Daytime-Restricted Feeding Ameliorates Oxidative Stress by Increasing NRF2 Transcriptional Factor in the Rat Hippocampus in the Pilocarpine-Induced Acute Seizure Model.

Seizure-mediated oxidative stress is a crucial mechanism in the pathophysiology of epilepsy. This study evaluated the antioxidant effects of daytime-restricted feeding (DRF) and the role of the Nrf2 signaling pathway in a lithium-pilocarpine model seizure model that induces status epilepticus (SE). We performed a lipoperoxidation assay and dihydroethidium fluorescence to measure oxidative stress markers in the hippocampus (malondialdehyde and reactive oxygen species). The protein content of Nrf2 and its downstream protein SOD2 was evaluated using Western blotting. The cellular distribution of the Nrf2 and SOD2 proteins in the pyramidal cell layer of both the CA1 and CA3 hippocampal subfields and astrocytes (GFAP marker) were quantified using immunofluorescence and immunohistochemistry, respectively. Our results indicate that DRF reduced the malondialdehyde levels and the production of reactive oxygen species. Furthermore, a significant increase in Nrf2 and SOD2 protein content was observed in animals subjected to restrictive diet. In addition, DRF increased the relative intensity of the Nrf2 fluorescence in the perinuclear and nuclear compartments of pyramidal neurons in the CA1 subfield. Nrf2 immunoreactivity and the astrocyte marker GFAP also increased their colocalization under DRF conditions. Additionally, SOD2 immunoreactivity was increased in CA1 pyramidal neurons but not in the CA3 region. Our findings suggest that DRF partially prevents oxidative stress by increasing the Nrf2 transcriptional factor and the SOD2 enzyme during the development of SE.

Circadian modulation of microglial physiological processes and immune responses.

Microglia is considered the central nervous system (CNS) resident macrophages that establish an innate immune response against pathogens and toxins. However, the recent studies have shown that microglial gene and protein expression follows a circadian pattern; several immune activation markers and clock genes are expressed rhythmically without the need for an immune stimulus. Furthermore, microglia responds to an immune challenge with different magnitudes depending on the time of the day. This review examines the circadian control of microglia function and the possible physiological implications. For example, we discuss that synaptic prune is performed in the cortex at a certain moment of the day. We also consider the implications of daily microglial function for maintaining biological rhythms like general activity, body temperature, and food intake. We conclude that the developmental stage, brain region, and pathological state are not the only factors to consider for the evaluation of microglial functions; instead, emerging evidence indicates that circadian time as an essential aspect for a better understanding of the role of microglia in CNS physiology.

Sucrose Consumption during Late Adolescence Impairs Adult Neurogenesis of the Ventral Dentate Gyrus without Inducing an Anxiety-like Behavior.

Sucrose consumption impairs behavioral and cognitive functions that correlate with decreased neurogenesis in animal models. When consumed during early adolescence, this disaccharide promotes anxious and depressive behaviors, along with a reduction in the generation of new neurons in the dentate gyrus of the hippocampus. Data concerning sucrose consumption during late adolescence are lacking, and the effect of sucrose intake on the ventral dentate gyrus of the hippocampus (which modulates anxiety and depression) remains elusive. Here, we tested whether sucrose intake during late adolescence causes anxiety or impaired neurogenesis in the ventral dentate gyrus. Rats did not display anxiety-like behaviors neither at the light−dark box test nor at the open field exploration. However, there was a significant increase in proliferative cells in the subgranular zone of the ventral dentate gyrus in rats exposed to sucrose (p < 0.05). This increased proliferation corresponded to neural stem cells (Radial Type 1 cells) in the group exposed to sucrose until adulthood but was not present in rats exposed to sucrose only during late adolescence. Remarkably, the phosphorylation of ERK1/2 kinases was increased in the hippocampi of rats exposed to sucrose only during late adolescence, suggesting that the increased proliferation in this group could be mediated by the MAPK pathway. On the other hand, although no differences were found in the number of immature granular neurons, we observed more immature granular neurons with impaired dendritic orientation in both groups exposed to sucrose. Finally, GAD65/67 and BCL2 levels did not change between groups, suggesting an unaltered hippocampal GABAergic system and similar apoptosis, respectively. This information provides the first piece of evidence of how sucrose intake, starting in late adolescence, impacts ventral dentate gyrus neurogenesis and contributes to a better understanding of the effects of this carbohydrate on the brain at postnatal stages.

