3: Brain Res 2000 Jun 2;866(1-2):211-7 Antioxidant-rich diets improve cerebellar physiology and motor learning in aged rats. Bickford PC, Gould T, Briederick L, Chadman K, Pollock A, Young D, Shukitt-Hale B, Joseph J. Department of Pharmacology, Boston, MA, USA. paula.bickford@uchsc.edu The free radical theory of aging predicts that reactive oxygen species are involved in the decline in function associated with aging. The present paper reports that diets supplemented with either spinach, strawberries or blueberries, nutritional sources of antioxidants, reverse age-induced declines in beta-adrenergic receptor function in cerebellar Purkinje neurons measured using electrophysiological techniques. In addition the spinach diet improved learning on a runway motor task, previously shown to be modulated by cerebellar norepinephrine. Motor learning is important for adaptation to changes in the environment and is thus critical for rehabilitation following stroke, spinal cord injury, and the onset of some neurodegenerative diseases. These data are the first to indicate that age-related deficits in motor learning and memory can be reversed with nutritional interventions. PMID: 10825496 [PubMed - indexed for MEDLINE]
5: Mech Ageing Dev 1999 Nov;111(2-3):141-54 Effects of aging on cerebellar noradrenergic function and motor learning: nutritional interventions. Bickford PC, Shukitt-Hale B, Joseph J. Department of Pharmacology, University of Colorado Health Sciences Center, Denver 80262, USA. paula.bickford@uchsc.edu Aging is associated with a decline in motor coordination and the ability to learn new motor learning skills. This loss of function is correlated with a decline in cerebellar beta-adrenergic receptor function. We have examined the role of oxidative stress on this system by exposing young rats to normobaric hyperoxia. This exogenous oxidative insult results in a decline in cerebellar beta-adrenergic receptor function that resembles what is observed in normal aged rats. This effect of hyperoxia is blocked by antioxidants. We have also examined the effects of nutritional supplementation of aged rats with diets high in antioxidant capacity. Foods such as blueberries and spinach can prevent and/or reverse age-related declines in cerebellar noradrenergic receptor function. PMID: 10656533 [PubMed - indexed for MEDLINE]
11: J Neurosci 1998 Oct 1;18(19):8047-55 Long-term dietary strawberry, spinach, or vitamin E supplementation retards the onset of age-related neuronal signal-transduction and cognitive behavioral deficits. Joseph JA, Shukitt-Hale B, Denisova NA, Prior RL, Cao G, Martin A, Taglialatela G, Bickford PC. United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts, Boston, Massachusetts 02111, USA. Recent research has indicated that increased vulnerability to oxidative stress may be the major factor involved in CNS functional declines in aging and age-related neurodegenerative diseases, and that antioxidants, e.g., vitamin E, may ameliorate or prevent these declines. Present studies examined whether long-term feeding of Fischer 344 rats, beginning when the rats were 6 months of age and continuing for 8 months, with diets supplemented with a fruit or vegetable extract identified as being high in antioxidant activity, could prevent the age-related induction of receptor-mediated signal transduction deficits that might have a behavioral component. Thus, the following parameters were examined: (1) oxotremorine-enhanced striatal dopamine release (OX-K+-ERDA), (2) cerebellar beta receptor augmentation of GABA responding, (3) striatal synaptosomal 45Ca2+ clearance, (4) carbachol-stimulated GTPase activity, and (5) Morris water maze performance. The rats were given control diets or those supplemented with strawberry extracts (SE), 9.5 gm/kg dried aqueous extract (DAE), spinach (SPN 6.4 gm/kg DAE), or vitamin E (500 IU/kg). Results indicated that SPN-fed rats demonstrated the greatest retardation of age-effects on all parameters except GTPase activity, on which SE had the greatest effect, whereas SE and vitamin E showed significant but equal protection against these age-induced deficits on the other parameters. For example, OX-K+-ERDA enhancement was four times greater in the SPN group than in controls. Thus, phytochemicals present in antioxidant-rich foods such as spinach may be beneficial in retarding functional age-related CNS and cognitive behavioral deficits and, perhaps, may have some benefit in neurodegenerative disease. PMID: 9742171 [PubMed - indexed for MEDLINE]
