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on the effects of cancer chemotherapy on cognitive function in rodent models. Given the increasing concern about cognitive dysfunction in patients receiving chemotherapy, the development of animal models to characterize chemotherapy-induced cognitive impairment has been proposed as a priority for future research (2, 3). Unexpectedly, Lee et al. (1) found an enhancement of both memory and hippocampal synaptic plasticity following several weeks of treatment with cyclophosphamide in rats.We too have used rodent models to investigate the cognitive effects of cyclophosphamide. In contrast to the findings reported by Lee et al. (1), we have observed a transient memory impairment following cyclophosphamide administration in mice. In our experiments, male CF1 mice (70-90 days of age) were trained and tested in step-down inhibitory avoidance conditioning, a type of emotionally motivated, hippocampus-dependent memory task where animals learn to associate a location in the training apparatus with a footshock. Inhibitory avoidance training was carried out as described previously (4). Either 1 day or 1 week before behavioral training, animals were given a systemic injection of cyclophosphamide (8, 40, or 200 mg/kg, i.p.). Control animals were injected with saline. Mice treated with cyclophosphamide at 40 or 200 mg/kg 1 day before training showed significant impairment of 24-hour memory retention when compared with control animals [mean F SE retention test latencies (seconds) were 61.30 F 20.93 in the control group, 80.91 F 25.02 in the group treated with 8 mg/kg cyclophosphamide, 22.0 F 12.02 in the group treated with 40 mg/kg cyclophosphamide, and 12.36 + 2.87 in the group treated with 200 mg/kg cyclophosphamide; both Ps < 0.01 compared with the control group with two-tailed Mann-Whitney U tests; n = 10-11 animals per group]. There was no significant difference among groups in training performance [overall mean F SE training trial latency (seconds) was 12.77 F 1.46; P = 0.16]. A control experiment showed that cyclophosphamide did not affect open field behavior (4), indicating that the impairing effects of cyclophosphamide on inhibitory avoidance could not be attributed to drug-induced alterations in locomotion, motivation, or anxiety (data not shown). Systemic administration of cyclophosphamide (8, 40, or 200 mg/kg, i.p.) did not affect inhibitory avoidance memory when given 1 week before training (data not shown).Our results show that a single administration of cyclophosphamide induces memory impairment in a mice model of aversive conditioning. Further studies are required to characterize cognitive deficits induced by cancer chemotherapy in animal models and investigate the mechanisms underlying the differential effects of cyclophosphamide on memory in different experimental paradigms. In Response: In their Letter to the Editor, Reiriz et al. have questioned the generalization of results that we recently presented about a rodent model to assess cognitive impairments induced by cyclophosphamide and 5-fluorouracil (1). In ...

Background: Both endocrine and immune systems are continuously remodeled during aging. Objective: Here, we investigated to what extent adrenal and somatosenescence are associated reciprocal changes in the immune system during strictly healthy aging. Methods: Forty-six elderly subjects and 33 young adults were recruited according to the health criteria of the SENIEUR protocol. Peripheral blood mononuclear cells were isolated and stimulated in vitro with lipopolysaccharide or phytohemagglutinin to assess the production of immunoreactive growth hormone (GH). Peripheral sensitivity to steroids was assessed in vitroby dexamethasone-, cortisol- or dehydroepiandrosterone (DHEA)-induced inhibition of T-cell proliferation. DHEA and GH levels were measured by radioimmunoassays. Results: Healthy elderly had lower salivary DHEA and serum GH levels (somatosenescence). They presented reduced T-cell sensitivity to dexamethasone but similar cellular sensitivities to cortisol and DHEA. Their cells produced similar levels of immunoreactive GH compared to the cells of young adults. Conclusions: These data indicate that healthy aging is associated with adrenal and somatosenescence as well as impaired neuroendocrine immunoregulation at the level of the lymphocyte. In addition, somatosenescence may not be associated with a reciprocal decline in immunoreactive GH.