Diabetes Induces Permanent Deleterious Effects in the Olfactory Bulb Associated with Increased Tyrosine Hydroxylase Expression and ERK1/2 Phosphorylation.

Diabetes mellitus type 2 (T2D) complications include brain damage which increases the risk of neurodegenerative diseases and dementia. An early manifestation of neurodegeneration is olfactory dysfunction (OD), which is also presented in diabetic patients. Previously, we demonstrated that OD correlates with IL-1ß and miR-146a overexpression in the olfactory bulb (OB) on a T2D rodent model, suggesting the participation of inflammation on OD. Here, we found that OD persists on a long-term T2D condition after the downregulation of IL-1ß. Remarkably, OD was associated with the increased expression of the dopaminergic neuronal marker tyrosine hydroxylase, ERK1/2 phosphorylation, and reduced neuronal activation on the OB of diabetic rats, suggesting the participation of the dopaminergic tone on the OD derived from T2D. Dopaminergic neurons are susceptible in neurodegenerative diseases such as Parkinson's disease; therefore further studies must be performed to completely elucidate the participation of these neurons and ERK1/2 signaling on olfactory impairment.

Aberrant Connection Formation and Glia Involvement in the Progression of Pharmacoresistant Mesial Temporal Lobe Epilepsy.

Epilepsy is the most common chronic neurological disease, affecting approximately 65 million people worldwide, with mesial temporal lobe epilepsy (mTLE) being the most common type, characterized by the presence of focal seizures that begin in the hippocampus, and subsequently generalize to structures such as the cerebral cortex. It is estimated that approximately 40% of patients with mTLE develop drug resistance (DR), whose pathophysiological mechanisms remain unclear. The neuronal network hypothesis is one attempt to understand the mechanisms underlying resistance to antiepileptic drugs (AEDs), since recurrent seizure activity generates excitotoxic damage and activation of neuronal death and survival pathways that, in turn, promote the formation of aberrant neuronal networks. This review addresses the mechanisms that are activated, perhaps as compensatory mechanisms in response to the neurological damage caused by epileptic seizures, but that affect the formation of aberrant connections that allow the establishment of inappropriate circuits. On the other hand, glia seems to have a relevant role in post-seizure plasticity, thus supporting the hypothesis of the neuronal network in drug-resistant epilepsy, which has been proposed for ELT.

Protein expression of P-glycoprotein in neocortex from patients with frontal lobe epilepsy.

Frontal lobe epilepsy (FLE) is the second most frequent type of epilepsy and the surgical outcome depends on the etiology. For instance, patients with posttraumatic FLE (PTE) have a worse surgical outcome compared to patients with FLE related to a tumoral lesion (TL). The present study focuses to determine if the FLE etiology is associated with the P-glycoprotein (P-gp) expression, a condition associated with drug resistance. P-gp expression and cellular localization were determined by Western Blot and immunohistochemical experiments in cortical brain samples obtained from patients with PTE (n = 5), TL (n = 5), and autopsies (n = 5). The neuronal count was estimated by Nissl and stereology procedure. Results showed that the autopsies tissue showed a neuronal count of 3514 ± 304.2 neurons per mm3. The P-gp expression ratio was 0.33 ± 0.02. Its expression was found in endothelial cells. Negligible P-gp expression was detected in neurons and astrocytes. Compared to the autopsies group, the TL group showed no changes in the neuronal count but, there was a decreased P-gp expression ratio (46%, p < 0.05). P-gp was located mainly in neurons, slight in astroglial, and endothelial cells. The PTE group showed a similar P-gp expression ratio compared to the autopsies group. P-gp was expressed in neurons, astrocytes, and endothelial cells in these samples. However, experiments revealed a high P-gp expression in a lower neuronal count (38%, p < 0.05 vs autopsy group). The present study reveals that patients with PTE present neuronal P-gp overexpression. This finding could underlie their worst surgical outcome.

