Beneficial effects of fruit extracts on neuronal function and behavior in a rodent model of accelerated aging

Abstract

Exposing young rats to particles of high-energy and charge (HZE particles) enhances indices of oxidative stress and inflammation and disrupts the functioning of the dopaminergic system and behaviors mediated by this system in a manner similar to that seen in aged animals. Previous research has shown that diets supplemented with 2% blueberry or strawberry extracts have the ability to retard and even reverse age-related deficits in behavior and signal transduction in rats, perhaps due to their antioxidant and anti-inflammatory properties. This study evaluated the efficacy of these diets on irradiation-induced deficits in these parameters by maintaining rats on these diets or a control diet for 8 weeks prior to being exposed to whole-body irradiation with 1.5 Gy of 1 GeV/n high-energy ⁵⁶Fe particles. Irradiation impaired performance in the Morris water maze and measures of dopamine release 1 month following radiation; these deficits were protected by the antioxidant diets. The strawberry diet offered better protection against spatial deficits in the maze because strawberry-fed animals were better able to retain place information (a hippocampally mediated behavior) compared to controls. The blueberry diet, on the other hand, seemed to improve reversal learning, a behavior more dependent on intact striatal function. These data suggest that ⁵⁶Fe particle irradiation causes deficits in behavior and signaling in rats which were ameliorated by an antioxidant diet and that the polyphenols in these fruits might be acting in different brain regions.

Introduction

Previous studies have shown that whole-body exposure of rats to HZE particles, primarily 600 MeV or 1 GeV ⁵⁶Fe, can produce profound deficits in neuronal functioning and behavior, similar to the adverse changes seen in aged animals [18], [19], [26]. Exposing rats to HZE particles affects the integrity of the dopaminergic system, possibly due to permanent changes in functioning of dopamine (DA) neurons [19]. Behaviors affected by radiation include deficits in motor performance [19], spatial learning and memory [5], [7], [49], [50], [52], amphetamine-induced conditioned taste aversion learning [35], [39], [40], [43], conditioned place preference [39], [41], and operant conditioning (fixed-ratio bar pressing) [33], [36]. These deficits occur soon after ⁵⁶Fe radiation, have a threshold for effect, lack a dose–response relationship, and fail to show recovery of function following exposure [19], [38].

Increased susceptibility to the long-term effects of oxidative stress (OS) and inflammatory insults are thought to be contributing factors to the neurochemical and behavioral deficits seen in normal aging as well as in the progression of neurodegenerative diseases [1], [12], [13], [30]. It is likely that the deficits seen from exposure to ⁵⁶Fe irradiation also involve insult from increased OS and inflammation on the brain [47], [53]. Increases in oxidative stress levels have been observed in the frontal cortex of rats irradiated with 1.5 Gy of ⁵⁶Fe particles [7].

Research by our laboratory and that of our collaborators has demonstrated that fruits and vegetables high in antioxidant and anti-inflammatory activity, such as blueberries and strawberries, can prevent the occurrence of the neurochemical and behavioral changes that occur in aging [3], [6], [11], [15], [24], [55]. Given the similarities between the normal aging process and the effects of exposure to heavy particles [26], it is possible that dietary polyphenolics, which possess antioxidant and anti-inflammatory properties [32], [46], will be equally effective in preventing the behavioral changes produced by exposure to ⁵⁶Fe particles.

In previous studies, we have shown that maintaining rats on 2% strawberry- or blueberry-supplemented diets prevented the disruption of conditioned taste aversion learning [43], while only the strawberry diet improved deficits in operant responding produced by exposure to 1.5 Gy of ⁵⁶Fe particles in rats tested 12 months following irradiation [37]. The strawberry diet also prevented the disruption of operant responding in rats tested 5 and 8 months after exposure to a higher dose of radiation (2.0 Gy of ⁵⁶Fe particles); however, when tested 13 and 18 months after irradiation there were no differences in performance between the irradiated rats maintained on control, strawberry or blueberry diets [34]. These observations suggest that the beneficial effects of these diets may be dependent upon the age of testing [34]. Furthermore, animals fed the berryfruit diets prior to exposure showed reduced heavy particle-induced tumorigenesis after 1 year compared to the animals fed the control diet [22]. Interestingly, the animals in these studies were only fed the diet containing strawberries and blueberries for 8 weeks prior to and 1 week following radiation exposure; they were fed an unsupplemented diet after that period.

Taken together, these findings and those previously found in aged animals suggest that foods such as berryfruits may serve as powerful agents in preventing motor and cognitive deficits in aging. The present study was carried out to extend these findings by assessing the ability of 8 weeks of feeding a 2% blueberry- or strawberry-enriched diet to offset the irradiation-induced deficits in spatial learning and memory (as assessed by Morris water maze performance) and signal transduction (oxotremorine-enhanced K(+)-evoked release of dopamine from striatal slices, an indicator of striatal dopamine integrity) produced by exposure to 1.5 Gy of accelerated iron particles. This dose of ⁵⁶Fe radiation has been shown to disrupt spatial learning and memory in previous experiments [5], [7], [50]. By measuring neuronal signaling, specifically muscarinic receptor sensitivity, under basal and conditions of oxidative stress (H₂O₂), we hope to examine multiple mechanisms that may be involved in the beneficial effects of berryfruits on radiation-induced deficits.