RESUMO
There is much biochemical evidence, but very few studies in animal models of stroke in vivo, to suggest that Ginkgo biloba (EGb 761) may offer neuroprotection against regional, ischemic brain damage; additional investigations are needed to ensure future clinical trials. This study reports the effects of EGb 761 given acutely or chronically before ischemia. Rats were subjected to middle cerebral artery occlusion (MCAO) for 2 h and the brain infarct size was assessed 24 h later. Dipyrone (100 mg/kg, i.p.) was injected 30 min before ischemia, and 2.5 and 5.5 h after ischemia, to reduce ischemia-induced fever. EGb 761 (Tebonin) was given acutely (200 mg/kg, p.o., 60 min before ischemia) or chronically (100 mg/kg, p.o., once daily, for 14 days before ischemia). Acute or chronic treatment with EGb 761, either alone or in combination with dipyrone, did not reduce the infarct size compared with saline alone (p > 0.05). Dipyrone failed to prevent ischemia-induced fever during the intra-ischemic period (p > 0.05 vs saline; p < 0.001 vs sham). In the reperfusion phase, dipyrone reduced fever to normothermic levels in the group treated acutely with EGb 761 (p < 0.01 vs saline, p > 0.05 vs sham) but not after chronic EGb 761 (p < 0.01 vs sham), indicating possible pharmacokinetic interaction. In conclusion, within the context of unprevented, ischemia-induced fever, the present results demonstrate that EGb 761 has no significant effect on brain infarct size.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Infarto da Artéria Cerebral Média/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Extratos Vegetais/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Isquemia Encefálica/complicações , Dipirona/uso terapêutico , Febre/tratamento farmacológico , Febre/etiologia , Ginkgo biloba , Masculino , Fitoterapia , Ratos , Ratos WistarRESUMO
Permanent, 3-stage, 4-vessel occlusion (4-VO) was evaluated as a practicable model of progressive, cerebral hypoperfusion in rats, resulting in quantifiable, reproducible, neuronal damage within a time interval shorter than that described in the 2-VO model. The effect of permanent and graded 4-VO on cognition was also evaluated using the newly developed, aversive radial maze. The vertebral arteries (VA) plus the common carotid arteries (CCA) or internal carotid arteries (ICA) were progressively and permanently occluded, following different experimental sequences (CCA--> VA; VA-->CCA-->CCA or VA-->ICA-->ICA) with inter-stage intervals ranging from 1 to 4 weeks. Only two of four groups subjected to 2-stage 4-VO (CCA-->VA) showed modest reduction in the number of normal-appearing CA1 pyramidal cells, despite the significant treatment effect (p < 0.001-0.01 versus sham). A high rate of mortality (63.8%) was associated with 2-stage 4-VO. More pronounced and consistent neuronal damage occurred 8 weeks after 3-stage 4-VO, following the sequence VA --> CCA --> CCA (p < 0.001). One month after this schedule, profound, persistent cognitive impairment was demonstrated in the aversive radial maze (p < 0.01-0.0001). This behavioral effect was not manifested when the ICA, rather than the CCA, were occluded, despite the presence of significant, although less severe, hippocampal lesioning. The mortality rate was significantly reduced when 3-stage 4-VO was used (p < 0.0001). These consistent, histological and behavioral effects, combined with a low mortality rate, suggest that permanent, 3-stage 4-VO may represent a reliable animal model of chronic, progressive, cerebral hypoperfusion.
Assuntos
Comportamento Animal/fisiologia , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Circulação Cerebrovascular/fisiologia , Animais , Dano Encefálico Crônico/mortalidade , Dano Encefálico Crônico/patologia , Dano Encefálico Crônico/fisiopatologia , Isquemia Encefálica/mortalidade , Contagem de Células/métodos , Modelos Animais de Doenças , Progressão da Doença , Masculino , Aprendizagem em Labirinto/fisiologia , Mortalidade , Análise Multivariada , Neurônios/patologia , Ratos , Tempo de Reação , Fatores de TempoRESUMO
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.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Hipóxia Encefálica/tratamento farmacológico , Transtornos da Memória/tratamento farmacológico , Tacrolimo/uso terapêutico , Animais , Isquemia Encefálica/patologia , Hipóxia Encefálica/patologia , Masculino , Transtornos da Memória/patologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/patologia , Ratos , Ratos Wistar , Tacrolimo/farmacologiaRESUMO
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.