Coumestrol pre-treatment improves spatial learning and memory deficits following transient cerebral ischemia recruiting hippocampal GluR2 AMPA receptors.

Transient global ischemia is a leading cause of learning and memory dysfunction and induces a pattern of delayed neuronal death in the CA1 subfield of the hippocampus by down-regulating GluR2 mRNA AMPA receptors in this cerebral area. This study sought to investigate the neuroprotective effect of coumestrol against spatial memory impairment induced by global ischemia that leads to neural death by reducing the GluR2 receptors content in the hippocampal CA1 area. Our studies demonstrated that coumestrol administration prevented spatial memory deficits in mice. These findings suggest a cognitive enhancement role of coumestrol against cognitive impairment in ischemic events.

Clozapine and olanzapine but not risperidone impair the pre-frontal striatal system in relation to egocentric spatial orientation in a Y-maze.

Many studies indicate a dissociation between two forms of orientation: allocentric orientation, in which an organism orients on the basis of cues external to the organism, and egocentric spatial orientation (ESO) by which an organism orients on the basis of proprioceptive information. While allocentric orientation is mediated primarily by the hippocampus and its afferent and efferent connections, ESO is mediated by the prefronto-striatal system. Striatal lesions as well as classical neuroleptics, which block dopamine receptors, act through the prefronto-striatal system and impair ESO. The purpose of the present study was to determine the effects of the atypical antipsychotics clozapine, olanzapine and risperidone which are believed to exert its antipsychotic effects mainly by dopaminergic, cholinergic and serotonergic mechanisms. A delayed-two-alternative-choice-task, under conditions that required ESO and at the same time excluded allocentric spatial orientation was used. Clozapine and olanzapine treated rats made more errors than risperidone treated rats in the delayed alternation in comparison with the controls. Motor abilities were not impaired by any of the drugs. Thus, with regard to the delayed alternation requiring ESO, clozapine and olanzapine but not risperidone affects the prefronto-striatal system in a similar way as classical neuroleptics does.

Effects of thyroid hormones on memory and on Na(+), K(+)-ATPase activity in rat brain.

Thyroid hormones (THs), including triiodothyronine (T3) and tetraiodothyronine (T4), are recognized as key metabolic hormones of the body. THs are essential for normal maturation and function of the mammalian central nervous system (CNS) and its deficiency, during a critical period of development, profoundly affects cognitive function. Sodium-potassium adenosine 5'-triphosphatase (Na(+), K(+)-ATPase) is a crucial enzyme responsible for the active transport of sodium and potassium ions in the CNS necessary to maintain the ionic gradient for neuronal excitability. Studies suggest that Na(+), K(+)-ATPase might play a role on memory formation. Moreover, THs were proposed to stimulate Na(+), K(+)-ATPase activity in the heart of some species. In this work we investigated the effect of a chronic administration of L-thyroxine (L-T4) or propylthiouracil (PTU), an antithyroid drug, on some behavioral paradigms: inhibitory avoidance task, open field task, plus maze and Y-maze, and on the activity of Na(+), K(+)-ATPase in the rat parietal cortex and hippocampus. By using treatments which have shown to induce alterations in THs levels similar to those found in hyperthyroid and hypothyroid patients, we aimed to understand the effect of an altered hyperthyroid and hypothyroid state on learning and memory and on the activity of Na(+), K(+)-ATPase. Our results showed that a hyper and hypothyroid state can alter animal behavior and they also might indicate an effect of THs on learning and memory.

Effects of an acute treatment with L-thyroxine on memory, habituation, danger avoidance, and on Na+, K+ -ATPase activity in rat brain.

Thyroid hormones (THs) have a relevant action on brain development and maintenance. By using an acute treatment to induce a hyperthyroid animal model, we aimed at investigating the effect of an altered THs levels on learning and memory and on the activity of Na(+), K(+)-ATPase in the rat brain. Our results have shown that the acute treatment with L-T4 did not alter the retrieval of the inhibitory avoidance task, but had a significant effect on the elevated plus maze and on open-field performance in rats. We suggest that animals subjected to L-T4 administration improved the habituation to a novel environment as well as a better evaluation of a dangerous environment, respectively. Na(+), K(+)-ATPase activity is increased in parietal cortex (30%), but it is not altered in hippocampus in L-T4 treated group. These both brain structures are involved in memory processing and it was previously demonstrated that there is a double dissociation between them for spatial location information, perceptual and episodic memory. We propose the hypothesis that this increase of Na(+), K(+)-ATPase activity in parietal cortex may be correlated to our results in behavior tests, which suggest a role of THs as well as of the Na(+), K(+)-ATPase in the cognitive process.

Coumestrol treatment prevents Na+, K+ -ATPase inhibition and affords histological neuroprotection to male rats receiving cerebral global ischemia.

OBJECTIVE: In this study, we investigated the possible mechanisms underlying the neuroprotective effects of coumestrol, a potent isoflavonoid with antioxidant activities and binding affinities for both estrogen receptors (ER) ER-alpha and ER-beta that are comparable to those of 17beta-estradiol, in a model of global ischemia in male subjects. METHODS: Wistar rats underwent global ischemia (10 minutes) or sham surgery and received a single intracerebroventricular (icv) infusion of 20 µg of coumestrol or vehicle 1 hour before ischemia or 0, 3, 6, or 24 hours after reperfusion. RESULTS: The data analysis revealed an extensive neuronal death in the CA1 hippocampal subfield at 7 days, and a significant decrease in the Na+, K+ -ATPase activity at 1 and 24 hours after ischemia, and both injuries were attenuated by coumestrol administration. CONCLUSIONS: Coumestrol treatment was effective in preventing neuronal loss in all times of administration as well as able to rescue the Na+, K+ -ATPase activity, suggesting its potential benefits for either prevention or therapeutics use against cerebral ischemia in males.