Regulation of Metabolic Health by an "Olfactory-Hypothalamic Axis" and Its Possible Implications for the Development of Therapeutic Approaches for Obesity and T2D.

The olfactory system is responsible for the reception, integration and interpretation of odors. However, in the last years, it has been discovered that the olfactory perception of food can rapidly modulate the activity of hypothalamic neurons involved in the regulation of energy balance. Conversely, the hormonal signals derived from changes in the metabolic status of the body can also change the sensitivity of the olfactory system, suggesting that the bidirectional relationship established between the olfactory and the hypothalamic systems is key for the maintenance of metabolic homeostasis. In the first part of this review, we describe the possible mechanisms and anatomical pathways involved in the modulation of energy balance regulated by the olfactory system. Hence, we propose a model to explain its implication in the maintenance of the metabolic homeostasis of the organism. In the second part, we discuss how the olfactory system could be involved in the development of metabolic diseases such as obesity and type two diabetes and, finally, we propose the use of intranasal therapies aimed to regulate and improve the activity of the olfactory system that in turn will be able to control the neuronal activity of hypothalamic centers to prevent or ameliorate metabolic diseases.

MCP-1 Signaling Disrupts Social Behavior by Modulating Brain Volumetric Changes and Microglia Morphology.

Autism spectrum disorder (ASD) is a disease characterized by reduced social interaction and stereotypic behaviors and related to macroscopic volumetric changes in cerebellar and somatosensory cortices (SPP). Epidemiological and preclinical models have confirmed that a proinflammatory profile during fetal development increases ASD susceptibility after birth. Here, we aimed to globally identify the effect of maternal exposure to high-energy dense diets, which we refer to as cafeteria diet (CAF) on peripheral and central proinflammatory profiles, microglia reactivity, and volumetric brain changes related to assisting defective social interaction in the mice offspring. We found a sex-dependent effect of maternal exposure to CAF diet or inoculation of the dsARN mimetic Poly (I:C) on peripheral proinflammatory and social interaction in the offspring. Notably, maternal exposure to CAF diet impairs social interaction and favors an increase in anxiety in male but not female offspring. Also, CAF diet exposure or Poly (I:C) inoculation during fetal programming promote peripheral proinflammatory profile in the ASD-diagnosed male but not in females. Selectively, we found a robust accumulation of the monocyte chemoattractant protein-1 (MCP-1) in plasma of ASD-diagnosed males exposed to CAF during fetal development. Biological assessment of MCP-1 signaling in brain confirms that systemic injection of MCP-1-neutralizing antibody reestablished social interaction and blocked anxiety, accompanied by a reduction in cerebellar lobule X (CbX) volume and an increase volume of the primary somatosensory (SSP) cortex in male offspring. These data highlight the contribution of diet-dependent MCP-1 signaling on volumetric brain changes and microglia morphology promoting ASD-like behavior in male mice.

Deficiency in the Essential Amino Acids l-Isoleucine, l-Leucine and l-Histidine and Clinical Measures as Predictors of Moderate Depression in Elderly Women: A Discriminant Analysis Study.