9: Ann N Y Acad Sci 1998 Nov 20;854:268-76 Membrane and receptor modifications of oxidative stress vulnerability in aging. Nutritional considerations. Joseph JA, Denisova N, Fisher D, Shukitt-Hale B, Bickford P, Prior R, Cao G. USDA-ARS Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts 02111, USA. joseph_ne@hnrc.tufts.edu Evidence suggests that oxidative stress (OS) may contribute to the pathogenesis of age-related decrements in neuronal function and that OS vulnerability increases as a function of age. In addition to decreased endogenous protection, increases in OS vulnerability may result from changes in membrane lipids and distribution of receptor subtype. Using a PC-12 cell model system, we have shown that H2O2 or dopamine (DA) exposure induced deficits in the cell's ability to clear (extrude/sequester, E/S) Ca2+ that are similar to those seen in aging. When plasma membrane concentrations of sphingomyelin (SPM) were used, the SPM metabolite, sphingosine-1-phosphate was increased to the same levels as those seen in aging, and enhancement of OS-induced decreases in calcium E/S following KCL depolarization was observed. Differential decreases in CA2+ E/S were also seen following DA-induced OS in COS-7 cells transfected with one of five muscarinic receptor subtypes. Cells transfected with either M1, M2, or M4 receptors showed significantly greater vulnerability to OS (as expressed by greater decrements in calcium E/S and cell death) than those transfected with M3 or M5 receptors. The vitamin E analogue, Trolox, and the nitrone-trapping agent, PBN, were not effective in altering E/S decrements but were effective in preventing cell death 24 h after OS exposure. These findings suggest that putative regional (e.g., striatum and hippocampus) increases in OS vulnerability and loss of neuronal function in aging may be dependent upon membrane SPM concentration and receptor subtype. In related studies, attempts were made to determine whether increased OS protection via nutritional increases in antioxidant levels in rats [using diets supplemented with vitamin E (500IU/kg), strawberry extracts (9.4 g/kg dried aqueous extract, DAE), spinach (6.7 g/kg DAE), or blueberry extracts (10 g/kg DEA for six weeks)] would protect against exposure to 100% O2 (a model of accelerated neuronal aging). Results indicated that these diets were effective in preventing OS-induced decrements in several parameters (e.g., nerve growth factor decreases), suggesting that although there may be increases in OS vulnerability in aging, phytochemicals present in antioxidant-rich foods may be beneficial in reducing or retarding the functional central nervous system deficits seen in aging or oxidative insult. Publication Types: Review Review, tutorial PMID: 9928436 [PubMed - indexed for MEDLINE]
7: Exp Gerontol 1999 Sep;34(6):797-808 The effects of dietary antioxidants on psychomotor performance in aged mice. Shukitt-Hale B, Smith DE, Meydani M, Joseph JA. United States Department of Agriculture-Agricultural Research Service, Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA. hale_ne@hnrc.tufts.edu Male C57BL/6NIA mice were provided one of six different antioxidant diets: vitamin E, glutathione, vitamin E plus glutathione, melatonin, strawberry extract, or control, beginning at 18 months of age. A battery of motor tests--rod walk, wire hang, plank walk, and inclined screen-was administered either: 1) before dietary treatment and then 6 months later at 24 months of age: or 2) only after 6 months of dietary treatment at age 24 months. An untreated group of 4-month-old mice served as young controls. Psychomotor performance was lower in 18-month-old mice compared with 4-month-old mice in the rod walk, wire hang, and inclined screen tests; however, no further decline was seen from 18 to 24 months on any measure. Chronic dietary antioxidant treatments were not effective in reversing age-related deficits in psychomotor behavior, except for the glutathione diet on inclined screen performance. It seems that motor performance deteriorates profoundly with age, because deficits at 18 months of age were as severe as they were at 24 months, and these age-associated motor deficits may be difficult to reverse, even with antioxidant treatment. PMID: 10579639 [PubMed - indexed for MEDLINE]
8: J Neurosci 1999 Sep 15;19(18):8114-21 Reversals of age-related declines in neuronal signal transduction, cognitive, and motor behavioral deficits with blueberry, spinach, or strawberry dietary supplementation. Joseph JA, Shukitt-Hale B, Denisova NA, Bielinski D, Martin A, McEwen JJ, Bickford PC. United States Department of Agriculture, Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts 02111, USA. Ample research indicates that age-related neuronal-behavioral decrements are the result of oxidative stress that may be ameliorated by antioxidants. Our previous study had shown that rats given dietary supplements of fruit and vegetable extracts with high antioxidant activity for 8 months beginning at 6 months of age retarded age-related declines in neuronal and cognitive function. The present study showed that such supplements (strawberry, spinach, or blueberry at 14.8, 9.1, or 18.6 gm of dried aqueous extract per kilogram of diet, respectively) fed for 8 weeks to 19-month-old Fischer 344 rats were also effective in reversing age-related deficits in several neuronal and behavioral parameters including: oxotremorine enhancement of K(+)-evoked release of dopamine from striatal slices, carbachol-stimulated GTPase activity, striatal Ca(45) buffering in striatal synaptosomes, motor behavioral performance on the rod walking and accelerod tasks, and Morris water maze performance. These findings suggest that, in addition to their known beneficial effects on cancer and heart disease, phytochemicals present in antioxidant-rich foods may be beneficial in reversing the course of neuronal and behavioral aging. PMID: 10479711 [PubMed - indexed for MEDLINE]
