Vanessa Athaíde Garcia

Memantine reduces oxidative damage and enhances long-term recognition memory in aged rats

Many neurodegenerative diseases, including Alzheimers (AD), Parkinsons (PD) and Huntingtons diseases (HD), are caused by different mechanisms but may share a common pathway to neuronal injury as a result of the overstimulation of glutamate receptors. It has been suggested that this pathway can be involved in generation of cognitive deficits associated with normal aging. Previous studies performed in our laboratory have demonstrated that aged rats presented recognition memory deficits. The aim of the present study was to evaluate the effect of memantine, a low-affinity N-methyl-D-aspartate (NMDA) receptor antagonist, on age-induced recognition memory deficits. Additionally, parameters of oxidative damage in cerebral regions related to memory formation were evaluated. In order to do that, male Wistar rats (24 months old) received daily injections of saline solution or memantine (20 mg/kg i.p.) during 21 days. The animals were submitted to a novel object recognition task 1 week after the last injection. Memantine-treated rats showed normal recognition memory while the saline group showed long-term recognition memory deficits. The results show that memantine is able to reverse age-induced recognition memory deficits. We also demonstrated that memantine reduced the oxidative damage to proteins in cortex and hippocampus, two important brain regions involved in memory formation. Thus, the present findings suggest that, at least in part, age-induced cognitive deficits are related to oxidative damage promoted by NMDA receptor overactivation.

Modulatory influence of dopamine receptors on consolidation of object recognition memory.

The role of dopamine receptors in regulating the formation of recognition memory remains poorly understood. Here we show the effects of systemic administration of dopamine receptor agonists and antagonists on the formation of memory for novel object recognition in rats. In Experiment I, rats received an intraperitoneal (i.p.) injection of vehicle, the selective D1 receptor agonist SKF38393 (1.0 and 5.0mg/kg), or the D2 receptor agonist quinpirole (1.0 and 5.0mg/kg) immediately after training. In Experiment II, rats received an injection of vehicle, the dopamine receptor antagonist SCH23390 (0.1 and 0.05 mg/kg), or the D2 receptor antagonist raclopride (0.5 and 0.1mg/kg) before training, followed by an injection of vehicle or the nonselective dopamine receptor agonist apomorphine (0.05 mg/kg) immediately after training. SKF38393 at 5mg/kg produced an enhancement of novel object recognition memory measured at both 24 and 72 h after training, whereas the dose of 10mg/kg impaired 24-h retention. Posttraining administration of quinpirole did not affect 24-h retention. Apomorphine enhanced memory in rats given pretraining raclopride, suggesting that the effect was mediated by selective activation of D1 receptors. The results indicate that activation of D1 receptors can enhance recognition memory consolidation. Importantly, pharmacological activation of D1 receptors enhanced novel object recognition memory even under conditions in which control rats showed significant retention.

Posttraining systemic administration of the histone deacetylase inhibitor sodium butyrate ameliorates aging-related memory decline in rats

Here we show that a systemic injection of the histone deacetylase inhibitor (HDACi) sodium butyrate (NaB) ameliorated an aging-associated deficit in object recognition memory in rats when the injection was given immediately, but not 6h after training. NaB had no effect in younger rats with normal memory retention. The results indicate that HDACis can ameliorate aging-related memory impairments by influencing the early consolidation phase of memory formation.

Amelioration of recognition memory impairment associated with iron loading or aging by the type 4-specific phosphodiesterase inhibitor rolipram in rats

Increasing evidence indicates that iron deposition in the brain might play a role in cognitive dysfunction associated with neurodegenerative disorders and aging. Previous studies have not examined whether iron-induced memory deficits can be attenuated by acute treatments with memory-enhancing agents. Phosphodiesterase type 4 (PDE4) inhibitors such as rolipram (ROL) ameliorate memory impairments in several rodent models of amnesia and have been proposed as candidate cognitive-enhancing drugs. Here we show that a single posttraining systemic injection of ROL dose-dependently attenuates the impairment of memory for novel object recognition (NOR) in rats given neonatal iron loading, a model of iron-induced cognitive impairment. Posttraining administration of ROL also recovered NOR deficits associated with aging in rats. These findings provide the first evidence that stimulation of an intracellular second messenger signaling pathway can attenuate iron-induced memory impairment, and support the view that PDE4 inhibitors might ameliorate cognitive dysfunction associated with aging and neurodegenerative disorders.

Reversion of age-related recognition memory impairment by iron chelation in rats.

It is now generally accepted that iron accumulates in the brain during the ageing process. Increasing evidence demonstrate that iron accumulation in selective regions of the brain may generate free radicals, thereby possessing implications for the etiology of neurodegenerative disorders. In a previous study we have reported that aged rats present recognition memory deficits. The aim of the present study was to evaluate the effect of desferoxamine (DFO), an iron chelator agent, on age-induced memory impairment. Aged Wistar rats received intraperitoneal injections of saline or DFO (300mg/kg) for 2 weeks. The animals were submitted to a novel object recognition task 24h after the last injection. DFO-treated rats showed normal recognition memory while the saline group showed long-term recognition memory deficits. The results show that DFO is able to reverse age-induced recognition memory deficits. We also demonstrated that DFO reduced the oxidative damage to proteins in cortex and hippocampus. Thus, the present findings provide the first evidence that iron chelators might prevent age-related memory dysfunction.

