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OBJECTIVE: To investigate the effects of cannabidiol (CBD) on emotional and cognitive symptoms in rats with intra-nigral 6-hydroxydopamine (6-OHDA) lesions. METHODS: Adult male Wistar rats received bilateral intranigral 6-OHDA infusions and were tested in a battery of behavioural paradigms to evaluate non-motor symptoms. The brains were obtained to evaluate the effects of CBD on hippocampal neurogenesis. RESULTS: 6-OHDA-lesioned rats exhibited memory impairments and despair-like behaviour in the novelty-suppressed feeding test and forced swim test, respectively. The animals also exhibited dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc), striatum, and ventral tegmental area and a reduction of hippocampal neurogenesis. CBD decreased dopaminergic neuronal loss in the SNpc, reduced the mortality rate and decreased neuroinflammation in 6-OHDA-lesioned rats. In parallel, CBD prevented memory impairments and attenuated despair-like behaviour that were induced by bilateral intranigral 6-OHDA lesions. Repeated treatment with CBD favoured the neuronal maturation of newborn neurons in the hippocampus in Parkinsonian rats. CONCLUSION: The present findings suggest a potential beneficial effect of CBD on non-motor symptoms induced by intra-nigral 6-OHDA infusion in rats.
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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
Inhibition of phosphodiesterase 4 (PDE4) is a promising pharmacological strategy for the treatment of cerebral ischemic conditions. To increase the relevance and increase the translational value of preclinical studies, it is important to conduct experiments using different animal species and strains, different animal models, and to evaluate long-term functional outcomes after cerebral ischemia. In the present study, the effects of the selective PDE4 inhibitor roflumilast were evaluated in vivo and in vitro. Balb/c mice were subjected to bilateral common carotid artery occlusion (BCCAO) and tested during 21 days in multiple behavioral tasks to investigate the long-term effects of roflumilast on functional recovery. The effects of roflumilast were also investigated on hippocampal cell loss, white matter injury, and expression of neuroinflammatory markers. Roflumilast prevented cognitive and emotional deficits induced by BCCAO in mice. Roflumilast also prevented neurodegeneration and reduced the white matter damage in the brain of ischemic animals. Besides, roflumilast decreased Iba-1 (microglia marker) levels and increased Arginase-1 (Arg-1; microglia M2 phenotype marker) levels in the hippocampus of these mice. Likewise, roflumilast suppressed inducible nitric oxide synthase (microglia M1 phenotype marker) expression and increased Arg-1 levels in a primary mouse microglia culture. These findings support evidence that PDE4 inhibition by roflumilast might be beneficial in cerebral ischemic conditions. The neuroprotective effects of roflumilast appear to be mediated by a decrease in neuroinflammation.
Assuntos
Aminopiridinas/farmacologia , Arginase/metabolismo , Benzamidas/farmacologia , Isquemia Encefálica , Proteínas de Ligação ao Cálcio/metabolismo , Disfunção Cognitiva , Proteínas dos Microfilamentos/metabolismo , Doenças Neuroinflamatórias , Animais , Comportamento Animal/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/imunologia , Isquemia Encefálica/psicologia , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Ciclopropanos/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/metabolismo , Fármacos Neuroprotetores/farmacologia , Inibidores da Fosfodiesterase 4/farmacologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Resultado do Tratamento , Substância Branca/efeitos dos fármacos , Substância Branca/metabolismoRESUMO
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
Fear extinction is a form of new learning that inhibits expression of the original fear memory without erasing the conditioned stimulus-unconditioned stimulus association. Much is known about the mechanisms that underlie the acquisition of extinction, but the way in which fear extinction is maintained has been scarcely explored. Evidence suggests that protein kinase A (PKA) in the frontal cortex might be related to the persistence of extinction. Phosphodiesterase-4 (PDE4) specifically hydrolyzes cyclic adenosine monophosphate (cAMP). The present study evaluated the effect of the selective PDE4 inhibitor roflumilast (ROF; 0.01, 0.03, and 0.1 mg/kg given i.p.) on acquisition and consolidation of the extinction of fear memory in male Wistar rats in a contextual fear conditioning paradigm. When administered before acquisition, 0.1 mg/kg ROF disrupted short-term (1 day) extinction recall. In contrast, 0.03 mg/kg ROF administration in the late consolidation phase (3 h after extinction learning) but not in the early phase immediately after learning improved long-term extinction recall at 11 days, suggesting potentiation of the persistence of extinction. This effect of ROF requires the first (day 1) exposure to the context. A similar effect was observed when 9 ng ROF or 30 µM 8-bromoadenosine 3',5'-cAMP (PKA activator) was directly infused in the infralimbic cortex (IL), a brain region necessary for memory extinction. The PKA activity-dependent ROF-induced effect in the IL was correlated with an increase in its brain-derived neurotrophic factor (BDNF) protein expression, while blockade of PKA with 10 µM H89 in the IL abolished the ROF-induced increase in BDNF expression and prevented the effect of ROF on extinction recall. These effects were not associated with changes in anxiety-like behavior or general exploratory behavior. Altogether, these findings suggest that cAMP-PKA activity in the IL during the late consolidation phase after extinction learning underlies the persistence of extinction.
