roth†, Julie Mattison†, Mark A. Lane†, Richard E. Carson§, Robert M. Cohen¶, Peter R. Mouton†, Christopher Quigley†, Mark P. Mattson*ʈ**, and Donald K. Ingram† Laboratories of *Neurosciences and †Experimental Gerontology, National Institute on Aging Intramural Research Program, 5600 Nathan Shock Drive, Baltimore, MD 21224; ‡Department of Anatomy and Neurobiology and the Morris K. Udall Parkinson’s Disease Research Center of Excellence, University of Kentucky, 800 Rose Street, Lexington, KY 40536; §PET Department, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892; ¶Neuroimaging Section, Geriatric Psychiatry Branch, National Institute of Mental Health, Bethesda, MD 20892; and ʈDepartment of Neuroscience, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205 Edited by Richard D. Palmiter, University of Washington School of Medicine, Seattle, WA, and approved November 9, 2004 (received for review August 9, 2004) We report that a low-calorie diet can lessen the severity of explanation to the results suggesting an age-related loss of nigral neurochemical deficits and motor dysfunction in a primate model neurons (13). of Parkinson’s disease. Adult male rhesus monkeys were main- In a wide range of laboratory animals, caloric restriction (CR) tained for 6 months on a reduced-calorie diet [30% caloric restric- has been shown to prolong lifespan, decrease the incidence of tion (CR)] or an ad libitum control diet after which they were several age-related diseases, improve stress responses, and main- subjected to treatment with a neurotoxin to produce a hemipar- tain youthful function (14–16). CR can attenuate age-related kinson condition. After neurotoxin treatment, CR monkeys exhib- decreases in DA signaling in rodents (2), and intermittent fasting ited significantly higher levels of locomotor activity compared with can protect neurons against dysfunction and degeneration in control monkeys as well as higher levels of dopamine (DA) and DA rodent models of some neurodegenerative disorders (17, 18), but metabolites in the striatal region. Increased survival of DA neurons results from CR studies have not always been positive regarding in the substantia nigra and improved manual dexterity were noted neuroprotection (19). In the current study, we tested the hy- but did not reach statistical significance. Levels of glial cell line- pothesis that CR would increase the resistance of DA neurons derived neurotrophic factor, which is known to promote the to dysfunction and degeneration in a nonhuman primate model survival of DA neurons, were increased significantly in the caudate of PD. Specifically, we assessed whether CR affects the vulner- nucleus of CR monkeys, suggesting a role for glial cell line-derived ability of nigro-striatal DA neurons to the neurotoxin 1-methyl- neurotrophic factor in the anti-Parkinson’s disease effect of the 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP causes se- low-calorie diet. lective degeneration of DA neurons and PD-like neurochemical brain-derived neurotrophic factor ͉ cell death ͉ dopamine and histopathological alterations and motor dysfunction in hu- mans (20) and monkeys (21–23) and therefore has been used extensively in rhesus monkeys to assess cellular and molecular arkinson’s disease (PD) results from the dysfunction and de- mechanisms of PD and to evaluate potential treatments (24). Pgeneration of dopamine (DA) neurons in the substantia nigra (SN) and DA axon terminals, resulting in progressive motor Methods dysfunction (1). The risk of PD increases with advancing age, NEUROSCIENCE suggesting that cellular and molecular changes that occur in the Animals. Thirteen adult male rhesus monkeys (Macaca mulatta) brain during normal aging may promote the degeneration of DA (9–17 years old) were singly housed and quasi-randomly divided neurons. In this regard, increased oxidative stress and impaired into two diet groups, control diet (n ϭ 6) and CR (30% restriction energy metabolism and protein turnover occur in DA neurons in calories, n ϭ 7) with intention of matching initial body weights. during normal aging, and these changes are greatly exacerbated in Mean Ϯ SEM body weights at the beginning of the study were 9.6 Ϯ PD (2, 3). Although a small number of cases of PD result from 0.5 kg for controls and 9.8 Ϯ 0.8 kg for CR. The diets differed only inherited genetic mutations in one of three genes, ␣-synuclein, in caloric content, but were otherwise identical in their nutrient Parkin,orDJ-1 (4), most cases are sporadic with an unknown composition. Details of the diet composition are described in ref. environmental cause(s). Nevertheless, studies of genetic and neu- 25. Monkeys were maintained on the normal and low-calorie diets rotoxin-based animal models of PD point to the involvement of throughout the duration of the study. Changes