Long-term treatment with antioxidants and a program of behavioral enrichment reduces age-dependent impairment in discrimination and reversal learning in beagle dogs

Milgram, Norton W.; Head, Elizabeth; Zicker, Steven C.; Ikeda-Douglas, Candace J; Murphey, Heather; Muggenberg, Bruce A.; Siwak, Christina T.; Tapp, P. Dwight; Lowry, Stephen R.; Cotman, Carl W.

doi:10.1016/j.exger.2004.01.007

Cited by 117 publications

(101 citation statements)

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“…The significant decrease in oxidation and expression of some of these key brain proteins was also shown to correlate with improved cognitive function in the aged canines undergoing these interventions. These findings suggest possible mechanisms for the improved memory and cognitive function previous reported in the canine model of human aging [40,79] and are discussed herein with relevance to AD.…”

Section: Discussionsupporting

confidence: 60%

“…Previous studies in aged canines show that oxidative damage may be critically involved in the maintenance of cognitive function and long-term treatment with antioxidants and a program of behavioral enrichment reduces cognitive decline [40,54,79,80]. In the canine model of human aging, short term and long term treatment with a diet rich in a broad spectrum of antioxidants leads to rapid and sustained learning ability and improved spatial attention; these effects were further enhanced with the addition of behavioral enrichment [78,40].…”

Section: Introductionmentioning

confidence: 99%

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Proteomic identification of brain proteins in the canine model of human aging following a long-term treatment with antioxidants and a program of behavioral enrichment: Relevance to Alzheimer's disease

Opii

Joshi

Head

et al. 2008

Neurobiology of Aging

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175

135

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Aging and age-related disorders such as Alzheimer's disease (AD) are usually accompanied by oxidative stress as one of the main mechanisms contributing to neurodegeneration and cognitive decline. Aging canines develop cognitive dysfunction and neuropathology similar to those seen in humans, and the use of antioxidants results in reductions in oxidative damage and in improvement in cognitive function in this canine model of human aging. In the present study, the effect of a longterm treatment with an antioxidant fortified diet and a program of behavioral enrichment on oxidative damage was studied in aged canines. To identify the neurobiological mechanisms underlying these treatment effects, the parietal cortex from 23 beagle dogs (8.1-12.4 years) were treated for 2.8 years in one of four treatment groups: i.e., control food-control behavioral enrichment (CC); control food -behavioral enrichment (CE); antioxidant food-control behavioral enrichment (CA); and enriched environment -antioxidant fortified food (EA). We analyzed the levels of the oxidative stress biomarkers, i.e., protein carbonyls, 3-nitrotyroine (3NT), and the lipid peroxidation product, 4- Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeurobiol Aging. Author manuscript; available in PMC 2009 January 1. Published in final edited form as:Neurobiol Aging. 2008 January ; 29(1): 51-70. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript hydroxynonenal (HNE), and observed a decrease in their levels on all treatments when compared to control, with the most significant effects found in the combined treatment, EA. Since EA treatment was most effective, we also carried out a comparative proteomics study to identify specific brain proteins that were differentially expressed and used a parallel redox proteomics approach to identify specific brain proteins that were less oxidized following EA. The specific protein carbonyl levels of glutamate dehydrogenase [NAD (P)], glyceraldehyde-3-phosphate dehydrogenase (GAPDH), α-enolase, neurofilament triplet L protein, glutathione S-transferase (GST) and fascin actin bundling protein were significantly reduced in brain of EA-treated dogs compared to control. We also observed significant increases in expression of Cu/Zn superoxide dismutase, fructose-bisphosphate aldolase C, creatine kinase, glutamate dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase. The increased expression of these proteins and in particular Cu/Zn SOD correlated with improved cognitive function. In addition, there was a significant increas...

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Section: Discussionsupporting

confidence: 60%

Section: Introductionmentioning

confidence: 99%

Proteomic identification of brain proteins in the canine model of human aging following a long-term treatment with antioxidants and a program of behavioral enrichment: Relevance to Alzheimer's disease

Opii

Joshi

Head

et al. 2008

Neurobiology of Aging

Self Cite

175

135

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“…iron, copper) (1,2). This salutary antioxidant role has been implicated as part of the mechanism underlying the clinical benefits for orally supplied LA as a diabetes medicine and its means to improve age-associated cardiovascular, cognitive, and neuromuscular declines in animal models (3)(4)(5)(6). As excellent reviews exist, which summarize the functions of LA as a mitochondrial enzyme cofactor (7), we will mainly confine the present discussion to the evidence suggesting that (DH)LA solely acts as a true oxidant scavenger in vivo or whether its physiological ''antioxidant'' actions may actually be provided through induction of stress-activated signaling mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Is α‐lipoic acid a scavenger of reactive oxygen species in vivo? Evidence for its initiation of stress signaling pathways that promote endogenous antioxidant capacity

