RESUMO
Phosphodiesterase 4 inhibitors (PDE4-I), which selectively increase cyclic adenosine monophosphate (cAMP) levels, have shown neuroprotective effects after several neurological injuries inducing blood-brain barrier (BBB) damage including local/focal cerebral ischemia. The present investigated whether roflumilast confers BBB neuroprotection in the hippocampus after transient global cerebral ischemia (TGCI) in rats. TGCI resulted in whole BBB disruption as measured by the increase of Evans blue (EB) and IgG extravasation, neurodegeneration, and downregulation of claudin-5 and endothelial nitric oxide synthase (eNOS) levels in the CA1 hippocampal subfield of ischemic rats. Roflumilast attenuated BBB disruption and restored the levels of eNOS in the CA1 hippocampal area. Moreover, roflumilast increased the levels of B2 cell lymphoma (BcL-2) and neuron-glial antigen-2 (NG2) in the CA1 subfield after global ischemia in rats. The protective effects of roflumilast against TGCI-induced BBB breakdown might involve preservation of BBB integrity, vascularization and angiogenesis, and myelin repair.
Assuntos
Isquemia Encefálica , Ataque Isquêmico Transitório , Ratos , Animais , Barreira Hematoencefálica/metabolismo , Isquemia Encefálica/metabolismo , Hipocampo/metabolismoRESUMO
Evidence for the clinical use of neuroprotective drugs for the treatment of cerebral ischemia (CI) is still greatly limited. Spatial/temporal disorientation and cognitive dysfunction are among the most prominent long-term sequelae of CI. Cannabidiol (CBD) is a non-psychotomimetic constituent of Cannabis sativa that exerts neuroprotective effects against experimental CI. The present study investigated possible neuroprotective mechanisms of action of CBD on spatial memory impairments that are caused by transient global cerebral ischemia (TGCI) in rats. Hippocampal synaptic plasticity is a fundamental mechanism of learning and memory. Thus, we also evaluated the impact of CBD on neuroplastic changes in the hippocampus after TGCI. Wistar rats were trained to learn an eight-arm aversive radial maze (AvRM) task and underwent either sham or TGCI surgery. The animals received vehicle or 10 mg/kg CBD (i.p.) 30 min before surgery, 3 h after surgery, and then once daily for 14 days. On days 7 and 14, we performed a retention memory test. Another group of rats that received the same pharmacological treatment was tested in the object location test (OLT). Brains were removed and processed to assess neuronal degeneration, synaptic protein levels, and dendritic remodeling in the hippocampus. Cannabidiol treatment attenuated ischemia-induced memory deficits. In rats that were subjected to TGCI, CBD attenuated hippocampal CA1 neurodegeneration and increased brain-derived neurotrophic factor levels. Additionally, CBD protected neurons against the deleterious effects of TGCI on dendritic spine number and the length of dendritic arborization. These results suggest that the neuroprotective effects of CBD against TGCI-induced memory impairments involve changes in synaptic plasticity in the hippocampus.
Assuntos
Canabidiol/uso terapêutico , Hipocampo/efeitos dos fármacos , Ataque Isquêmico Transitório/prevenção & controle , Plasticidade Neuronal/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Animais , Canabidiol/farmacologia , Modelos Animais de Doenças , Hipocampo/metabolismo , Hipocampo/patologia , Ataque Isquêmico Transitório/metabolismo , Ataque Isquêmico Transitório/patologia , Masculino , Plasticidade Neuronal/fisiologia , Neuroproteção/fisiologia , Técnicas de Cultura de Órgãos , Ratos , Ratos Wistar , Memória Espacial/efeitos dos fármacos , Memória Espacial/fisiologia , Sinapses/metabolismo , Sinapses/patologiaRESUMO
Phosphodiesterase 4 (PDE4) inhibitors have been shown to present beneficial effects in cerebral ischemic injury because of their ability to improve cognition and target different phases and mechanisms of cerebral ischemia, including apoptosis, neurogenesis, angiogenesis, and inflammation. The present study investigated whether repeated treatment with the PDE4 inhibitor roflumilast rescued memory loss and attenuated neuroinflammation in rats following transient global cerebral ischemia (TGCI). TGCI caused memory impairments, neuronal loss (reflected by Neuronal nuclei (NeuN) immunoreactivity), and compensatory neurogenesis (reflected by doublecortin (DCX) immunoreactivity) in the hippocampus. Also, increases in the protein expression of the phosphorylated response element-binding protein (pCREB) and inflammatory markers such as the glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule 1 (Iba-1), were detected in the hippocampus in TGCI rats. Repeated treatment with roflumilast (0.003 and 0.01 mg/kg) prevented spatial memory deficits without promoting hippocampal protection in ischemic animals. Roflumilast increased the levels of pCREB, arginase-1, interleukin (IL) 4, and IL-10 in the hippocampus 21 days after TGCI. These data suggest a protective effect of roflumilast against functional sequelae of cerebral ischemia, which might be related to its anti-inflammatory properties.
