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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.
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Isquemia Encefálica , Ataque Isquêmico Transitório , Ratos , Animais , Barreira Hematoencefálica/metabolismo , Isquemia Encefálica/metabolismo , Hipocampo/metabolismoRESUMO
5-HT1A serotonin receptors may play a role in cognitive function changes related to advanced age. Here, we investigated the effects of acute and repeated treatment with NLX-101 (F15599), a postsynaptic 5-HT1A receptor-biased agonist, and F13714, a presynaptic 5-HT1A receptor-biased agonist on spatial object pattern separation (OPS) in aged (22-24 months) rats. Neuroplasticity markers including brain-derived neurotrophic factor, PSD95, synaptophysin, and doublecortin were evaluated in the hippocampus. Unlike younger rats, aged rats were incapable of discriminating any new position of the objects in the arena, reflecting the detrimental effect of aging on pattern separation. However, aged animals treated with NLX-101 showed a significant cognitive improvement in the OPS test, accompanied by increases in hippocampal brain-derived neurotrophic factor and PSD95 protein levels. In contrast, no improvement in OPS performance was observed when aged rats received F13714. Both F13714 and NLX-101 increased the number of newborn neurons in the hippocampi of aged rats. These findings provide a rationale for targeting post-synaptic 5-HT1A as a treatment for cognitive deficits related to aging.
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Fator Neurotrófico Derivado do Encéfalo , Receptor 5-HT1A de Serotonina , Ratos , Animais , Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Agonistas do Receptor de SerotoninaRESUMO
Diabetic encephalopathy is related to serious damage to the Central Nervous System leading to several disturbances in memory processing and emotions. It is known that the cyclic adenosine 3',5'-monophosphate (cAMP) responsive element-binding protein (CREB) pathway participates in neuronal plasticity and prevention of neuroinflammation, as well as the mediation of learning/memory processes and emotions in brain areas such as the hippocampus (HIP) and prefrontal cortex (PFC). We aimed to investigate the effect of acute (one injection) and long-term treatment (21 days) with roflumilast (ROF; i.p.; 0, 0.01, 0.03, 0.1 mg/kg), a drug able to inhibit the enzyme phosphodiesterase-4 (PDE-4) responsible for cAMP hydrolysis, on parameters related to the acquisition of fear extinction memory and anxiety-like responses in animals with type-1 diabetes mellitus (T1DM) induced through one injection of streptozotocin (60 mg/kg; ip; STZ animals). When we performed acute treatment, no difference was observed between all the groups when resubmitted to the same context paired with an aversive stimulus (footshock) or to a neutral context. In contrast, long-term treatment was able to improve learning of extinction fear memory and discriminating between a conditioned and neutral context. Moreover, this treatment decreased the pronounced anxiety-like response of STZ animals. In addition, there was an increase in the product of the CREB signaling pathway, the pro brain-derived neurotrophic factor, in the HIP and PFC of these animals. The treatment did not impair glycemic control, whereas it decreased the animal's blood glucose levels. To conclude, these findings suggest that ROF treatment repositioning has potential for future translational investigations involving diabetic patients considering its beneficial effects on emotional processes related to fear memory and anxiety, in addition to improvement of glycemic control.
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Diabetes Mellitus Tipo 1 , Medo , Animais , Medo/fisiologia , Extinção Psicológica/fisiologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Ansiedade/tratamento farmacológico , Modelos Animais de DoençasRESUMO
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.
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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
The present study investigated the pharmacological mechanisms of the antidepressant-like effects of amantadine in mice and their influence on hippocampal neurogenesis. To improve the translational validity of preclinical results, reproducibility across laboratories and replication in other animal models and species are crucial. Single amantadine administration at doses of 50 and 75 mg/kg resulted in antidepressant-like effects in mice in the tail suspension test (TST), reflected by an increase in immobility time. The effects of amantadine were seen at doses that did not alter locomotor activity. The tyrosine hydroxylase inhibitor α-methyl-ρ-tyrosine did not influence the anti-immobility effect of amantadine in the TST. Pretreatment with the α1 adrenergic receptor antagonist prazosin, ß adrenergic receptor antagonist propranolol, α2 adrenergic receptor antagonist yohimbine, and α2 adrenergic receptor agonist clonidine did not alter the antidepressant-like effect of amantadine. However, amantadine's effect was blocked by the dopamine D2 receptor antagonist haloperidol and glutamate receptor agonist N-methyl-D-aspartate (NMDA). Repeated amantadine administration (50 mg/kg) also exerted an antidepressant-like effect, paralleled by an increase in hippocampal neurogenesis. The present results demonstrate that the antidepressant-like effects of amantadine may be mediated by its actions on D2 and NMDA receptors and likely involve hippocampal neurogenesis.
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Agonistas Adrenérgicos/farmacologia , Antagonistas Adrenérgicos/farmacologia , Amantadina/farmacologia , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Agonistas de Aminoácidos Excitatórios/farmacologia , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Amantadina/administração & dosagem , Animais , Antidepressivos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , Neurogênese/efeitos dos fármacos , alfa-Metiltirosina/farmacologiaRESUMO
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.