in body weight of the oxidative stress and impaired energy metabolism and protein monkeys in relation to major events in the protocol are shown in turnover in the pathogenesis of PD (3–6). There is currently no Fig. 1. established intervention to prevent, or decrease the risk of, PD. Most studies of humans have concluded that a decrease in the number of DA neurons in the SN occurs during normal aging, with This paper was submitted directly (Track II) to the PNAS office. PD being an acceleration of this process (7–9). However, some Abbreviations: BDNF, brain-derived neurotrophic factor; CN, caudate nucleus; CR, caloric investigators have reported no age-related decline in the number of restriction; DA, dopamine; DOPAC, 3,4-dihydroxyphenylacetic acid; [18F]FMT, 6-[18F]fluoro- DA neurons (10). Studies in rhesus monkeys have been more m-tyrosine; GDNF, glial cell line-derived neurotrophic factor; HVA, homovanillic acid; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PD, Parkinson’s disease; PET, consistent in reporting age-related decline in the number of tyrosine positron-emission tomography; SN, substantia nigra; TH, tyrosine hydroxylase; VTA, ventral hydroxylase (TH)-positive SN neurons (11, 12). However, because tegmental area. some monkey studies have reported increased numbers of TH- See Commentary on page 17887. positive nigral neurons after treatment with neurotrophic factors, **To whom correspondence should be sent at the * address. E-mail: mattsonm@ such as glial cell line-derived neurotrophic factor (GDNF), an grc.nia.nih.gov. age-related decline in expression of TH could be an alternative © 2004 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0405831102 PNAS ͉ December 28, 2004 ͉ vol. 101 ͉ no. 52 ͉ 18171–18176 Downloaded by guest on September 25, 2021 The video records were analyzed for distance traveled (cm) and movement speed (cm͞sec). Each observation period was ana- lyzed at a rate of six samples per second for 20 min. To assess the impact of MPTP on fine-motor movement, the monkeys were trained to use their left and right hands to retrieve treats from a monkey movement assessment panel. The time of treat re- trieval (recorded from sensors attached to the panel) and also the ability of each monkey to retrieve treats from three levels of difficulty (platform, straight rod, and hook) were noted from the weekly testing procedure described in ref. 26. Monkeys received preliminary shaping on the task before their diet group assign- ments and then received formal training 6–10 weeks before MPTP treatment, and beginning 7 weeks afterward, they were tested every other week over a 10-week period. Fig. 1. Experimental design and body weights of monkeys in each diet group during the course of the study. All monkeys were injected with MPTP after being on their respective diet for 6 months. PET scans were conducted 1–3 Positron-Emission Tomography (PET). PET scans were performed 1–3 weeks before MPTP-injections (after being on the diet for 5 months) and 12–16 weeks before and 12–16 weeks after MPTP administration. Mon- weeks after MPTP injection while monkeys were being maintained on their keys were anesthetized and placed into a GE Advance PET scanner respective diet. Movement assessment panel testing to measure manual dex- (interslice interval of 4.25 mm and an in-plane full width at half terity was conducted 7 weeks after MPTP injections. All monkeys were eutha- maximum of Ϸ6.5 mm; General Electric) by using a head holder to nized 16–18 weeks after MPTP injection. There was a significant decline in acquire coronal slices. Two [O15]water injections of 10 mCi (1 Ci ϭ body weights of the CR group compared with the control diet group (CON) Ͻ 37 GBq) were followed by 60-sec scans. Subsequently, a 60-sec throughout the study (P 0.05, repeated-measures ANOVA). injection of Ϸ10 mCi of 6-[18F]fluoro-m-tyrosine ([18F]FMT) was followed by2hofdynamic scanning. Cerebellar regions of interest 15 MPTP Treatment. After being on their respective diet for Ϸ6 months, were then drawn on three adjacent slices of the averaged [O ]water 18 all monkeys were injected with a single dose of the neurotoxin scans and transferred onto the [ F]FMT scans to generate an FMT MPTP into the right carotid artery to induce hemiparkinsonism. cerebellar input function. By using the cerebellar input function, we Each monkey was administered 12 ml of a solution containing 0.2 performed a pixel-by-pixel Patlak analysis (29) to create images of mg͞ml MPTP, for a total amount of 2.4 mg of MPTP per monkey. the irreversible uptake rate KI over the time interval of 60–120 sec. MPTP⅐HCl was purchased from Sigma-Aldrich and was dissolved With the help of MRI scans obtained on each monkey, the KI for in sterile saline on the day of the injection.
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