RESUMO
Recently we provided data showing that amygdala stimulation can ameliorate spatial memory impairments in rats with lesion in the fimbria-fornix (FF). The mechanisms for this improvement involve early gene expression and synthesis of BDNF, MAP-2, and GAP43 in the hippocampus and prefrontal cortex. Now we have studied which brain structures are activated by the amygdala using c-Fos as a marker of neural activation. First, we studied neuronal activation after tetanic stimulation to the amygdala in intact rats. We then carried out a second study in FF-lesioned rats in which the amygdala was stimulated 15 min after daily spatial memory training in the water maze. Our results showed that amygdala stimulation produces widespread brain activation, that includes cortical, thalamic, and brain stem structures. Activation was particularly intense in the dentate gyrus and the prefrontal cortex. Training in the water maze increased c-Fos positive nuclei in the dentate gyrus of the hippocampus and in medial prefrontal cortex. Amygdala stimulation to trained FF-lesioned rats induced an increase of neural activity in the dentate gyrus and medial prefrontal cortex relative to the FF-lesioned, but not stimulated group, like the c-Fos activity seen in trained control rats. Based on these and previous results we explain the mechanisms of amygdala reinforcement of neural plasticity and the partial recovery of spatial memory deficits.
Assuntos
Tonsila do Cerebelo/fisiologia , Excitabilidade Cortical , Fórnice/fisiologia , Transtornos da Memória/terapia , Memória Espacial , Tonsila do Cerebelo/fisiopatologia , Animais , Estimulação Encefálica Profunda/métodos , Fórnice/metabolismo , Fórnice/fisiopatologia , Masculino , Neurônios/metabolismo , Neurônios/fisiologia , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos WistarRESUMO
We originally reported that an ethyl-acetate fraction (EAF) of Trichilia catigua prevented the impairment of water maze learning and hippocampal neurodegeneration after transient global cerebral (TGCI) in mice. We extended that previous study by evaluating whether T. catigua (i) prevents the loss of long-term retrograde memory assessed in the aversive radial maze (AvRM), (ii) confers hippocampal and cortical neuroprotection, and (iii) mitigates oxidative stress and neuroinflammation in rats that are subjected to the four vessel occlusion (4-VO) model of TGCI. In the first experiment, naive rats were trained in the AvRM and then subjected to TGCI. The EAF was administered orally 30min before and 1h after TGCI, and administration continued once per day for 7days post-ischemia. In the second experiment, the EAF was administered 30min before and 1h after TGCI, and protein carbonylation and myeloperoxidase (MPO) activity were assayed 24h and 5days later, respectively. Retrograde memory performance was assessed 8, 15, and 21days post-ischemia. Ischemia caused persistent retrograde amnesia, and this effect was prevented by T. catigua. This memory protection (or preservation) persisted even after the treatment was discontinued, despite the absence of histological neuroprotection. Protein carbonyl group content and MPO activity increased around 43% and 100%, respectively, after TGCI, which were abolished by the EAF of T. catigua. The administration of EAF did not coincide with the days of memory testing. The data indicate that antioxidant and/or antiinflammatory actions in the early phase of ischemia/reperfusion contribute to the long-term antiamnesic effect of T. catigua.
Assuntos
Amnésia Retrógrada/tratamento farmacológico , Amnésia Retrógrada/etiologia , Isquemia Encefálica/complicações , Inflamação/tratamento farmacológico , Inflamação/etiologia , Meliaceae/química , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/uso terapêutico , Animais , Biomarcadores/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Extratos Vegetais/química , RatosRESUMO
A series of our previous studies demonstrated that fish oil (FO), equivalent to 300mg/kg docosahexahenoic acid (DHA), facilitates memory recovery after transient, global cerebral ischemia (TGCI) in the aversive radial maze (AvRM). The present study sought to address two main issues: (i) whether the memory-protective effect of FO that has been observed in the AvRM can be replicated in the passive avoidance test (PAT) and object location test (OLT) and (ii) whether FO at doses that are lower than those used previously can also prevent TGCI-induced memory loss. In Experiment 1, naive rats were trained in the PAT, subjected to TGCI (4-vessel occlusion model), and tested for retrograde memory performance 8 and 15days after ischemia. Fish oil (300mg/kg/day DHA) was given orally for 8days. The first dose was delivered 4h postischemia. In Experiment 2, the rats were subjected to TGCI, treated with the same FO regimen, and then trained and tested in the OLT. In Experiment 3, the rats were trained in the AvRM, subjected to TGCI, administered FO (100, 200, and 300mg/kg DHA), and tested for memory performance up to 3weeks after TGCI. At the end of the behavioral tests, the brains were examined for neurodegeneration and neuroblast proliferation. All of the behavioral tests (PAT, OLT, and AvRM) were sensitive to ischemia, but only the AvRM was able to detect the memory-protective effect of FO. Ischemia-induced neurodegeneration and neuroblast proliferation were unaffected by FO treatment. These results suggest that (i) the beneficial effect of FO on memory recovery after TGCI is task-dependent, (ii) doses of FO<300mg/kg DHA can protect memory function in the radial maze, and (iii) cognitive recovery occurs in the absence of neuronal rescue and/or hippocampal neurogenesis.
