Antioxidant extract counteracts the effects of aging on cortical spreading depression and oxidative stress in the brain cortex

Abstract Purpose: To investigate the effects of Murici extract on the brain excitability-dependent phenomenon known as cortical spreading depression (CSD) and on brain oxidative stress. Methods: Adult and aged Wistar rats were supplemented with murici extract (150 mg/kg/day or 300 mg/kg/day) by gavage for fifteen days. Afterwards, the animals were submitted to a CSD electrophysiological recording and to brain oxidative stress evaluation. Results: Our results showed that aging decreased CSD propagation velocity, catalase activity and glutathione/oxidized glutathione ratio (GSH/GSSG) in the brain cortex of the rats, and increased malondialdehyde (MDA) concentrations and superoxide dismutase (SOD) activity. The highest dose (300 mg/kg/day) of murici extract accelerated CSD, whereas the lowest (150mg/kg/day) decelerated, in both adult and aged animals. In contrast, aged animals supplemented with murici extract in both doses presented low MDA levels and high GSG/GSSG ratio in comparison to the control-aged animals. Conclusion: Murici extract supplementation seems to revert detrimental effects in aged brains and could be considered as a strategy in the treatment of pathologies related to aging and cortical spreading depression.

Brimonidine tartrate effect on retinal spreading depression depends on Müller cells / O efeito do tartarato de brimonidina sobre a depressão alastrante retiniana depende das células de Müller

Objective: Demonstrate the Brimonidine effect over Retinal Spreading Depression (SD). Brimonidine is an alpha-2–adrenergic receptor agonist, used in the management of glaucoma. Alpha2-agonists have been shown to be neuroprotective in various experimental models, however the molecular and cellular targets leading to these actions are still poorly defined. The SD of neuronal electric activity is a wave of cellular massive sustained depolarization that damages the nervous tissue. Local trauma, pressure, ischemic injuries and other chemical agents as high extracellular potassium concentration or glutamate, can trigger SD, leading to exaggerated focal electrical followed by an electrical silence. Methods: Using chicken retina as model, we performed alpha2-receptor detection by Western Blotting and Immunohistochemistry. After that we obtained electrical signals of SD by microelectrodes on retina in the absence or presence of Brimonidine. For in vivo visualization we observed retina with optical coherence tomography on normal state, with SD passing, and with SD + Brimonidine. Results: Our data demonstrated that: (1) alpha2-adrenergic receptors are present in Müller cells, (2) the treatment with Brimonidine decreases the SD‘s velocity as well as the voltage of SD waves and (3) OCT revealed that SD creates a hyper reflectance at inner plexiform layer, but on retinal treatment with brimonidine, SD was not visualized. Conclusions: Our study about brimonidine possible pathways of neuroprotection we observed it reduces SD (a neuronal damage wave), identified a new cellular target – the Müller cells, as well as, firstly demonstrated SD on OCT, showing that the inner plexiform layer is the main optically affected layer on SD. .

Objetivo: Demonstrar o efeito do Tartarato de Brimonidina, um alfa2-agonista usado no manejo do glaucoma, sobre a depressão alastrante (DA) retiniana. Esses agonistas têm demonstrado ser neuroprotetores em vários modelos experimentais, contudo seus alvos celulares e moleculares continuam indefinidos. A DA da atividade elétrica neuronal é uma onda de despolarização celular massiva e sustentada que leva ao dano no tecido nervoso. Trauma local, pressão, isquemia e outros agentes químicos como o aumento do potássio extracelular e o glutamato podem disparar a DA, levando a uma atividade elétrica exagerada seguida de silêncio elétrico. Métodos: Usando a retina de pinto como modelo, realizamos a detecção do alfa2-receptor por Western Blotting e ensaio Imunohistoquímico. Após isso, obtivemos os sinais elétricos da DA através de microeletrodos inseridos na retina durante sua passagem na presença ou ausência de Brimonidina. Para visualização do tecido utilizamos o tomógrafo de coerência optica (OCT), analisando como é a retina no seu estado de repouso, durante a passagem da DA, e a DA + brimonidina. Resultados: Nossos dados demonstraram que: (1) os receptores alfa adrenérgicos presentes na retina são do subtipo-2A e estão localizados nas células de Müller; (2) o tratamento com Brimonidina diminui a velocidade e a voltagem da onda de DA; (3) A OCT demonstrou que a DA retiniana possui um sinal óptico de maior reflectância na camada plexiforme interna, fato não observado quando foi associada à Brimonidina. Conclusão: A Brimonidina foi capaz de reduzir a DA (uma onda de lesão neuronal) e identificamos um novo possível alvo celular – a célula de Müller e demonstramos pela primeira vez uma OCT da DA, visualizando a camada plexiforme interna como a mais afetada opticamente pelo fenômeno. .