Assuntos
Isquemia Encefálica , Ataque Isquêmico Transitório , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Animais , Benzamidas , Isquemia Encefálica/tratamento farmacológico , Ciclopropanos , Proteína Duplacortina , Hipocampo , Ratos , Memória EspacialRESUMO
Cerebral ischemia-induced hyperglycemia has been reported to accentuate neurological damage following focal or global cerebral ischemia. Hyperglycemia found in rats following focal brain ischemia occurs in the first 24â¯h and has been claimed to be caused by increased liver gluconeogenesis and insulin resistance. However, liver gluconeogenesis and the mechanisms leading to hyperglycemia after global cerebral ischemia remain uncertain. This study investigated the glycemic homeostasis and hepatic metabolism in rats after transient four-vessel occlusion (4-VO)-induced global cerebral ischemia, an event that mimics to a certain degree the situation during cardiac arrest. Several metabolic fluxes were measured in perfused livers. Activities and mRNA expressions of hepatic glycolysis and glyconeogenesis rate-limiting enzymes were assessed as well as respiratory activity of hepatic isolated mitochondria. Global cerebral ischemia was associated with hyperglycemia and hyperinsulinemia 24â¯h after ischemia. Insulin resistance developed later and was prominent after the 5th day. Hepatic anabolism and catabolism were both modified in a complex and time-dependent way. Gluconeogenesis, ß-oxidation, ketogenesis and glycolysis were diminished at 24â¯h after ischemia. At 5â¯days after ischemia glycolysis had normalized, but gluconeogenesis, ketogenesis and ß-oxidation were accelerated. The overall metabolic modifications suggest that a condition of depressed metabolism was established in response to the new conditions generated by the cerebral global ischemia. Whether the modifications in the liver metabolism found in rats after the ischemic insult can be translated to individuals following global brain ischemia remains uncertain, but the results of this study are hoped to encourage further investigations.
Assuntos
Glicemia/metabolismo , Isquemia Encefálica/metabolismo , Homeostase , Fígado/metabolismo , Animais , Masculino , Ratos , Ratos WistarRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Trichilia catigua preparations have antinociceptive, antiinflammatory, and neuroprotective activity. Recently, a neuroprotective role for T. catigua was proposed using an in vitro model of ischemia-reperfusion in rat hippocampal slices. The aim of the present study was to evaluate the effects of an ethyl-acetate fraction (EAF) of T. catigua, which has potent antioxidant activity, in mice subjected to an in vivo model of cerebral ischemia. MATERIAL AND METHODS: Male Swiss mice were subject to the bilateral common carotid occlusion (BCCAO) model of cerebral ischemia. The animals were orally administered the T. catigua EAF (200, 400, or 800 mg/kg) 30 min before and once per day for 7 days after BCCAO. Histological and behavioral outcomes were assessed using Nissl staining and the Morris water maze test of cognition, respectively. RESULTS: Mice that were subjected to BCCAO exhibited cognitive impairments in the Morris water maze. The spatial cognitive deficits were counteracted by T. catigua EAF administration (200-800 mg/kg). The T. catigua EAF significantly increased the number of intact-appearing Nissl-stained cells in the hippocampus in BCCAO mice. CONCLUSIONS: These results show that the T. catigua EAF promoted functional recovery, decreased the delayed hippocampal cell loss, and mitigated the ongoing neurodegenerative processes induced by BCCAO in mice.
Assuntos
Transtornos Cognitivos/tratamento farmacológico , Meliaceae/química , Extratos Vegetais/farmacologia , Acetatos/química , Animais , Isquemia Encefálica/complicações , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/patologia , Artéria Carótida Primitiva/patologia , Estenose das Carótidas/complicações , Morte Celular/efeitos dos fármacos , Transtornos Cognitivos/etiologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hipocampo/patologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Extratos Vegetais/administração & dosagemRESUMO
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 reported that fish oil (FO) abolishes retrograde amnesia consistently following transient global cerebral ischemia (TGCI) in young rats, provided it covered the first days prior to and after ischemia. Here, we further evaluated whether FO given post-ischemia in older rats (15-18 months old) is equally effective in facilitating memory recovery. We also tested whether the antiamnesic effect of FO observed after TGCI can be reproduced after chronic cerebral hypoperfusion (CCH). FO (300 mg/kg docosahexaenoic acid [DHA]) was delivered orally 4h after TGCI and continued once per day for 9 days. In the CCH group, FO treatment began soon after the first stage of 4-VO/ICA and continued daily for 43 days. Two weeks after surgery, the animals were tested for retrograde memory performance across 5 weeks. Both TGCI and CCH caused persistent memory impairment and hippocampal and cortical neurodegeneration. TGCI-induced retrograde amnesia was reversed by FO, an effect that was sustained for at least 5 weeks after discontinuing treatment. In contrast, the memory deficit caused by CCH remained unchanged after FO treatment. Both hippocampal and cortical damage was not alleviated by FO. We conclude that the FO-mediated antiamnesic effect following TGCI can be extended to older rats, even when the treatment begins 4h postischemia. Such efficacy was not reproduced after CCH. Therefore, the present results support the notion that FO may have therapeutic utility in treating learning/memory dysfunction after acute/transient cerebral ischemia and suggest that such benefits may not apply when a state of chronic cerebrovascular insufficiency is present.