RESUMO
ABSTRACTThe brain aging process triggers cognitive function impairment, such as memory loss and compromised quality of life. Cognitive impairment is based on bioenergetic status, with reduced glucose uptake and metabolism in aged brains. Anaplerotic substrates are reported to promote mitochondrial ATP generation, having been tested in clinical trials for the treatment of neurological disorders and metabolic diseases.Objectives and Methods: To assess whether the improvement in oxidative capacity ameliorates cognitive function in adults (12 weeks), and aged (22-month-old) C57/6BJ mice, they received (1) a ketogenic diet, (2) a ketogenic diet supplemented with the anaplerotic substance, triheptanoin, or (3) a control diet for 12 weeks. Spontaneous alternation and time spent in a previously closed arm in the Y-maze test and time interacting with an unknown object in the novel object recognition test (NORT) were used to evaluate working memory. Acetylcholinesterase (AChE) activity in the prefrontal lobe, brain left hemisphere, and cerebellum was also evaluated. Glucose transporter 3 (GLUT3) expression in the prefrontal lobe was analyzed by western blotting.Results: The ketogenic diet (KD) reduced spontaneous alternation in aged mice, leading to lower AChE activity in the aged prefrontal lobe and cerebellum, and in the parieto-temporal-occipital lobe of adult mice. Furthermore, KD decreased GLUT3 protein expression in the frontal lobe of the adults.Discussion: Supplementation of KD with triheptanoin prevented memory impairment and showed similar values of AChE activity and GLUT3 expression compared to the controls. Our data suggest that triheptanoin has a potential role in the bioenergetic capacity of the brain, improving cognitive function.
Assuntos
Acetilcolinesterase , Qualidade de Vida , Camundongos , Animais , Transportador de Glucose Tipo 3/metabolismo , Acetilcolinesterase/metabolismo , Triglicerídeos , Encéfalo/metabolismo , CogniçãoRESUMO
BACKGROUND: Epidemiological studies have indicated the lack of breast feeding as a risk factor associated with later development of inflammatory bowel disease. Nevertheless, the repercussion of little feeding during suckling on large intestine inflammatory response and anti-oxidant resources has not yet been completely understood. This study hypothesized that unfavorable lactation is able to induce oxidative stress and release of inflammatory mediators modifying the integrity of the colon epithelium in weanling rats. METHODS: Wistar rats were reared under different early nutritional conditions according to litter size in two groups: N6 (6 pups/dam) and N15 (15 pups/dam) until the 25th postnatal day. The distal colon was removed and processed for biochemical, morphometric, and immunohistochemical analyzes. Lipoperoxidation, nitric oxide (NO), reduced (GSH) and oxidized (GSSG) glutathione, tumor necrosis factor-alpha (TNF-α), interleukins-1ß, 4 and 10 (IL-1ß; IL-4; IL-10) levels, and total superoxide dismutase (tSOD), and catalase (CAT) activities were assessed. Morphometric analysis was carried out using paraffin sections and wholemount myenteric plexus preparations. KEY RESULTS: Increased lipoperoxidation, NO, TNF-α and IL-1b levels, reduced tSOD and increased CAT activities were found in the N15 compared to N6 group. No intergroup difference was detected for IL-10, while lower levels of IL-4, GSH and GSSG and lower neuronal size and density were induced by undernutrition. CONCLUSIONS & INFERENCES: Reduced feeding during suckling changed the inflammatory response and oxidative status in the colon of weanling rats. These data suggest potential mechanisms by which malnutrition early in life may increase the vulnerability of the large intestine to insults.
Assuntos
Colo/metabolismo , Inflamação/metabolismo , Lactação/metabolismo , Desnutrição/metabolismo , Óxido Nítrico/biossíntese , Estresse Oxidativo/fisiologia , Animais , Catalase/metabolismo , Citocinas/metabolismo , Feminino , Glutationa/metabolismo , Masculino , Ratos , Ratos WistarRESUMO
Retinocollicular connections form precise topographical maps that are normally completed through the selective elimination of misplaced axons and the stabilization of topographically ordered axon terminals during early development. Omega-3 fatty acids, acquired exclusively through the diet, and its main metabolite, docosahexaenoic acid (DHA), are involved in brain development and synaptic maturation. We have previously shown that the nutritional restriction of omega-3/DHA results in abnormal retinocollicular topographical fine-tuning. Therefore, we studied the role of omega-3 fatty acids nutritional supplementation and the developmental time windows during which this postnatal supplementation would restore normal topographical maps in the visual system. Female rats and their litters were chronically fed with either control (soy oil) or restricted omega-3 (coconut oil) diets. Fish oil supplementation was introduced between either postnatal day (PND) 7-13, PND7-28 or PND21-42. At PND13, PND28 or PND42, animals received an anterograde eye injection of a neuronal tracer to visualize retinocollicular axons. Confirming previous observations we found that an omega-3/DHA deficiency resulted in an abnormally high innervation density of retinal axons at the visual layers of the superior colliculus (SC). Although a short-term fish oil supplementation between PND7-13 could not restore normal retinocollicular topography, an extended treatment between PND7-28 completely recovered normal innervation densities of retinotectal axons. However, a late onset supplementation protocol, between PND28-42, was no longer effective in the restoration of the abnormal topographical pattern induced by an early omega-3 nutritional malnutrition. The results suggest a critical period for omega3/DHA dietary intake for the proper development of visual topographical maps.