6: Phys Med Rehabil Clin N Am 1999 May;10(2):447-61 Neuroprotective agents. Richardson JS. College of Medicine, University of Saskatchewan, Saskatoon, Canada. richardson@sask.usask.ca Although basic research has revealed many mechanisms involved in the repair or elimination of damaged neurons, turning these mechanisms into clinically useful neuroprotective interventions is a slow process. Numerous neurotrophic factors seem to mediate neuronal repair and viability, but because the neurotrophic factors are proteins or polypeptides, they cannot be given orally and do not enter the brain if given intravenously. Tapping into the neuroprotective potential of the neurotrophic factor mechanisms must await further developments. Similarly, pharmacological agents that protect damaged neurons by reducing glutamate excitotoxicity, by scavenging free radicals, or by increasing adenosine inhibitory influences, are not ready yet for widespread clinical use. Also, appropriate therapeutic protocols for currently available neuroprotective agents such as vitamin E, selegiline, and NSAIDs remain to be determined. Given the rate of advance of research in this area, however, meaningful neuroprotection and neurorescue will be attainable in the very near future. In the meantime, neuron damaging oxidative stress can be kept in check by insuring adequate dietary sources of antioxidants. Although there is as yet little or no scientific evidence that dietary antioxidants are neuroprotective, the consumption of high antioxidant foods, such as blueberries and strawberries, is appealing to most people regardless of any neuroprotective potential. Publication Types: Review Review, tutorial PMID: 10370940 [PubMed - indexed for MEDLINE]
4: J Agric Food Chem 1999 Jun;47(6):2274-9 Content of the flavonols quercetin, myricetin, and kaempferol in 25 edible berries. Hakkinen SH, Karenlampi SO, Heinonen IM, Mykkanen HM, Torronen AR. Department of Clinical Nutrition, University of Kuopio, Finland. The amounts of quercetin, myricetin, and kaempferol aglycons in 25 edible berries were analyzed by an optimized RP-HPLC method with UV detection and identified with diode array and electrospray ionization mass spectrometry detection. Sixteen species of cultivated berries and nine species of wild berries were collected in Finland in 1997. Quercetin was found in all berries, the contents being highest in bog whortleberry (158 mg/kg, fresh weight), lingonberry (74 and 146 mg/kg), cranberry (83 and 121 mg/kg), chokeberry (89 mg/kg), sweet rowan (85 mg/kg), rowanberry (63 mg/kg), sea buckthorn berry (62 mg/kg), and crowberry (53 and 56 mg/kg). Amounts between 14 and 142 mg/kg of myricetin were detected in cranberry, black currant, crowberry, bog whortleberry, blueberries, and bilberry. Kaempferol was detected only in gooseberries (16 and 19 mg/kg) and strawberries (5 and 8 mg/kg). Total contents of these flavonols (100-263 mg/kg) in cranberry, bog whortleberry, lingonberry, black currant, and crowberry were higher than those in the commonly consumed fruits or vegetables, except for onion, kale, and broccoli. PMID: 10794622 [PubMed - indexed for MEDLINE]
2: Mech Ageing Dev 2000 Jul 31;116(2-3):141-53 Oxidative stress protection and vulnerability in aging: putative nutritional implications for intervention. Joseph JA, Denisova NA, Bielinski D, Fisher DR, Shukitt-Hale B. USDA Human Nutrition Research Center on Aging, Tufts University, 711 Washington Street, Boston, MA 02111, USA. jjoseph@hnrc.tufts.edu Research indicates that vulnerability to oxidative stress (OSV) may increase in aging, suggesting that age-related neurodegenerative diseases such as Alzheimer's disease (AD) or vascular dementia (VAD) may be superimposed upon a vulnerable neuronal environment. Determinations in cell models have suggested that the enhanced OSV may be the result of, (a) increases in membrane lipids, especially sphingomyelin and the sphingomyelin metabolite, sphingosine-1-phosphate, (b) decreases in glutathione, and (c) CNS distribution of OS-sensitive neuronal muscarinic receptor subtypes (e.g. M1, M2 and M4). These changes appear to enhance, (a) decrements in cellular calcium buffering following KCl-induced depolarization, and (b) cell death under OS conditions. Among the most effective agents that antagonized cellular OSV were the combination of polyphenolics found in fruits (e.g. blueberry extract) with high antioxidant activity. Subsequent experiments using dietary supplementation with fruit (strawberry) or vegetable (spinach) extracts have shown that such extracts are also effective in forestalling and reversing the deleterious effects of behavioral aging in F344 rats. Thus, it appears that the beneficial effects of the polyphenolics found in fruits and vegetables in neuronal aging and behavior may be similar to those seen with respect to carcinogenesis and cardiovascular disease. Publication Types: Review Review, tutorial PMID: 10996014 [PubMed - indexed for MEDLINE]
