RESUMEN
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.
Asunto(s)
Cannabidiol/uso terapéutico , Hipocampo/efectos de los fármacos , Ataque Isquémico Transitorio/prevención & control , Plasticidad Neuronal/efectos de los fármacos , Neuroprotección/efectos de los fármacos , Sinapsis/efectos de los fármacos , Animales , Cannabidiol/farmacología , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Hipocampo/patología , Ataque Isquémico Transitorio/metabolismo , Ataque Isquémico Transitorio/patología , Masculino , Plasticidad Neuronal/fisiología , Neuroprotección/fisiología , Técnicas de Cultivo de Órganos , Ratas , Ratas Wistar , Memoria Espacial/efectos de los fármacos , Memoria Espacial/fisiología , Sinapsis/metabolismo , Sinapsis/patologíaRESUMEN
An ever-increasing body of preclinical studies has shown the multifaceted neuroprotective profile of cannabidiol (CBD) against impairments caused by cerebral ischemia. In this study, we have explored the neuropharmacological mechanisms of CBD action and its impact on functional recovery using a model of transient global cerebral ischemia in mice. C57BL/6J mice were subjected to bilateral common carotid artery occlusion (BCCAO) for 20 min and received vehicle or CBD (10 mg/Kg) 0.5 hr before and 3, 24, and 48 hr after reperfusion. To investigate the neuropharmacological mechanisms of CBD, the animals were injected with CB1 (AM251, 1 mg/kg), CB2 (AM630, 1 mg/kg), 5-HT1A (WAY-100635, 10 mg/kg), or PPAR-γ (GW9662, 3 mg/kg) receptor antagonists 0.5 hr prior to each injection of CBD. The animals were evaluated using a multi-task testing battery that included the open field, elevated zero maze, Y-maze (YM), and forced swim test. CBD prevented anxiety-like behavior, memory impairments, and despair-like behaviors induced by BCCAO in mice. The anxiolytic-like effects of CBD in BCCAO mice were attenuated by CB1 , CB2 , 5-HT1A , and PPAR-γ receptor antagonists. In the YM, both CBD and the CB1 receptor antagonist AM251 increased the exploration of the novel arm in ischemic animals, indicating beneficial effects of these treatments in the spatial memory performance. Together, these findings indicate the involvement of CB1 , CB2 , 5-HT1A, and PPAR-γ receptors in the functional recovery induced by CBD in BCCAO mice.
Asunto(s)
Cannabidiol , Disfunción Cognitiva , Animales , Isquemia , Ratones , Ratones Endogámicos C57BL , PPAR gamma , Receptor Cannabinoide CB1 , Receptor Cannabinoide CB2 , Receptor de Serotonina 5-HT1ARESUMEN
Diabetes and aging are risk factors for cognitive impairments after chronic cerebral hypoperfusion (CCH). Cannabidiol (CBD) is a phytocannabinoid present in the Cannabis sativa plant. It has beneficial effects on both cerebral ischemic diseases and diabetes. We have recently reported that diabetes interacted synergistically with aging to increase neuroinflammation and memory deficits in rats subjected to CCH. The present study investigated whether CBD would alleviate cognitive decline and affect markers of inflammation and neuroplasticity in the hippocampus in middle-aged diabetic rats submitted to CCH. Diabetes was induced in middle-aged rats (14 months old) by intravenous streptozotocin (SZT) administration. Thirty days later, the diabetic animals were subjected to sham or CCH surgeries and treated with CBD (10 mg/kg, once a day) during 30 days. Diabetes exacerbated cognitive deficits induced by CCH in middle-aged rats. Repeated CBD treatment decreased body weight in both sham- and CCH-operated animals. Cannabidiol improved memory performance and reduced hippocampal levels of inflammation markers (inducible nitric oxide synthase, ionized calcium-binding adapter molecule 1, glial fibrillary acidic protein, and arginase 1). Cannabidiol attenuated the decrease in hippocampal levels of brain-derived neurotrophic factor induced by CCH in diabetic animals, but it did not affect the levels of neuroplasticity markers (growth-associated protein-43 and synaptophysin) in middle-aged diabetic rats. These results suggest that the neuroprotective effects of CBD in middle-aged diabetic rats subjected to CCH are related to a reduction in neuroinflammation. However, they seemed to occur independently of hippocampal neuroplasticity changes.