Increases in depression are common in some elderly women. Elderly women often show moderate depressive symptoms, while others display minimal depressive symptoms. These discrepancies have produced contradictory and inconclusive outcomes, which have not been explained entirely by deficits in neurotransmitter precursors. Deficiency in some amino acids have been implicated in major depression, but its role in non-clinical elderly women is not well known. An analysis of essential amino acids, depression and the use of discriminant analysis can help to clarify the variation in depressive symptoms exhibited by some elderly women. The aim was to investigate the relationship of essential amino acids with affective, cognitive and comorbidity measures in elderly women without major depression nor severe mood disorders or psychosis, specifically thirty-six with moderate depressive symptoms and seventy-one with minimal depressive symptoms. The plasma concentrations of nineteen amino acids, Beck Depression Inventory (BDI) scores, Geriatric Depression Scale (GDS) scores, global cognitive scores and comorbidities were submitted to stepwise discriminant analysis to identify predictor variables. Seven predictors arose as important for belong to the group based on amino acid concentrations, with the moderate depressive symptoms group characterized by higher BDI, GDS and cognitive scores; fewer comorbidities; and lower levels of l-histidine, l-isoleucine and l-leucine. These findings suggest that elderly women classified as having moderate depressive symptoms displayed a deficiency in essential amino acids involved in metabolism, protein synthesis, inflammation and neurotransmission.

Effects of time-of-day on the concentration of defined excitatory and inhibitory amino acids in the cerebrospinal fluid of rats: a microdialysis study.

Amino acid neurotransmitters are responsible for many physiological and pathological processes, and their cerebral concentrations respond to external influences such as the light-dark cycle and to the synthesis, release, and recapture rhythms and form part of the biochemical relationships derived from excitatory-inhibitory (E/I), glutamine-glutamate sum (GLX), glutamatergic processing (glutamine-glutamate ratio) and excitotoxic indexes. The changes in these variables during a 24-h period (1 day) are important because they allow organisms to adapt to external stimuli and form part of physiological processes. Under pathological conditions, the damage produced by acute events may depend on diurnal variations. Therefore, it is important to analyze the extracellular levels of amino acids as well as the above-mentioned indexes over a 24-h period. We focused on determining the cerebrospinal fluid levels of different amino acid neurotransmitters, and the E/I, GLX, glutamatergic processing and excitotoxic indexes, determined by microdialysis over a 24-h cycle. Our results showed significant changes during the 24-h light/dark cycle. Specifically, we found increments in the levels of glutamate (325%), GABA (550%), glutamine (300%), glycine (194%), alanine (304%) and the GLX index (263%) throughout the day, and the maximum levels of glutamate, glutamine, glycine, and alanine were obtained during the last period of the light period. In conclusion, the concentration of some amino acid neurotransmitters and the GLX index show variations depending on the light-dark cycle.

Protective effects of intracerebroventricular adiponectin against olfactory impairments in an amyloid ß1-42 rat model.

BACKGROUND: Alzheimer's disease (AD) is characterized by cognitive impairment that eventually develops into dementia. Amyloid-beta (Aß) accumulation is a widely described hallmark in AD, and has been reported to cause olfactory dysfunction, a condition considered an early marker of the disease associated with injuries in the olfactory bulb (OB), the hippocampus (HIPP) and other odor-related cortexes. Adiponectin (APN) is an adipokine with neuroprotective effects. Studies have demonstrated that APN administration decreases Aß neurotoxicity and Tau hyperphosphorylation in the HIPP, reducing cognitive impairment. However, there are no studies regarding the neuroprotective effects of APN in the olfactory dysfunction observed in the Aß rat model. The aim of the present study is to determine whether the intracerebroventricular (i.c.v) administration of APN prevents the early olfactory dysfunction in an i.c.v Amyloid-beta1-42 (Aß1-42) rat model. Hence, we evaluated olfactory function by using a battery of olfactory tests aimed to assess olfactory memory, discrimination and detection in the Aß rat model treated with APN. In addition, we determined the number of cells expressing the neuronal nuclei (NeuN), as well as the number of microglial cells by using the ionized calcium-binding adapter molecule 1 (Iba-1) marker in the OB and, CA1, CA3, hilus and dentate gyrus (DG) in the HIPP. Finally, we determined Arginase-1 expression in both nuclei through Western blot. RESULTS: We observed that the i.c.v injection of Aß decreased olfactory function, which was prevented by the i.c.v administration of APN. In accordance with the olfactory impairment observed in i.c.v Aß-treated rats, we observed a decrease in NeuN expressing cells in the glomerular layer of the OB, which was also prevented with the i.c.v APN. Furthermore, we observed an increase of Iba-1 cells in CA1, and DG in the HIPP of the Aß rats, which was prevented by the APN treatment. CONCLUSION: The present study describes the olfactory impairment of Aß treated rats and evidences the protective role that APN plays in the brain, by preventing the olfactory impairment induced by Aß1-42. These results may lead to APN-based pharmacological therapies aimed to ameliorate AD neurotoxic effects.