et al. 2008

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SummaryThe chemical reduction and oxidation (redox) properties of a-lipoic acid (LA) suggest that it may have potent antioxidant potential. A significant number of studies now show that LA and its reduced form, dihydrolipoic acid (DHLA), directly scavenge reactive oxygen species (ROS) and reactive nitrogen species (RNS) species and protect cells against a host of insults where oxidative stress is part of the underlying etiology. However, owing to its limited and transient accumulation in tissues following oral intake, the efficacy of nonprotein-bound LA to function as a physiological antioxidant has been questioned. Herein, we review the evidence that the micronutrient functions of LA may be more as an effector of important cellular stress response pathways that ultimately influence endogenous cellular antioxidant levels and reduce proinflammatory mechanisms. This would promote a sustained improvement in cellular resistance to pathologies where oxidative stress is involved, which would not be forthcoming if LA solely acted as a transient ROS scavenger.

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“…Positive results have been recorded for memory, learning capacity and immune status [132][133][134][135][136][137][138].…”

Section: Dietary and Complimentary Therapymentioning

confidence: 99%

Dogs with Cognitive Dysfunction Syndrome: A Natural Model of Alzheimer’s Disease

Bosch¹,

Pugliese²,

Gimeno-Bayón³

et al. 2012

CAR

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In the search for appropriate models for Alzheimer's disease (AD) involving animals other than rodents, several laboratories are working with animals that naturally develop cognitive dysfunction. Among the animals tested, dogs are quite unique in helping to elucidate the cascade of events that take place in brain amyloid-beta (Aβ) deposition aging, and cognitive deficit. Recent innovative research has validated human methods and tools for the analysis of canine neuropathology and has allowed the development of two different approaches to investigate dogs as natural models of AD. The first approach relates AD-like neuropathy with the decline in memory and learning ability in aged housed dogs in a highly controlled laboratory environment. The second approach involves research in family-owned animals with cognitive dysfunction syndrome. In this review, we compare the strengths and limitations of housed and family-owned canine models, and appraise their usefulness for deciphering the early mechanisms of AD and developing innovative therapies.KEYWORDS: aging, Amyloid-beta, animal model, canine cognitive dysfunction syndrome, family dog, therapies. 6 Why a canine model of AD?For years, the search for appropriate animal models for Alzheimer's disease (AD) has focused on a variety of manipulations to reproduce the disease in various species, such as yeast, Drosophyla melanogaster, Caenorabditis elegans, rodents, and rabbits, with a particular interest in obtaining knockout and transgenic animals (for a review, see [1]research is currently performed in the mouse because its brain structure is somewhat similar to that of humans, and it is amenable to highly sophisticated genetic engineering. Because age-related cognitive decline is a common feature of most mammals, other laboratories have focused on the few species that naturally develop cognitive dysfunction with various Alzheimer-like characteristics. These animals include the monkey, polar bear, cat and dog [2][3][4][5]. Canine models are currently considered a useful intermediate between genetically modified mouse models and humans [6,7]. Although many of the transgenic AD models have provided insights into the molecular mechanisms of the pathology, none of them encompass all the cognitive deficits observed in AD (see Table 1). One of the first transgenic mouse AD models was the amyloid precursor protein transgenic mouse, PDAPP mouse, which develops age-dependent amyloid beta accumulation and deposition in both diffuse and fibrillar neuritic plaques in the hippocampus, cerebral cortex, and corpus callosum [8]. Other models with AD-like pathology are apolipoprotein E (ApoE) or Tau transgenic mice, and also mice in which other genes have been modified. In more sophisticated approaches, important information has been gained from crossing PDAPP and ApoE models and with mice lacking or over-expressing genes for beta-secretase, alpha-secretase, or the insulin-degrading enzyme [9,10].All these models have provided valuable information on AD pathology and on the poss...

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Long-term treatment with antioxidants and a program of behavioral enrichment reduces age-dependent impairment in discrimination and reversal learning in beagle dogs

Cited by 117 publications

References 50 publications

Proteomic identification of brain proteins in the canine model of human aging following a long-term treatment with antioxidants and a program of behavioral enrichment: Relevance to Alzheimer's disease

Proteomic identification of brain proteins in the canine model of human aging following a long-term treatment with antioxidants and a program of behavioral enrichment: Relevance to Alzheimer's disease

Is α‐lipoic acid a scavenger of reactive oxygen species in vivo? Evidence for its initiation of stress signaling pathways that promote endogenous antioxidant capacity

Dogs with Cognitive Dysfunction Syndrome: A Natural Model of Alzheimer’s Disease

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