Neurodegeneração crônica após a isquemia focal transitória em ratos: efeitos da hipertermia sobre o destino da zona de penumbra / Chronic neurodegenaration following focal brain ischemia in rats: effects ofhyperthermia in the destiny of ischemic penumbra

A hipertermia vem se mostrando um fator de grande importância clínica quando relacionado ao acidente vascular encefálico (AVE), visto que os estudos clínicos apontam para uma piora da evolução clínica e maior mortalidade de pacientes vitimados pelo AVC sob condições de hipertermia. Devido à relevância clínica dessa questão, o presente estudo investigou os efeitos agudos e crônicos da hipertermia ambiental iniciada precoce ou tardiamente. Ratos Wistar machos foram submetidos à 60 minutos de oclusão da artéria cerebral média. Na primeira fase do estudo, os animais foram submetidos à 6 horas de hipertermia ou normotermia iniciada imediatamente após a reperfusão, seguidos de sobrevida de 7 dias e 2 meses. Na segunda fase, os animais foram submetidos à hipertermia de 2 horas iniciada 2 horas, 6 horas ou 24 horas após a reperfusão, com sobrevidas de 7 dias e 2 meses. Na terceira fase de experimentos, os animais foram submetidos à hipertermia de 2 horas iniciada imediatamente após a reperfusão, ou hipertermia de 6 horas iniciada 2 horas, 6 horas ou 24 horas após a reperfusão. Nesta fase as sobrevidas programadas foram de 7 dias, 2 meses e 6 meses. Os efeitos da hipertermia pós-isquêmica foram avaliados segundo parâmetros histopatológicos. A extensão da lesão foi efetuada através da quantificação da porcentagem de tecido cortical e subcortical remanescente no hemisfério infartado ao nível de -0,30 mm em relação ao Bregma. A porcentagem de tecido remanescente (não infartado) foi calculada através de regra de três simples considerando-se a média das áreas cortical e subcortical do hemisfério contralateral (não infartado) como equivalente a 100 por cento. Os resultados histopatológicos observados demonstram que a hipertermia de 6 horas, quando iniciada 24 horas após a reperfusão promove uma diminuição significativa na área de tecido remanescente cortical nos animais com sobrevida de 6 meses (63,26 ± 11,97 por cento), quando comparados ao animais com sobrevida de 2 meses (94,97 ± 5,02 por cento). Esses dados obtidos sob tais condições experimentais corroboram com a hipótese de que a hipertermia pode desempenhar um papel importante na perpetuação do estresse oxidativo que ocorre após a recirculação, podendo levar à instalação de um processo neurodegenerativo crônico auto-sustentado

Effect of tacrolimus (FK506) on ischemia-induced brain damage and memory dysfunction in rats.

The behavioral and neurohistological protective effects of tacrolimus (FK506) were examined in rats subjected to 15-min global forebrain ischemia. Learning and memory performance were evaluated in an aversive, non-food-motivated, eight-arm radial maze. In one experiment, naive rats were rendered ischemic, and 15 days later they were tested for acquisition of a spatial task (postoperative training). In a complementary experiment, rats were trained for 8 days and then subjected to ischemia (preoperative training); 15 days later (on Day 24 of testing) they were retested for retention of cognition. FK506 (1.0 mg/kg) was given intravenously at the beginning of reperfusion, followed by doses applied intraperitoneally 6, 24, 48 and 72 h postischemia. Behavioral performance was expressed by latency to find the goal box, and number of errors. Ischemia did not affect acquisition performance. In contrast, retention of cognition was markedly impaired by ischemia, particularly working memory (P<.05-.001). This ischemia-induced, retrograde amnesia was significantly reduced by FK506 compared to vehicle alone on Day 24, as measured by latency and working memory errors (P<.025). A neuroprotective effect of FK506 was also seen on working memory, when postischemic performance was compared to that prior to ischemia (P>.05, Day 24 vs. Day 8, paired samples), in contrast to the significant, retrograde amnesia found in the ischemic, vehicle-treated group (P<.01). FK506 also significantly reduced the extent of hippocampal CA1 cell loss; however, this effect did not correlate with behavior. The present results suggest that the histological, neuroprotective effect of FK506 may be accompanied by a reduction in cognitive impairment, as assessed in a novel, non-food-motivated, eight-arm radial maze after transient, global, cerebral ischemia in rats.

A novel version of the 8-arm radial maze: effects of cerebral ischemia on learning and memory.

A novel version of the 8-arm radial maze task was developed to quantify spatial learning and memory in rats subjected to transient cerebral ischemia (TCI) using the 4-VO model. This maze uses the rat's natural behavior of avoiding open, illuminated areas, and preference for a darkened, enclosed shelter. Ischemic rats were required to escape from the central area into the darkened goal box. Ischemia was induced before or after training to examine its influence on acquisition and retention of cognition, respectively. During the acquisition test, latency of ischemic rats to find the goal box, and working memory performance were significantly impaired (P < 0.005-0.001). The performance for retention of cognition was also disrupted by ischemia (P < 0.05-0.01). There was no correlation between the degree of CA1 pyramidal cell loss and behavioral deficits. The present data reveal that the aversive version of the 8-arm radial maze is sensitive to the cognitive effects of ischemia. Since it excludes the need for food deprivation or immersion of the animal in water, the method should provide a sensitive and more practical behavioral test with which to evaluate the effects of ischemic brain damage on cognition.