Expression of VEGF- and tight junction-related proteins in the neocortical microvasculature of patients with drug-resistant temporal lobe epilepsy.

The blood-brain barrier (BBB) maintains the optimal microenvironment for brain function. Tight junctions (TJs) allow endothelial cells to adhere to each other, leading to the formation of a barrier that prevents the penetration of most molecules via transcellular routes. Evidence has indicated that seizure-induced vascular endothelial growth factor (VEGF) type 2 receptor (VEGFR-2) pathway activation weakens TJs, inducing vasodilatation and increasing vascular permeability and subsequent brain injury. The present study focused on investigating the expression levels of VEGF-related (VEGF-A and VEGFR-2) and TJ-related proteins (claudin-5, occludin and ZO-1) in the neocortical microvasculature of patients with drug-resistant temporal lobe epilepsy (TLE). The results obtained from hippocampal sclerosis TLE (HS-TLE) patients were compared with those obtained from patients with TLE secondary to lesions (lesion-TLE) and autopsy samples. The Western blotting and immunofluorescence results showed that VEGF-A and VEGFR-2 protein expression levels were increased in HS-TLE and lesion-TLE patients compared to autopsy group. On the other hand, claudin-5 expression was higher in HS-TLE patients and lesion-TLE patients than autopsies. The expression level of occludin and ZO-1 was decreased in HS-TLE patients. Our study described modifications to the integrity of the BBB that may contribute to the pathogenesis of TLE, in which the VEGF system may play an important role. We demonstrated that the same modifications were present in both HS-TLE and lesion-TLE patients, which suggests that seizures modify these systems and that they are not associated with the establishment of epilepsy.

Olfactory Dysfunction in Diabetic Rats is Associated with miR-146a Overexpression and Inflammation.

Type 2 diabetes (T2D) is associated with cognitive decline and dementia. Both neurodegenerative conditions are characterized by olfactory dysfunction (OD) which is also observed in diabetic patients. Diabetes and neurodegeneration display altered miRNAs expression; therefore, the study of miRNAs in the diabetic olfactory system is important in order to know the mechanisms involved in neurodegeneration induced by T2D. In this work we evaluated the expression of miRs206, 451, 146a and 34a in the olfactory bulb (OB) of T2D rats and its association with OD. T2D induction was performed by administering streptozotocin to neonatal rats. The olfactory function was evaluated after reaching the adulthood by employing the buried pellet and social recognition tests. After 18 weeks, animals were sacrificed to determinate miRNAs and protein expression in the OB. T2D animals showed a significant increase in the latency to find the odor stimulus in the buried pellet test and a significant reduction in the interest to investigate the novel juvenile subjects in the social recognition test, indicating OD. In miRNAs analysis we observed a significant increase of miR-146a expression in the OB of T2D rats when compared to controls. This increase in miR-146a correlated with the overexpression of IL-1ß in the OB of T2D rats. The present results showed that OD in T2D rats is associated with IL-1ß mediated-inflammation and miR-146a overexpression, suggesting that high levels of IL-1ß could trigger miR-146a upregulation as a negative feedback of the inflammatory response in the OB of T2D rats.