Depressão alastrante cortical em ratos adultos tratados com L-arginina durante o aleitamento / Cortical spreading depression in adult rats treated with L-arginine during lactation

Como um precursor essencial para a síntese de moléculas proteícas com grande importância biológica, a arginina apresenta marcável versatilidade metabólica e regulatória. O Óxido Nítrico (NO), gerado a partir da arginina exerce papel multifuncional no sistema nervoso, incluindo modulação da liberação de neurotransmissores, regulação do fluxo sanguíneo local cerebral e plasticidade sináptica. Estudo recente tem sugerido que a sinalização mediada pelo óxido está envolvida na depressão alastrante cortical (DA; Wang et al., Neuropharmacol. 44:949-957, 2003). Nós investigamos em ratos o efeito da administração de L-arginina (ARG) combinado ao estado nutricional, durante o período do aleitamento, na propagação da depressão alastrante crtical (DA), em ratos adultos. Ratos Wistar foram amentados em ninhadas de 6 ou 12 filhotes por mãe (respectivamente N6 e N12). Nesse período os filhotes receberam, por gavagem, ou solução contendo o aminoácido ARG (5, 10, 20 mg/dia respectivamente, durante a primeira, segunda e terceira semana de tratamento) ou água destilada (C). Os pesos corporais foram obtidos nos dias 7/14/21/25/30/60/90 e no dia do registro eletrofisiológico. Os animais foram submetidos ao registro da DA, por 4 horas, quando tornaram-se adultos (90-110 dias). A DA foi deflagrada a cada 20 min pela aplicação de KCI a 2 por cento, por 1 min, na região do córtex frontal, e registrada durante 4 horas em 2 pontos do córtex parietal, através do eletrocorticograma e da variação lenta de voltagem (VLV) que acompanha a DA. Ao final do registro, foram determinados os pesos encefálicos úmidos. Os animais N12 apresentaram pesos corporais e encefálicos menores e velocidades menores e velocidades da DA maiores do que os respectivos grupos N6. Aos 90 dias de vida, os animais ARG-N6 apresentaram pesos corporais estatisticamente superiores aos dos grupos HIS-N6 e C-N6...

Diferential effect of changes in blood glucose levels on the velocity of propagation of cortical spreading depression in normal and malnourished rats

The effects of intravenous glucose (1ml,40% solution) and insulin (1.5-3U/Kg in 0.2-0.4 ml Ringer solution) on the velocity of propagation (VP) of cortical spreading depression (SD) were studied in 36 well-nourished (W) and 25 malnourished (M) adult (90 days old) Wistar rats of both sexes. Blood levels, measured 40-70 min after glucose, were increased by 330% in the W group (N = 18) and by 202.9% in the M rats (N=12), when compared to the pre-injection levels. Insulin decreased it by 43.5% and 61.2% in W and M rats, respectively (N=13). In the W rats, SD VP decreased after glucose and increased after insulin. The effect of glucose could not be attributed to increases in blood osmolarity, since iv mannitol (1 ml, 20% solution, N = 5) failed to decrease SD VP. The mean ñ SEM VP before and after the treatments were as follows (in mm/min): W rats, glucose 3.31 ñ 0.16 and 3.11 ñ 0.13; insulin 3.50 ñ 0.12 and 3.81 ñ 0.11; mannitol 3.53 ñ 0.46 and 3.92 ñ 0.48. In the M rats, the above effects on SD were not seen (SD VP: glucose 3.89 ñ 0.20 and 4.13 ñ 0.24; insulin 3.51 ñ 0.19 and 3.63 ñ 0.17). The results suggest that changes in the production of brain energy influence SD propagation

The effect of diphenylhydantoin on spreading depression

The present study examines the effect of diphenylhydantoin on the elicitation by K+ and propagation of spreading depression in chick retina preparations in vitro. A dose-related decrease in the velocity of propagation was observed, this effect being lessened by increasing the pH of the Ringer bathing the preparation. Changes in Ringer C1- concentration also altered the efficacy of the drug, higher concentrations enhancing and lower concentrations reducing efficacy. The threshold concentration of K+ necessary to elicit the reaction was elevated by dyphenylhydantoin

Extracellular Ca2+ and retinal spreading depression

The present study focuses on the influence of changes in extracellular Ca2+ on retinal spreading depression in vitro. It shows that changes in Ca2+ concentration alter the speed of the reaction. This effects is more pronounced for variations occuring within limits close to the physiological concentration level. The experiments also indicate that if the tissue is initially exposed to a lowered extracellular Ca2+ concentration, then the effects of transient variation in Ca2+ are significantly enhanced. Finally, a synergistic action of Ca2+ and K+ is observed with respect to the spreading of the reaction

Apomorphine does not mimic the effects of rem-sleep deprivation on cortical spreading depression

The propagation of cortical spreading depression (SD) and the incidence of "spontaneous" SD were enhanced in rats after rapid-eye-movement sleep deprivation (REMD) as compared to control animals. Pseudo-deprived rats were similar to controls, suggesting that the facilitatory effect on SD is due to REMD rather than to the stress accompanying deprivation. In control rats, apomorphine (0.5 to 8 mg/kg) failed to reproduce the effects of REMD and also failed to enhance the REMD effects in deprived rats, suggesting that the dopaminergic system does not play an important role in propagation of cortical SD