The aim of this study was to investigate the effects of phenylalanine on oxidative stress and some metabolic parameters in astrocyte cultures from newborn Wistar rats. Astrocytes were cultured under four conditions: control (0.4 mM phenylalanine concentration in the Dulbecco's Modified Eagle Medium (DMEM) solution), Phe addition to achieve 0.5, 1.0 or 1.5 mM final phenylalanine concentrations. After 72 h the astrocytes were separated for the biochemical measurements. Overall measure of mitochondrial function by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and cell viability measured by lactate dehydrogenase (LDH) assays indicated that phenylalanine induced cell damage at the three concentrations tested. The alteration on the various parameters of oxidative stress indicated that phenylalanine was able to induce free radicals production. Therefore, our results strongly suggest that Phe at concentrations usually found in PKU induces oxidative stress and consequently cell death in astrocytes cultures. Considering the importance of the astrocytes for brain function, it is possible that these astrocytes alterations may contribute to the brain damage found in PKU patients.

These data suggest that FBP may be beneficial as auxiliary drug for the treatment of patients with acquired glucocorticoid resistance.

Maple syrup urine disease is an autosomal metabolic disease caused by a deficiency of branched-chain α-keto acid dehydrogenase complex activity. In this disease occur the accumulation of the branched-chain amino acids leucine, isoleucine, and valine and their corresponding branched-chain α-keto acids in the tissues and body fluids. The affected patients may present psychomotor development delay and mental retardation. The pathophysiology of maple syrup urine disease is not entirely understood, but leucine seems to be the primary neurotoxic metabolite. Creatine and pyruvate are energetics and antioxidants substances. In this study, we investigated the effects of leucine administration and co-administration of creatine plus pyruvate on several parameters of oxidative stress and phosphoryl transfer network in cerebral cortex and hippocampus of Wistar rats treated from the 8th to the 21st postpartum day. Leucine induced oxidative stress and diminished the activities of pyruvate kinase, adenylate kinase, cytosolic and mitochondrial creatine kinase. Co-administration of creatine plus pyruvate prevented the alterations provoked by leucine administration on the oxidative stress and the enzymes of phosphoryltransfer network. These results indicate that chronic administration of leucine may stimulate oxidative stress and alters the enzymes of phosphoryltransfer network in the cerebral cortex and hippocampus of the rats. It is possible that these effects may contribute, along with other mechanisms, to the neurological dysfunction found in patients affected by maple syrup urine disease. In this case, it is possible that creatine plus pyruvate supplementation could benefit to the patients.

Increasing evidence indicates that the gastrin-releasing peptide receptor (GRPR) is implicated in regulating synaptic plasticity and memory formation in the hippocampus and other brain areas. However, the molecular mechanisms underlying the memory-impairing effects of GRPR antagonism have remained unclear. Here we report that basic fibroblast growth factor (bFGF/FGF-2) rescues the memory impairment induced by GRPR antagonism in the rat dorsal hippocampus. The GRPR antagonist [D-Tpi(6), Leu(13) psi(CH(2)NH)-Leu(14)] bombesin (6-14) (RC-3095) at 1.0 microg impaired, whereas bFGF at 0.25 microg enhanced, 24 h retention of inhibitory avoidance (IA) when infused immediately after training into the CA1 hippocampal area in male rats. Coinfusion with an otherwise ineffective dose of bFGF blocked the memory-impairing effect of RC-3095. These findings suggest that the memory-impairing effects of GRPR antagonists might be partially mediated by an inhibition in the function and/or expression of neuronal bFGF or diminished activation of intracellular protein kinase pathways associated with bFGF signaling.

Vimang is an aqueous extract of Mangifera indica L, used in Cuba for the treatment of immunopathological disorders. Increasing evidence from preclinical studies indicates that Vimang displays antioxidant, antiallergic, analgesic and antiinflammatory actions. The present study investigated the effects of systemic administration of Vimang on behavioural outcomes of neurological function in rats. A single oral administration of Vimang produced an impairment of short- and long-term retention of memory for aversive training when given either 1 h pretraining or immediately posttraining, but not 8 h posttraining. Vimang did not affect open field behaviour or habituation. The results indicate that Vimang might induce deficits of emotionally motivated memory without affecting nonassociative memory, locomotion, exploratory behaviour or anxiety.