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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
We previously found that fish oil (FO) facilitated memory recovery in the absence of pyramidal neuron rescue after transient, global cerebral ischemia (TGCI). Fish oil preserved the expression of microtubule-associated protein 2 (MAP-2), suggesting a relationship between dendritic plasticity and memory recovery that is mediated by FO after TGCI. The present study examined whether postischemic treatment with FO prevents ischemia-induced loss of dendritic processes in remaining pyramidal neurons. The effects of FO on neuroplasticity-related proteins were also examined after TGCI. Rats were subjected to TGCI (15 min, four-vessel occlusion model) and then received vehicle or FO (300 mg/kg docosahexaenoic acid) once daily for 7 days. The first dose was administered 4 h postischemia. Golgi-Cox staining was used to evaluate dentrict morphology in the pyramidal neurons of hippocampus (CA1 and CA3 subfields) and prefrontal cortex (PFC). Neuronal nuclei protein (NeuN), brain-derived neurotrophic factor (BDNF), growth-associated protein 43 (GAP-43), synaptophysin (SYP), and postsynaptic density protein 95 (PSD-95) levels were measured by Western blot in both structures. Fifteen minutes of TGCI reduced consistently the length of dendrites, number of dendritic branches and dendritic spine density (average of 25%, 43%, 32%, respectively) 7, 14, and 21 days postischemia, indicating that they did not recover spontaneously. This outcome of TGCI was reversed by FO treatment, an effect that was sustained even after treatment cessation. The NeuN and BDNF protein levels were reduced in both the hippocampus and PFC, which were recovered by FO treatment. GAP-43 protein levels decreased after ischemia in the PFC only, and this effect was also mitigated by FO. Neither SYP nor PSD-95 levels were altered by ischemia, but PDS-95 levels almost doubled after FO treatment in the ischemic group. These data support our hypothesis that synaptic plasticity at the level of dendrites may at least partially underlie the memory-protective effect of FO after TGCI and strengthen the possibility that FO has therapeutic potential for treating the sequelae of brain ischemia/reperfusion injury.
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Dendritos/efeitos dos fármacos , Óleos de Peixe/farmacologia , Ataque Isquêmico Transitório/patologia , Plasticidade Neuronal/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Animais , Dendritos/patologia , Ácidos Docosa-Hexaenoicos/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Masculino , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Wistar , Sinapses/patologiaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Trichilia catigua A. Juss (Meliaceae) preparations have been used in folk medicine to alleviate fatigue, stress, and improve memory. Antinociceptive, antiinflammatory, and in vitro neuroprotective effects have been observed in animals. Cerebral ischemia/reperfusion (I/R) leads to severe neuropsychological deficits that are largely associated with oxidative stress, inflammation and neurodegeneration. We reported previously that an ethyl-acetate fraction (EAF) of T. catigua reduced brain ischemia-induced learning and memory impairments in the absence of histological protection. AIM OF THE STUDY: Continuing those studies, here we aimed to investigate the antioxidant and antiinflammatory properties of T. catigua in an in vivo model of I/R. MATERIAL AND METHODS: Rats were subjected to 15â¯min of brain ischemia (4-VO model) followed by up to 15 days of reperfusion. Vehicle was given by gavage 30â¯min before ischemia and at 1â¯h of reperfusion. In a first experiment, brain ischemia-induced changes in oxidative stress markers, i.e., reduced glutathione (GSH), oxidized glutathione (GSSG), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), and protein carbonyl groups (PCGs) were measured on days 1, 3, and 5 post-ischemia. Similar time course analysis was done for neuroinflammation markers, i.e., microglia (OX42 immunorreactivity) and astrocytes (GFAP immunorreactivity), in the hippocampus. In a second experiment, the time points at which these markers of oxidative stress and neuroinflammation peaked were used to test the effects of T. catigua (400â¯mg/kg, p.o.). RESULTS: Oxidative stress markers peaked on day 1 post-ischemia. GSH decreased (-23.2%) while GSSG increased (+ 71.1%), which yielded a significant reduction in the GSH/GSSG ratio (-39.1%). The activity of CAT was largely reduced by ischemia (-54.6% to -65.1%), while the concentration of PCG almost doubled in the brain of ischemic rats (+99.10%) in comparison to sham. Treatment with the EAF of T. catigua normalized these changes in oxidative markers to the control levels (GSH: +27.5%; GSSG: -23.8%; GSH/GSSG: +44.6%; PCG: -80.3%). In the hippocampus, neuroinflammation markers peaked on day 5 post-ischemia, with microglial and astrocytic responses increasing to 54.8% and 37.1%, respectively. The elevation in glial cells response was completely prevented by EAF. CONCLUSION: These results demonstrate that T. catigua has both antioxidant and antiinflammatory activities after transient global cerebral ischemia in rats, which may contribute to the previously reported memory protective effect of T. catigua.
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Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Meliaceae , Fármacos Neuroprotetores/uso terapêutico , Extratos Vegetais/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Acetatos/química , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Isquemia Encefálica/metabolismo , Antígeno CD11b/metabolismo , Catalase/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Glutationa/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fitoterapia , Extratos Vegetais/farmacologia , Caules de Planta/química , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Solventes/química , Superóxido Dismutase/metabolismoRESUMO
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.