Search

Brain-derived neurotrophic factor (BDNF) plays a key role in neural development and physiology, as well as in pathological states. Post-mortem studies demonstrate that BDNF is reduced in the brains of patients affected by neurodegenerative diseases. Iron accumulation has also been associated to the pathogenesis of neurodegenerative diseases. In rats, iron overload induces persistent memory deficits, increases oxidative stress and apoptotic markers, and decreases the expression of the synaptic marker, synaptophysin. Deferiprone (DFP) is an oral iron chelator used for the treatment of systemic iron overload disorders, and has recently been tested for Parkinson's disease. Here, we investigated the effects of iron overload on BDNF levels and on mRNA expression of genes encoding TrkB, p75 NTR , catalase (CAT) and NQO1. We also aimed at investigating the effects of DFP on iron-induced impairments. Rats received iron or vehicle at postnatal days 12-14 and when adults, received chronic DFP or water (vehicle). Recognition memory was tested 19 days after the beginning of chelation therapy. BDNF measurements and expression analyses in the hippocampus were performed 24 h after the last day of DFP treatment. DFP restored memory and increased hippocampal BDNF levels, ameliorating iron-induced effects. Iron overload in the neonatal period reduced, while treatment with DFP was able to rescue, the expression of antioxidant enzymes CAT and NQO1.

It has been demonstrated that experiences taking place early in life have a profound influence on brain development, interacting with the genetic background and determining differences in the vulnerability to the onset of bipolar disorder when the individual is exposed to a second adverse event later in life. Here, we investigated the effects of exposure to an early adverse life event (maternal deprivation) and to a later adverse life event [D-amphetamine (AMPH)] on cognition in an animal model of mania. We have previously demonstrated that that repeated AMPH exposure produces severe and persistent cognitive impairment, which was more pronounced when the animals were maternal deprived, suggesting that the early adverse life event could be potentiating the effects of the exposure to the second adverse life event later in life. Here, we show that valproic acid ameliorated the cognitive deficits induced by AMPH, but it was not effective when the animals were exposed to both stressors: maternal deprivation and AMPH treatment.

We have previously shown that pharmacological blockade of the gastrin-releasing peptide receptor (GRPR) during the neonatal period in rats produces behavioral features of developmental neuropsychiatric disorders. Here, we show that social interaction deficits in this model are reversed by the atypical antipsychotic clozapine given in the adulthood. In addition, we analyzed the mRNA expression of three neuronal receptors potentially involved in the etiology of disorders of the autism spectrum. Rats were injected with the GRPR antagonist RC-3095 or saline (SAL) from postnatal days 1-10, and tested for social behavior and recognition memory in the adulthood. One hour prior to the behavioral testing, rats were given a systemic injection of clozapine or saline. The mRNA expression of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor, the epidermal growth factor receptor (EGFR), and GRPR was measured in the hippocampus and cortex of a separate set of rats given RC-3095 or SAL neonatally. Rats given neonatal RC-3095 showed decreased social interaction and impaired object recognition memory. Clozapine rescued the social interaction impairment. Neonatal treatment with RC-3095 also resulted in dose-dependent decreases in the expression of GRPR, NR1, and EGFR in the cortex, whereas all three receptor mRNAs were increased in the hippocampus in rats treated with the lower dose of RC-3095. The results contribute to further validate the novel rat model of neurodevelopmental disorders induced by GRPR blockade, and shows alterations in the expression of neuronal receptors in this model.

Adverse experiences early in life may have profound influences on brain development, for example, determining alterations in response to psychostimulant drugs, an increased risk of developing a substance abuse disorder, and individual differences in the vulnerability to neuropsychiatric disorders later in life. Here, we investigated the effects of exposure to an early adverse life event, maternal deprivation, combined with repeated d-amphetamine (AMPH) administration in adulthood, on recognition memory and brain-derived neurotrophic factor (BDNF) levels in rats' brain and serum. Rats were exposed to one of the following maternal rearing conditions from postnatal days 1 to 14: non-deprived (ND) or deprived (D). In adulthood, both groups received injections of saline (SAL) or AMPH (2.0mg/kg, i.p.) for 7 days. In Experiment I (performed 24h after the last AMPH injection), AMPH induced long-term memory (LTM) impairments in ND and D groups. The D+AMPH group also presented short-term memory (STM) impairments, indicating that the effects of AMPH on memory were more pronounced when the animals where maternally deprived. The group exposed to D+SAL (SAL) showed only LTM impairments. In Experiment II (performed 8 days after the last injection), AMPH detrimental effects on memory persisted in ND and D groups. BDNF levels were decreased in the hippocampus of D+SAL rats. In conclusion, AMPH produces severe and persistent recognition memory impairments that were more pronounced when the animals were maternally deprived, suggesting that an early adverse life event may increase the vulnerability of cognitive function to exposure to a psychostimulant later in life., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Alterations in attachment behavior might play a role in the dysfunction in social behavior displayed by autistic infants. Here we show that neonatal gastrin-releasing peptide receptor (GRPR) blockade induces a reduction in maternal odor preference, a task involving attachment behavior, in infant rats. These findings provide the first evidence that the GRPR regulates odor preference, supporting the view that the GRPR is involved in attachment and social behaviors., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

Increased levels of iron in brain regions have been reported in neurodegenerative disorders as well as in normal brain aging. We have previously demonstrated that neonatal iron loading induces cognitive impairment in adult rats. Here, we evaluate the effects of neonatal iron treatment on cognition in aged rats. We also investigated the effects of a late subchronic rosuvastatin treatment on iron- and age-induced cognitive deficits. Rats received vehicle or 10.0mg/kg Fe(2+) orally at postnatal days 12-14. When animals reached the age of 23 months, they received daily intraperitoneal injections of saline or rosuvastatin (0.2 or 2.0mg/kg) for 21 days. Twenty-four hours after the last injection, they were submitted to novel object recognition training. Retention test sessions were performed 1.5 and 24h after training, in order to assess short-term and long-term memory, respectively. Results indicated that aged animals that received iron in the neonatal period showed more severe memory deficits than vehicle-treated ones, suggesting that iron potentiates age-associated memory impairments. Rosuvastatin improved recognition memory deficits associated with iron loading and aging, providing evidence that statins may be considered for the treatment of age-associated cognitive decline.

Abnormally high levels of iron are observed in the brain of patients suffering from neurodegenerative disorders. The mechanisms involved in iron accumulation in neurodegenerative disorders remain poorly understood. In the present study we investigated the effects of aging and neonatal iron overload on the mRNA expression of proteins critically involved in controlling iron homeostasis. Wistar rat pups received a single daily dose of vehicle or iron (10 mg/kg of b.w. of Fe(2+)), at postnatal days 12-14. The expression of Transferrin Receptor (TfR), H-Ferritin, and IRP2 were analyzed by a semi-quantitative reverse transcriptase polymerase chain reaction assay in cortex, hippocampus and striatum of rats sacrificed at three different ages (15-day-old; 90-day-old and 2-year old rats). Results indicate that TfR, H-ferritin, and IRP2 mRNA expression was differentially affected by aging and by neonatal iron treatment in all three brain regions. These findings might have implications for the understanding of iron homeostasis misregulation associated with neurodegenerative disorders.