Assuntos
Ácidos Graxos Ômega-3/administração & dosagem , Retina/crescimento & desenvolvimento , Colículos Superiores/crescimento & desenvolvimento , Vias Visuais/crescimento & desenvolvimento , Animais , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/administração & dosagem , Feminino , Ratos , Retina/citologia , Colículos Superiores/citologia , Fatores de TempoRESUMO
We investigated in young rats the effects of malnutrition on the main structures of the circadian timing system: retina, hypothalamic suprachiasmatic nuclei (SCN), thalamic intergeniculate leaflet, retinohypothalamic- and geniculohypothalamic tracts. Control rats were born from mothers fed a commercial diet since gestation, and malnourished rats from mothers fed a multideficient diet since gestation (GLA group) or lactation (LA group). After weaning, pups received the same diet as their mothers, and were analysed at postnatal days 27, 30-33 and 60-63. Brain sections were processed to visualise in the SCN neuropeptide Y immunoreactivity and terminal labeling after intraocular tracer injections. Nissl staining was used to assess cytoarchitectonic boundaries of the SCN and cell features in retinal whole mounts. Cell counts, morphometric and densitometric analysis were performed. Compared with controls, the total retinal surface was reduced and the topographical distribution of retinal ganglion cells was altered in malnourished rats, with changes in their density. Alterations were also detected in the SCN dimensions in the GLA and LA groups at one and two postnatal months, as well as in the SCN portion occupied by the retinal input in the GLA group at days 30-33, but not in the NPY-containing geniculohypothalamic tract. The present data point to subtle changes, with a low and differential vulnerability to early malnutrition, of structures involved in circadian timing regulation. Furthermore, the present findings suggest that the altered circadian rhythmicity previously documented in malnourished rats cannot be ascribed to impaired development of the retino- and geniculohypothalamic projections to the SCN.
Assuntos
Encéfalo/patologia , Corpos Geniculados/patologia , Desnutrição/patologia , Retina/patologia , Núcleo Supraquiasmático/patologia , Fatores Etários , Animais , Animais Recém-Nascidos , Peso Corporal/fisiologia , Encéfalo/citologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Contagem de Células/métodos , Tamanho Celular , Feminino , Corpos Geniculados/anatomia & histologia , Corpos Geniculados/crescimento & desenvolvimento , Corpos Geniculados/metabolismo , Imuno-Histoquímica/métodos , Lactação , Masculino , Vias Neurais/crescimento & desenvolvimento , Vias Neurais/patologia , Neurônios/metabolismo , Neurônios/patologia , Neuropeptídeo Y/metabolismo , Tamanho do Órgão/fisiologia , Ratos , Ratos Wistar , Retina/citologia , Retina/crescimento & desenvolvimento , Retina/metabolismo , Fatores Sexuais , Coloração e Rotulagem/métodos , Núcleo Supraquiasmático/crescimento & desenvolvimento , Núcleo Supraquiasmático/metabolismoRESUMO
The effects of excitatory amino acids (EAAs) upon transporter-mediated gamma-aminobutyric acid (GABA) release were investigated in cells containing tyrosine hydroxylase (TH) or nitric oxide synthase (NOS) in retina of the primate Cebus apella. Retinas were treated in vitro with 50 microM Kainate (KA) or 5 mM L-Glutamate (L-Glu), for 30 min at 37 degrees C, in an Mg2+-free Locke's solution with or without Ca2+. The effects of EAAs were measured immunocytochemically by determining the GABA content in TH or NOS-immunoreactive cells in the inner retina, after stimulation. L-Glu and KA induced a Ca2+-independent GABA release from most GABA-immunoreactive cells of the inner retina. Double label experiments indicated that this release occurs in NOS+/GABA+ cells, but not in TH+/GABA+ cells suggesting that these cell subpopulations may be differentiated in some functional aspects.
