RESUMO
Neuroblasts from the subventricular zone (SVZ) migrate to striatum following stroke, but most of them die in the ischaemic milieu and this can be related to exacerbated microglial activation. Here, we explored the effects of the non-steroidal anti-inflammatory indomethacin on microglial activation, neuronal preservation and neuroblast migration following experimental striatal stroke in adult rats. Animals were submitted to endothelin-1 (ET-1)-induced focal striatal ischaemia and were treated with indomethacin or sterile saline (i.p.) for 7 days, being perfused after 8 or 14 days. Immunohistochemistry was performed to assess neuronal loss (anti-NeuN), microglial activation (anti-Iba1, ED1) and migrating neuroblasts (anti-DCX) by counting NeuN, ED1 and DCX-positive cells in the ischaemic striatum or SVZ. Indomethacin treatment reduced microglia activation and the number of ED1+ cells in both 8 and 14 days post injury as compared with controls. There was an increase in the number of DCX+ cells in both SVZ and striatum at the same survival times. Moreover, there was a decrease in the number of NeuN+ cells in indomethacin-treated animals as compared with the control group at 8 days but not after 14 days post injury. Our results suggest that indomethacin treatment modulates microglia activation, contributing to increased neuroblast proliferation in the SVZ and migration to the ischaemic striatum following stroke.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Corpo Estriado/efeitos dos fármacos , Indometacina/administração & dosagem , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Isquemia Encefálica/induzido quimicamente , Isquemia Encefálica/patologia , Proliferação de Células/efeitos dos fármacos , Corpo Estriado/patologia , Proteína Duplacortina , Endotelina-1/toxicidade , Humanos , Ventrículos Laterais/efeitos dos fármacos , Ventrículos Laterais/patologia , Microglia/efeitos dos fármacos , Microglia/patologia , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/patologia , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Ratos , Acidente Vascular Cerebral/induzido quimicamente , Acidente Vascular Cerebral/patologiaRESUMO
We explored whether the modulation of microglia activation with minocycline is beneficial to the therapeutic actions of bone marrow mononuclear cells (BMMCs) transplanted after experimental stroke. Male Wistar adult rats were divided in four experimental groups: ischemic control saline treated (G1, N = 6), ischemic minocycline treated (G2, N = 5), ischemic BMMC treated (G3, N = 5), and ischemic minocycline/BMMC treated (G4, N = 6). There was a significant reduction in the number of ED1+ cells in G3 animals (51.31 ± 2.41, P < 0.05), but this effect was more prominent following concomitant treatment with minocycline (G4 = 29.78 ± 1.56). There was conspicuous neuronal preservation in the brains of G4 animals (87.97 ± 4.27) compared with control group (G1 = 47.61 ± 2.25, P < 0.05). The behavioral tests showed better functional recovery in animals of G2, G3, and G4, compared with G1 and baseline (P < 0.05). The results suggest that a proper modulation of microglia activity may contribute to a more permissive ischemic environment contributing to increased neuroprotection and functional recovery following striatal ischemia.
Assuntos
Transplante de Medula Óssea , Isquemia Encefálica/terapia , Microglia/efeitos dos fármacos , Minociclina/uso terapêutico , Acidente Vascular Cerebral/terapia , Animais , Células da Medula Óssea/metabolismo , Isquemia Encefálica/induzido quimicamente , Isquemia Encefálica/tratamento farmacológico , Células Cultivadas , Endotelina-1 , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Microglia/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Ratos , Ratos Wistar , Recuperação de Função Fisiológica , Acidente Vascular Cerebral/induzido quimicamente , Acidente Vascular Cerebral/tratamento farmacológicoRESUMO
Operant response rate changes within the course of a typical free-operant experimental session. These changes are orderly, and reliably demonstrated with subjects from different species, responding under different experimental conditions. Killeen (1995) postulated that the response rate changes are a function of the interplay between arousal and satiation and offered a mathematical model for this hypothesis. Here we analyze Killeen's model, demonstrating that, although solid in its principles, it presents some flaws in its implementation. Then, based on the same principles, we build and test a new model of within-session motivation dynamics. We also demonstrate that, by representing arousal as a variable that ranges between 0 and 1, we can obtain a surprisingly simple model of free-operant response rate.