Endocannabinoid System and Cannabinoid 1 Receptors in Patients With Pharmacoresistant Temporal Lobe Epilepsy and Comorbid Mood Disorders.

Experimental evidence points out that the activation of the endocannabinoid system induces neuroprotective effects and reduces mood disorders. In the hippocampus of patients with mesial temporal lobe epilepsy (MTLE), studies indicated augmented cannabinoid 1 receptor (CB1R) binding, in spite of its low mRNA and protein expressions. Although this situation suggests an enhanced CB1R-induced neurotransmission in patients with MTLE, especially those with pharmacoresistant seizures, which present important neuronal damage and high comorbid mood disorders. The present study focused to investigate the status of CB1R and the endocannabinoid system by obtaining CB1R-induced G-protein signaling efficacy and measuring the tissue levels of endocannabinoids in the hippocampus and the temporal neocortex of patients with pharmacoresistant MTLE. Furthermore, the obtained results were correlated with comorbid anxiety and depression. The experiments revealed that patients with MTLE present increased CB1R-induced G-protein signaling efficacy (Emax) as well as an augmented tissue content of anandamide and oleoylethanolamine and low 2-arachidonoylglycerol. Some of these changes were more evident in patients with MTLE without mood disorders. The current findings indicate that pharmacoresistant MTLE is associated with increased CB1R-induced transductional mechanisms as well as augmented tissue content of specific endocannabinoids in the hippocampus and the temporal neocortex. The enhanced endocannabinoid neurotransmission may be involved in the absence of comorbid mood disorders in some patients with MTLE.

National panorama of adolescent pregnancy in Mexico: lessons learned in a six-year period.

Globally, adolescent pregnancy constitutes a serious public health problem of a multifactorial nature. Specifically for women, it entails various educational, economic and social implications that affect their life project and widen the social gaps in this age group. Furthermore, adolescent girls are more vulnerable because of the health risk involved with pregnancy at a younger age. According to the World Health Organization, "the probability of maternal death is twice as high in adolescents in comparison with women aged between 20 and 30 years, and for those younger than 15 years, the risks are five times higher". In general, adolescents are in great need for education on sexual and reproductive health issues, which should be aimed at increasing information and knowledge about correct use and access to modern contraceptive methods, as well as at demystifying fears and beliefs around their possible side effects. Ensuring proper counseling with trained personnel is equally vital. Public institutions have a social responsibility to support efforts aimed at preventing adolescent pregnancy, based on relevant lines of action and health policies.

En el mundo, el embarazo adolescente constituye un grave problema de salud pública de índole multifactorial. Específicamente para la mujer conlleva diversas implicaciones educativas, económicas y sociales que afectan su proyecto de vida y amplían las brechas sociales en este grupo etario. Asimismo, las adolescentes son más vulnerables por el riesgo en salud que implica un embarazo a corta edad; según la Organización Mundial de la Salud, "la probabilidad de muerte materna es dos veces más en las adolescentes respecto a las mujeres que se encuentran entre los 20 y 30 años de edad, y para las menores de 15 años los riesgos son cinco veces mayores". En general, las y los adolescentes experimentan una gran necesidad de educación en temas sobre salud sexual y reproductiva, la cual debe dirigirse al aumento de información y conocimientos sobre el uso correcto y acceso a métodos anticonceptivos modernos, así como a desmitificar los temores y creencias en torno a sus posibles efectos secundarios. Asegurar una consejería adecuada y con personal capacitado es igualmente vital. Las instituciones públicas tienen la responsabilidad social de respaldar los esfuerzos encaminados a prevenir el embarazo adolescente, con base en las líneas de acción y políticas sanitarias.