The Evaluation of Folic Acid-Deficient or Folic Acid-Supplemented Diet in the Gestational Phase of Female Rats and in Their Adult Offspring Subjected to an Animal Model of Schizophrenia.

Although folic acid (FA) supplementation is known to influence numerous physiological functions, especially during pregnancy, little is known about its direct effects on the mothers' health. However, this vitamin is essential for the health of the mother and for the normal growth and development of the fetus. Thus, the aim of this study was (1) to evaluate the cognitive effects and biochemical markers produced by the AIN-93 diet (control), the AIN-93 diet supplemented with different doses of FA (5, 10, and 50 mg/kg), and a FA-deficient diet during pregnancy and lactation in female mother rats (dams) and (2) to evaluate the effect of maternal diets on inflammatory parameters in the adult offspring which were subjected to an animal model of schizophrenia (SZ) induced by ketamine (Ket). Our study demonstrated through the Y-maze test that rats subjected to the FA-deficient diet showed significant deficits in spatial memory, while animals supplemented with FA (5 and 10 mg/kg) showed no deficit in spatial memory. Our results also suggest that the rats subjected to the FA-deficient diet had increased levels of carbonylated proteins in the frontal cortex and hippocampus and also increased plasma levels of homocysteine (Hcy). Folate was able to prevent cognitive impairments in the rats supplemented with FA (5 and 10 mg/kg), data which may be attributed to the antioxidant effect of the vitamin. Moreover, FA prevented protein damage and elevations in Hcy levels in the rats subjected to different doses of this vitamin (5, 10, and 50 mg/kg). We verified a significant increase of the anti-inflammatory cytokine (interleukin-4 (IL-4)) and a reduction in the plasma levels of proinflammatory cytokines (interleukin-6 (IL-6)) and TNF-α) in the dams that were subjected to the diets supplemented with FA (5, 10, and 50 mg/kg), showing the possible anti-inflammatory effects of FA during pregnancy and lactation. In general, we also found that in the adult offspring that were subjected to an animal model of SZ, FA had a protective effect in relation to the levels of IL-4, IL-6, and TNF-α, which indicates that the action of FA persisted in the adult offspring, since FA showed a lasting effect on the inflammatory response, which was similar in both the dams and their offspring. In conclusion, the importance of supplementation with FA during pregnancy and lactation should be emphasized, not only for the benefit of the offspring but also for the health of the mother. All this is due to the considerable protective effect of this vitamin against oxidative damage, cognitive impairment, hyperhomocysteinemia, immune function, and also its ability in preventing common processes in post-pregnancy stages, as well as in reducing the risks of neurodevelopmental disorders and enhancing fetal immune development.

Lithium and memantine improve spatial memory impairment and neuroinflammation induced by ß-amyloid 1-42 oligomers in rats.

Alzheimer's disease (AD) is the most common cause of dementia in the elderly. The main hallmarks of this disease include progressive cognitive dysfunction and an accumulation of soluble oligomers of ß-amyloid (Aß) 1-42 peptide. In this research, we show the effects of lithium and memantine on spatial memory and neuroinflammation in an Aß1-42 oligomers-induced animal model of dementia in rats. Aß 1-42 oligomers were administered intrahippocampally to male wistar rats to induce dementia. Oral treatments with memantine (5mg/kg), lithium (5mg/kg), or both drugs in combination were performed over a period of 17days. 14days after the administration of the Aß1-42 oligomers, the radial arm-maze task was performed. At the end of the test period, the animals were euthanized, and the frontal cortex and hippocampus were removed for use in our analysis. Our results showed that alone treatments with lithium or memantine ameliorate the spatial memory damage caused by Aß1-42. The animals that received combined doses of lithium and memantine showed better cognitive performance in their latency time and total errors to find food when compared to the results from alone treatments. Moreover, in our study, lithium and/or memantine were able to reverse the decreases observed in the levels of interleukin (IL)-4 that were induced by Aß1-42 in the frontal cortex. In the hippocampus, only memantine and the association of memantine and lithium were able to reverse this effect. Alone doses of lithium and memantine or the association of lithium and memantine caused reductions in the levels of IL-1ß in the frontal cortex and hippocampus, and decreased the levels of TNF-α in the hippocampus. Taken together, these data suggest that lithium and memantine might be a potential therapy against cognitive impairment and neuroinflammation induced by Aß1-42, and their association may be a promising alternative to be investigated in the treatment of AD-like dementia.

The Anti-Inflammatory Role of Minocycline in Alzheimer´s Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder where the main risk factor is age, since its incidence increases dramatically after the age of 60. It is the most common form of dementia, and is accompanied by memory loss and cognitive impairment. Although AD was discovered over a century ago, the only drugs approved by the US Food and Drug Administration for use in its treatment are four cholinesterase inhibitors and memantine. However, these drugs are not fully effective in the treatment of AD. Therefore, the incessant search for new methods of treating AD continues, with the hope of improving both the effectiveness of therapies and the quality of life for patients suffering with AD. Current evidence suggests that the antibiotic minocycline could be a potential therapeutic drug for use in the treatment of AD due to its anti-neuroinflammatory effects. Minocycline is a tetracycline derivative that combines an anti-inflammatory property that is capable of crossing the blood brain barrier with neuroprotective properties that work by limiting inflammation and oxidative stress. Several studies have established the presence of inflammatory markers in the brains of patients suffering with AD, including elevated levels of cytokines/chemokines and microgliosis in damaged regions. Cytokines have been associated with increased tau phosphorylation and decreased levels of synaptophysin, establishing their roles in the cytoskeletal and synaptic alterations that take place in AD. Therefore, pharmacological approaches that allow for the discovery and development of new anti-inflammatory agents such as minocycline will be welcomed in the continuing struggle against AD. Considering these facts, this review will discuss the anti-inflammatory mechanisms underlying the neuroprotective effects of minocycline as a novel therapeutic approach for the treatment of AD.