Assuntos
Extinção Psicológica/fisiologia , Medo/fisiologia , Memória/fisiologia , Córtex Pré-Frontal/fisiologia , Transdução de Sinais , Aminopiridinas/administração & dosagem , Animais , Benzamidas/administração & dosagem , AMP Cíclico/fisiologia , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Ciclopropanos/administração & dosagem , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Consolidação da Memória/efeitos dos fármacos , Consolidação da Memória/fisiologia , Inibidores da Fosfodiesterase 4/administração & dosagem , Córtex Pré-Frontal/efeitos dos fármacos , Ratos WistarRESUMO
ABSTRACT Introduction: The best strategy for improving knee extensor power, a major functional capacity indicator in older adults, is power training. Nonetheless, the training intensity required to induce optimal gains is yet to be found. Objective: Our purpose was to compare knee extensor peak power responses between low, moderate, and high intensity load conditions (30%, 50% and 70% of 1RM). Methods: Thirteen sedentary elderly women performed six knee extensions in each load condition, calculating knee extensor mechanical work/power output and knee extension peak angular velocity. Results: No difference in peak power was found between the high (207.0 ± 68.1 W) and moderate (206.1 ± 71.6 W) load conditions (p = 0.994), and both had higher values (p ≤0.004) than the low intensity condition (135.6 ± 56.3 W). Conclusion: Moderate load at 50% of 1RM appears to be the preferred strategy for inducing knee extensor power output because in contrast with the high intensity condition, the moderate load yielded higher angular peak velocity, which is also a functional indicator. Level of Evidence ll; Therapeutic studies - Investigating treatment results.
RESUMO Introdução: A melhor estratégia para melhorar a potência dos extensores do joelho, principal indicador da capacidade funcional em idosos, é o treinamento de força. No entanto, a intensidade do treinamento exigida para induzir a maiores benefícios ainda não é conhecida. Objetivo: Nosso objetivo consistiu em comparar as respostas de potência máxima dos extensores do joelho entre as condições de carga baixa, moderada e de alta intensidade (30%, 50% e 70% de uma repetição máxima). Métodos: Treze mulheres idosas sedentárias realizaram seis extensões de joelho em cada condição de carga, sendo calculado o trabalho mecânico/débito de força e a velocidade angular máxima (ou pico) dos extensores do joelho. Resultados: Não houve diferença significativa na potência máxima entre as condições de carga alta ((207,0 ± 68,1 W) e moderada (206,1 ± 71,6 W) (p = 0,994), e ambas apresentaram valores maiores (p ≤ 0,004) do que a condição de baixa intensidade (135,6 ± 56,3 W). Conclusão: A carga moderada a 50% de 1RM parece ser a estratégia preferida para induzir o débito de força dos extensores do joelho, uma vez que quando comparada com a condição de alta intensidade, a carga moderada apresentou um pico de velocidade angular maior, o que também é um indicador funcional. Nível de Evidência II; Estudos terapêuticos - Investigação dos resultados do tratamento.
RESUMEN Introducción: La mejor estrategia para mejorar la potencia de los extensores de la rodilla, principal indicador de la capacidad funcional en personas de la tercera edad, es el entrenamiento de fuerza. Sin embargo, la intensidad del entrenamiento exigida para inducir a mayores beneficios aún no es conocida. Objetivo: Nuestro objetivo consistió en comparar las respuestas de potencia máxima de los extensores de la rodilla entre las condiciones de carga baja, moderada y de alta intensidad (30%, 50% y 70% de una repetición máxima). Métodos: Trece mujeres de la tercera edad sedentarias realizaron seis extensiones de rodilla en cada condición de carga, siendo calculado el trabajo mecánico/débito de fuerza y la velocidad angular máxima (o pico) de los extensores de la rodilla. Resultados: No hubo diferencia significativa en la potencia máxima entre las condiciones de carga alta ((207,0 ± 68,1 W) y moderada (206,1 ± 71,6 W) (p = 0,994), y ambas presentaron valores mayores (p ≤ 0,004) que la condición de baja intensidad (135,6 ± 56,3 W). Conclusión: La carga moderada a 50% de 1RM parece ser la estrategia preferida para inducir el débito de fuerza de los extensores de la rodilla, dado que cuando comparada con la condición de alta intensidad, la carga moderada presentó un pico de velocidad angular mayor, lo que también es un indicador funcional. Nivel de Evidencia II; Estudios terapéuticos - Investigación de los resultados del tratamiento.