3: Brain Res 2000 Jun 2;866(1-2):211-7 Antioxidant-rich diets improve cerebellar physiology and motor learning in aged rats. Bickford PC, Gould T, Briederick L, Chadman K, Pollock A, Young D, Shukitt-Hale B, Joseph J. Department of Pharmacology, Boston, MA, USA. paula.bickford@uchsc.edu The free radical theory of aging predicts that reactive oxygen species are involved in the decline in function associated with aging. The present paper reports that diets supplemented with either spinach, strawberries or blueberries, nutritional sources of antioxidants, reverse age-induced declines in beta-adrenergic receptor function in cerebellar Purkinje neurons measured using electrophysiological techniques. In addition the spinach diet improved learning on a runway motor task, previously shown to be modulated by cerebellar norepinephrine. Motor learning is important for adaptation to changes in the environment and is thus critical for rehabilitation following stroke, spinal cord injury, and the onset of some neurodegenerative diseases. These data are the first to indicate that age-related deficits in motor learning and memory can be reversed with nutritional interventions. PMID: 10825496 [PubMed - indexed for MEDLINE]
4: Int J Dev Neurosci 2000 Jul-Aug;18(4-5):367-81 Neurobehavioral aspects of antioxidants in aging. Cantuti-Castelvetri I, Shukitt-Hale B, Joseph JA. Both aging and age-associated neurodegenerative diseases are associated with various degrees of behavioral impairments, and among the prime candidates responsible for producing the neuronal changes mediating these behavioral deficits appear to be free radicals and the oxidative stress they generate. Therefore, there have been a number of studies which have examined the putative positive benefits of antioxidants in altering, reversing, or forestalling these neuronal/behavioral decrements, with varying degrees of success. Additional experiments have examined the effects of diets rich in fruits and vegetables or herbal extracts in reducing certain types of cancer and cardiovascular diseases, and evidence emerging from such experiments suggests that these kinds of dietary modifications may be beneficial in altering neuronal/behavioral deficits in aging, as well. These kinds of diets are particularly rich in antioxidants such as vitamins A, C, E, and bioflavonoids (such as flavones, tannins, and anthocyanins), and thus, there may be synergistic effects among them. The present paper will review studies concerning the influence of dietary and synthetic antioxidants on normal, pathological age-related, and reactive oxygen species-induced behavioral changes in human and animal subjects. The antioxidants reviewed are vitamin E, alpha-lipoic acid, and the phytochemicals contained in herbals, fruits and vegetables. Publication Types: Review Review literature PMID: 10817921 [PubMed - indexed for MEDLINE]
5: J Gerontol A Biol Sci Med Sci 2000 Mar;55(3):B144-51 Effect of fruits, vegetables, or vitamin E--rich diet on vitamins E and C distribution in peripheral and brain tissues: implications for brain function. Martin A, Prior R, Shukitt-Hale B, Cao G, Joseph JA. Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts 02111, USA. amartin@hnrc.tufts.edu Age-related neurodegenerative conditions are the principal cause of declining cognitive and motor function during aging. Evidence support that fruits and vegetables containing generous amounts of antioxidant nutrients are important for neurological function. We investigated the effect of diets enriched with fruits or vegetables but low in vitamin E and a diet high in vitamin E on the distribution of vitamins C and E in the brain and dopamine release of Fischer 344 rat model, over an 8-month period. The low-vitamin E diet resulted in lowered alpha-tocopherol levels in brain and peripheral tissues, whereas the animals that received a diet enriched in vitamin E showed a significant increase, between 500-900%. Vitamin C concentration in plasma, heart, and liver was reduced in the vitamin E-supplemented group. It is concluded that supplementation or depletion of alpha-tocopherol for 8 months results in marked changes in vitamin E levels in brain tissue and peripheral tissues, and varied distribution of alpha-tocopherol throughout the different brain regions examined. In addition, compared to control group, rats supplemented with strawberry, spinach, or vitamin E showed a significant enhancement in striatal dopamine release. These findings suggest that other nutrients present in fruits and vegetables, in addition to the well-known antioxidants, may be important for brain function. PMID: 10795718 [PubMed - indexed for MEDLINE]