Assuntos
Ácido Glutâmico/farmacologia , Óxido Nítrico Sintase/efeitos dos fármacos , Retina/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/efeitos dos fármacos , Ácido gama-Aminobutírico/efeitos dos fármacos , Animais , Cebus , Agonistas de Aminoácidos Excitatórios/farmacologia , Ácido Caínico/farmacologia , Óxido Nítrico Sintase/metabolismo , Retina/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Ácido gama-Aminobutírico/metabolismoRESUMO
The number and topographical distribution of photoreceptors was studied in whole-mounted retinas of Cebus apella. It was estimated a total of 48 million rods and 3.8 million cones. The average peak foveal cone density and the Nyquist Limit at the foveola were estimated as 169, 127 cells/mm(2) and 46.77+/-7.98 cyc/deg, respectively. A cone-enriched rim was found near the ora serrata, more noticeable in the nasal retina. Rod distribution was asymmetrical along horizontal and vertical meridians with a higher density in the dorsal retina. The rod/cone ratio was variable and asymmetrical along both meridians.
Assuntos
Células Fotorreceptoras de Vertebrados/citologia , Retina/anatomia & histologia , Animais , Cebus , Contagem de Células , Feminino , Fóvea Central/anatomia & histologia , MasculinoRESUMO
The release of GABA from amacrine and interplexiform cells after exposure to excitatory amino acids (EAAs) agonists was investigated by immunohistochemistry. Cebus monkey retinas were treated in vitro with 50 microM kainate (KA) or 5 mM L-Glutamate (L-Glu), for 30 min at 37 degrees C. The effects of the EAAs were measured by detecting immunocytochemically the GABA remaining in the tissue after stimulation. L-Glu and KA reduced the number of GABA-immunoreactive perikarya in the innermost part of the inner nuclear layer by approximately 60% and 80%, respectively, as compared to controls. The cell processes in the inner plexiform layer (IPL) were restricted to only three defined bands in the strata 1, 3 and 5, as compared to an intense and homogeneous labeling in the IPL of the untreated retinas. The effect of KA was inhibited by 100 microM CNQX, 100 microM NNC-711, or when Na(+) was replaced by choline. The release of GABA was Ca(2+)-independent, suggesting the mobilization of GABA from the cytoplasmic pool of this neurotransmitter. At least two subsets of retinal neurons including amacrine and interplexiform cells retained GABA-immunoreactivity after stimulation with EAAs, as revealed by glutamic acid decarboxylase (GAD) immunocytochemistry. Our results suggest that non-NMDA receptor activation by KA and glutamate are associated with the efflux of GABA from cells of the inner retina (amacrine and interplexiform cells). The data also show that cells containing GAD-67 released GABA via its transporter, while cells containing exclusively GAD-65 apparently did not release the neurotransmitter by the reversal of the transporter.
Assuntos
Proteínas de Transporte/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Agonistas de Aminoácidos Excitatórios/farmacologia , Glutamato Descarboxilase/metabolismo , Isoenzimas/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Retina/efeitos dos fármacos , Retina/enzimologia , Ácido gama-Aminobutírico/metabolismo , Animais , Cálcio/farmacologia , Cebus , Contagem de Células , Células Cultivadas , Ácido Glutâmico/farmacologia , Imuno-Histoquímica , Ácido Caínico/farmacologia , Neurônios/citologia , Retina/citologia , Sódio/farmacologiaRESUMO
We have looked at the phenotypic expression of gamma-aminobutyric acid (GABA) and the two isoforms of its synthetic enzyme [glutamic acid decarboxylase (GAD)-65 and -67] in adult rat retinas that had the superior colliculus, pretectum and optic tract lesioned unilaterally at birth. It has been shown previously that this type of manipulation induces retrograde degeneration of retinal ganglion cells presumably without affecting other intraretinal neurons. We present evidence that GABAergic amacrine cells are affected by such manipulation. The number of cells immunoreactive for GABA, GAD-65 and GAD-67 decreased in the inner nuclear layer. In the retinal ganglion cell layer, however, the number of GABA- and GAD-65-labelled cells increased, while the number of GAD-67-labelled cells did not change. Biochemical assay showed that overall GAD activity was not altered in retinas of lesioned animals. Our results support the notion that, while neonatal lesion reorganizes the expression of GABA and GAD in the retina, enzyme activity is maintained within normal levels.
Assuntos
Glutamato Descarboxilase/metabolismo , Células Ganglionares da Retina/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Contagem de Células , Imuno-Histoquímica , Fenótipo , RatosRESUMO
The distribution of ganglion cell densities and sizes was studied in Nissl-stained flat-mount retinae of the two-toed sloth. The area centralis, a weak specialization with low ganglion cell density, is located in the temporal retina close to the center of the eye. The presence of a visual streak was noted. The distribution of different ganglion cell sizes was approximately equal throughout the retina. Although the retinal organization differs from that of the closely related three-toed sloth, the presumed function of retinal specializations in both species is to guide limb movements by permitting visualization of the branch along which the animal is climbing.