Adrenergic enhancement of consolidation of object recognition memory

Extensive evidence indicates that epinephrine (EPI) modulates memory consolidation for emotionally arousing tasks in animals and human subjects. However, previous studies have not examined the effects of EPI on consolidation of recognition memory. Here we report that systemic administration of EPI enhances consolidation of memory for a novel object recognition (NOR) task under different training conditions. Control male rats given a systemic injection of saline (0.9% NaCl) immediately after NOR training showed significant memory retention when tested at 1.5 or 24, but not 96h after training. In contrast, rats given a post-training injection of EPI showed significant retention of NOR at all delays. In a second experiment using a different training condition, rats treated with EPI, but not SAL-treated animals, showed significant NOR retention at both 1.5 and 24-h delays. We next showed that the EPI-induced enhancement of retention tested at 96h after training was prevented by pretraining systemic administration of the beta-adrenoceptor antagonist propranolol. The findings suggest that, as previously observed in experiments using aversively motivated tasks, epinephrine modulates consolidation of recognition memory and that the effects require activation of beta-adrenoceptors.

Selegiline protects against recognition memory impairment induced by neonatal iron treatment.

Excess of iron in the brain has been implicated in the pathogenesis of several human neurodegenerative diseases, for example Alzheimers disease and Parkinsons disease. It has been shown that the neonatal period is critical for the establishment of normal iron content in the adult brain. Moreover, it is known that aging alters the cerebral distribution of this metal. We have recently described that neonatal administration of iron severely impaired novel object recognition memory in rats. The aim of the present study was to determine whether selegiline, a monoamine oxidase (MAO) inhibitor known for its neuroprotective properties, could protect rats against cognitive impairment induced by neonatal administration of iron. In the first experiment, male Wistar rats received vehicle (5% sorbitol in water) or iron (10.0 mg/kg) orally from postnatal days 12 to 14 and saline (0.9% NaCl) or selegiline (1.0 or 10.0 mg/kg) intraperitoneally for 21 days, starting 24 h before the first iron dosing. In the second experiment, rats were given either vehicle or iron (10.0 mg/kg) orally from postnatal days 12 to 14 followed by saline or selegiline (1.0 or 10.0 mg/kg) intraperitoneally for 21 days, starting when rats reached adulthood (50th day after birth). Iron-treated rats given selegiline in both doses showed no deficits in recognition memory. Rats receiving iron but no selegiline presented memory deficits. This is the first study reporting the reversion of iron-induced memory impairment, supporting the view that our model can be considered as a useful tool in the search for new drugs with neuroprotective and/or memory enhancing properties.

Memory impairment induced by brain iron overload is accompanied by reduced H3K9 acetylation and ameliorated by sodium butyrate.

Iron accumulation in the brain has been associated to the pathogenesis of neurodegenerative disorders. We have previously demonstrated that iron overload in the neonatal period results in severe and persistent memory deficits in adult rats. Alterations in histone acetylation have been associated with memory deficits in models of neurological disorders. Here we examine histone acetylation in the brain and the effects of the histone deacetylase inhibitor (HDACi) sodium butyrate (NaB) on memory in the neonatal iron overload model in rats. Rats received vehicle or 30.0-mg/kg Fe⁺² orally at postnatal days 12-14. When animals reached adulthood, they were given training in either novel object recognition or inhibitory avoidance. Histone acetylation in the dorsal hippocampus and the effects of NaB were examined in separate sets of rats. Iron overload led to a reduction in H3 lysine 9 acetylation in the hippocampus, without affecting the acetylation of other H3 and H4 lysine residues. A single systemic injection of NaB (1.2 g/kg) immediately after training ameliorated iron-induced memory impairments. The results suggest that a reduction in H3K9 acetylation might play a role in iron-induced memory impairment and support the view that HDACis can rescue memory dysfunction in models of brain disorders.

Impairments of social behavior and memory after neonatal gastrin-releasing peptide receptor blockade in rats: Implications for an animal model of neurodevelopmental disorders

The gastrin-releasing peptide receptor (GRPR) has been implicated in central nervous system (CNS) diseases, including neurodevelopmental disorders associated with autism. In the present study we examined the effects of GRPR blockade during the neonatal period on behavioral measures relevant to animal models of neurodevelopmental disorders. Male Wistar rats were given an intraperitoneal (i.p.) injection of either saline (SAL) or the GRPR antagonist [D-Tpi(6), Leu(13) psi(CH(2)NH)-Leu(14)] bombesin (6-14) (RC-3095; 1 or 10mg/kg) twice daily for 10days from postnatal days (PN) 1 to 10. Animals treated with RC-3095 showed pronounced deficits in social interaction when tested at PN 30-35 and impaired 24-h retention of memory for both novel object recognition (NOR) and inhibitory avoidance (IA) tasks tested at PN 60-71. Neither short-term memory tested 1.5h posttraining nor open field behavior were affected by neonatal GRPR blockade. The implications of the findings for animal models of neurodevelopmental disorders are discussed.

Reversal of age-associated memory impairment by rosuvastatin in rats

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.