Assuntos
Óleos de Peixe/farmacologia , Hipocampo/efeitos dos fármacos , Ataque Isquêmico Transitório/tratamento farmacológico , Transtornos da Memória/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Complexo Nuclear Basolateral da Amígdala/patologia , Modelos Animais de Doenças , Hipocampo/patologia , Ataque Isquêmico Transitório/complicações , Ataque Isquêmico Transitório/patologia , Ataque Isquêmico Transitório/psicologia , Masculino , Transtornos da Memória/etiologia , Transtornos da Memória/patologia , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/psicologia , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Ratos Wistar , Recuperação de Função Fisiológica/fisiologia , Memória Espacial/efeitos dos fármacos , Memória Espacial/fisiologiaRESUMO
4-Hydroxy-3-methoxy-acetophenone (apocynin) is a naturally occurring methoxy-substitute catechol that is isolated from the roots of Apocynin cannabinum (Canadian hemp) and Picrorhiza kurroa (Scrophulariaceae). It has been previously shown to have antioxidant and neuroprotective properties in several models of neurodegenerative disease, including cerebral ischemia. The present study investigates the effects of apocynin on transient global cerebral ischemia (TGCI)-induced retrograde memory deficits in rats. The protective effects of apocynin on neurodegeneration and the glial response to TGCI are also evaluated. Rats received a single intraperitoneal injection of apocynin (5 mg/kg) 30 min before TGCI and were tested 7, 14, and 21 days later in the eight-arm aversive radial maze (AvRM). After behavioral testing, the hippocampi were removed for histological evaluation. The present results confirm that TGCI causes memory impairment in the AvRM and that apocynin prevents these memory deficits and attenuates hippocampal neuronal death in a sustained way. Apocynin also decreases OX-42 and glial fibrillary acidic protein immunoreactivity induced by TGCI. These findings support the potential role of apocynin in preventing neurodegeneration and cognitive impairments following TGCI in rats. The long-term protective effects of apocynin may involve inhibition of the glial response.
Assuntos
Acetofenonas/uso terapêutico , Hipocampo/metabolismo , Ataque Isquêmico Transitório/metabolismo , Transtornos da Memória/metabolismo , Neuroglia/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Acetofenonas/farmacologia , Animais , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Hipocampo/efeitos dos fármacos , Ataque Isquêmico Transitório/tratamento farmacológico , Ataque Isquêmico Transitório/psicologia , Masculino , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/psicologia , Neuroglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos WistarRESUMO
We previously reported that the phosphodiesterase-5 (PDE5) inhibitor sildenafil prevented neurodegeneration but not learning deficits in middle-aged rats that were subjected to the permanent, three-stage, four-vessel occlusion/internal carotid artery (4-VO/ICA) model of chronic cerebral hypoperfusion (CCH). In the present study, we examined whether the PDE3 inhibitor cilostazol alleviates the loss of long-term memory (i.e., retrograde amnesia) caused by CCH. The effect of sildenafil was then compared to cilostazol. Naive rats (12-15 months old) were trained in a non-food-rewarded eight-arm radial maze and subjected to CCH. One week later, retrograde memory was assessed for 5 weeks. Cilostazol (50mg/kg, p.o.) was administered for 42 days or 15 days, beginning approximately 45 min after the first occlusion stage. Sildenafil (3mg/kg, p.o.) was similarly administered for 15 days only. Histological examination was performed after behavioral testing. Chronic cerebral hypoperfusion caused persistent retrograde amnesia, which was reversed by cilostazol after both short-term and long-term treatment. This antiamnesic effect of cilostazol was sustained throughout the experiment, even after discontinuing treatment (15-day treatment group). This effect occurred in the absence of neuronal rescue. Sildenafil failed to prevent CCH-induced retrograde amnesia, but it reduced hippocampal cell death. Extending previous findings from this laboratory, we conclude that sildenafil does not afford memory recovery after CCH, despite its neuroprotective effect. In contrast, cilostazol abolished CCH-induced retrograde amnesia, an effect that may not depend on histological neuroprotection. The present data suggest that cilostazol but not sildenafil represents a potential strategy for the treatment of cognitive sequelae associated with CCH.