RESUMO
Deficiencies in adult hippocampal neurogenesis have been suggested to be a possible pathophysiological mechanism that underlies depressive symptoms that are often observed in patients with Parkinson's disease (PD). Pioglitazone, a selective peroxisome proliferator-activated receptor γ (PPAR-γ) agonist, has been shown to exert antiinflammatory and antidepressant effects and modulate neural plasticity in several neurodegenerative disorders. The present study investigated the effects of pioglitazone on depressive phenotypes and adult hippocampal neurogenesis in a rat model of PD that was induced by bilateral 6-hydroxydopamine (6-OHDA) infusions in the substantia nigra pars compact (SNpc). Rats with SNpc and ventral tegmental area (VTA) neurodegeneration exhibited despair-like behavior, concomitant with persistent microglial activation in the hippocampus. Pioglitazone reduced the rate of mortality and attenuated microglial activation in the early phase of 6-OHDA-induced nigral lesions. Pioglitazone exerted antidepressant-like effects and increased the survival of neurons in the hippocampus in rats with nigral lesions. These results indicate that pioglitazone exerts neuroprotective effects by facilitating hippocampal neurogenesis in 6-OHDA-lesioned rats, which might contribute to its antidepressant-like effect.
Assuntos
Depressão/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Oxidopamina/toxicidade , Doença de Parkinson Secundária/tratamento farmacológico , Tiazolidinedionas/uso terapêutico , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Depressão/patologia , Modelos Animais de Doenças , Hipocampo/patologia , Masculino , Mortalidade/tendências , Neurogênese/fisiologia , Doença de Parkinson Secundária/mortalidade , Doença de Parkinson Secundária/patologia , Pioglitazona , Distribuição Aleatória , Ratos , Tiazolidinedionas/farmacologiaRESUMO
Early impairments in cerebral glucose metabolism and insulin signaling pathways may participate in the pathogenesis of the sporadic form of Alzheimer's disease (sAD). Intracerebroventricular (ICV) injections of low doses of streptozotocin (STZ) are used to mimic sAD and study these alterations in rodents. Streptozotocin causes impairments in insulin signaling and has been reported to trigger several alterations in the brain, such as oxidative stress, neuroinflammation, and dysfunctions in adult neurogenesis, which may be involved in cognitive decline and are features of human AD. The aim of the present study was to assess the influence of neuroinflammation on the process of adult neurogenesis and consequent cognitive deficits in the STZ-ICV model of sAD in Wistar rats. Streptozotocin caused an acute and persistent neuroinflammatory response, reflected by reactive microgliosis and astrogliosis in periventricular areas and the dorsal hippocampus, accompanied by a marked reduction of the proliferation of neural stem cells in the dentate gyrus of the hippocampus and subventricular zone. Streptozotocin also reduced the survival, differentiation, and maturation of newborn neurons, resulting in impairments in short-term and long-term spatial memory. These results support the hypothesis that neuroinflammation has a detrimental effect on neurogenesis, and both neuroinflammation and impairments in neurogenesis contribute to cognitive deficits in the STZ-ICV model of sAD.
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Envelhecimento/patologia , Doença de Alzheimer/fisiopatologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Inflamação/patologia , Transtornos da Memória/fisiopatologia , Neurogênese , Memória Espacial , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Astrócitos/patologia , Comportamento Animal , Biomarcadores/metabolismo , Modelos Animais de Doenças , Proteínas do Domínio Duplacortina , Medo , Injeções Intraventriculares , Antígeno Ki-67/metabolismo , Masculino , Aprendizagem em Labirinto , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Microglia/patologia , Proteínas Associadas aos Microtúbulos/metabolismo , Neuropeptídeos/metabolismo , Ratos Wistar , EstreptozocinaRESUMO
Therapeutic effects of antidepressants and atypical antipsychotics may arise partially from their ability to stimulate neurogenesis. Cannabidiol (CBD), a phytocannabinoid present in Cannabis sativa, presents anxiolytic- and antipsychotic-like effects in preclinical and clinical settings. Anxiolytic-like effects of repeated CBD were shown in chronically stressed animals and these effects were parallel with increased hippocampal neurogenesis. However, antidepressant-like effects of repeated CBD administration in non-stressed animals have been scarcely reported. Here we investigated the behavioral consequences of single or repeated CBD administration in non-stressed animals. We also determined the effects of CBD on cell proliferation and neurogenesis in the dentate gyrus (DG) and subventricular zone (SVZ). Single CBD 3mg/kg administration resulted in anxiolytic-like effect in mice submitted to the elevated plus maze (EPM). In the tail suspension test (TST), single or repeated CBD administration reduced immobility time, an effect that was comparable to those of imipramine (20 mg/kg). Moreover, repeated CBD administration at a lower dose (3 mg/kg) increased cell proliferation and neurogenesis, as seen by an increased number of Ki-67-, BrdU- and doublecortin (DCX)-positive cells in both in DG and SVZ. Despite its antidepressant-like effects in the TST, repeated CBD administration at a higher dose (30 mg/kg) decreased cell proliferation and neurogenesis in the hippocampal DG and SVZ. Our findings show a dissociation between behavioral and proliferative effects of repeated CBD and suggest that the antidepressant-like effects of CBD may occur independently of adult neurogenesis in non-stressed Swiss mice.