Asunto(s)
Encéfalo/irrigación sanguínea , Encéfalo/efectos de los fármacos , Cannabidiol/uso terapéutico , Circulación Cerebrovascular/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Factores de Edad , Animales , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Encéfalo/metabolismo , Cannabidiol/farmacología , Circulación Cerebrovascular/fisiología , Enfermedad Crónica , Comorbilidad , Diabetes Mellitus Experimental/sangre , Masculino , Ratas , Ratas Wistar , Resultado del TratamientoRESUMEN
Both high fat diet (HFD) and high carbohydrate diet (HCD) modulate brain fatty acids (FA) composition. Notwithstanding, there is a lack of information on time sequence of brain FA deposition either for HFD or HCD. The changes in brain FA composition in mice fed with HFD or HCD for 7, 14, 28, or 56 days were compared with results of 0 (before starting given the diets). mRNA expressions of allograft inflammatory factor 1 (Aif1), cyclooxygenase-2 (Cox 2), F4/80, inducible nitric oxide synthase (iNOS), integrin subunit alpha m (Itgam), interleukin IL-1ß (IL-1ß), IL-6, IL-10, and tumor necrosis factor alpha (TNF-α) were measured. The HFD group had higher speed of deposition of saturated FA (SFA), monounsaturated FA (MUFA), and polyunsaturated FA (PUFA) at the beginning of the experimental period. However, on day 56, the total amount of SFA, MUFA, and PUFA were similar. mRNA expressions of F4/80 and Itgam, markers of microglia infiltration, were increased (p < 0.05) in the brain of the HCD group whereas inflammatory marker index (IMI) was higher (46%) in HFD group. In conclusion, the proportion of fat and carbohydrates in the diet modulates the speed deposition of FA and expression of inflammatory gene markers.
Asunto(s)
Encéfalo/metabolismo , Dieta de Carga de Carbohidratos/efectos adversos , Dieta Alta en Grasa/efectos adversos , Carbohidratos de la Dieta/efectos adversos , Grasas de la Dieta/efectos adversos , Ácidos Grasos/metabolismo , Animales , Antígenos de Diferenciación/metabolismo , Antígeno CD11b/metabolismo , Proteínas de Unión al Calcio/metabolismo , Ciclooxigenasa 2/metabolismo , Citocinas/metabolismo , Inflamación/metabolismo , Cadenas alfa de Integrinas/metabolismo , Masculino , Ratones , Proteínas de Microfilamentos/metabolismo , Óxido Nítrico Sintasa/metabolismo , ARN Mensajero/metabolismoRESUMEN
OBJECTIVE: Parkinson's disease (PD) is characterized by deterioration of the nigrostriatal system and associated with chronic neuroinflammation. Glial activation has been associated with regulating the survival of dopaminergic neurons and is thought to contribute to PD through the release of proinflammatory and neurotoxic factors, such as reactive nitric oxide (NO) that triggers or exacerbates neurodegeneration in PD. Polyunsaturated fatty acids (PUFAs) exert protective effects, including antiinflammatory, antiapoptotic, and antioxidant activity, and may be promising for delaying or preventing PD by attenuating neuroinflammation and preserving dopaminergic neurons. The present study investigated the effects of fish oil supplementation that was rich in PUFAs on dopaminergic neuron loss, the density of inducible nitric oxide synthase (iNOS)-immunoreactive cells, and microglia and astrocyte reactivity in the substantia nigra pars compacta (SNpc) and striatal dopaminergic fibers. METHODS: The animals were supplemented with fish oil for 50 days and subjected to unilateral intrastriatal 6-hydroxydopamine (6-OHDA)-induced lesions as a model of PD. RESULTS: Fish oil mitigated the loss of SNpc neurons and nerve terminals in the striatum that was caused by 6-OHDA. This protective effect was associated with reductions of the density of iNOS-immunoreactive cells and microglia and astrocyte reactivity. DISCUSSION: These results suggest that the antioxidant and antiinflammatory properties of fish oil supplementation are closely related to a decrease in dopaminergic damage that is caused by the 6-OHDA model of PD.
Asunto(s)
Ácidos Grasos Omega-3/farmacología , Fármacos Neuroprotectores/farmacología , Óxido Nítrico Sintasa de Tipo II/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Dopamina , Neuronas Dopaminérgicas/efectos de los fármacos , Aceites de Pescado/farmacología , Masculino , Microglía/efectos de los fármacos , Microglía/metabolismo , Degeneración Nerviosa/tratamiento farmacológico , Degeneración Nerviosa/etiología , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Oxidopamina , Enfermedad de Parkinson/etiología , Ratas , Ratas WistarRESUMEN
This study investigated the effects of cannabidiol (CBD), a non-psychotomimetic phytochemical present in Cannabis sativa, on the cognitive and emotional impairments induced by bilateral common carotid artery occlusion (BCCAO) in mice. Using a multi-tiered behavioral testing battery during 21days, we found that BCCAO mice exhibited long-lasting functional deficits reflected by increase in anxiety-like behavior (day 9), memory impairments (days 12-18) and despair-like behavior (day 21). Short-term CBD 10mg/kg treatment prevented the cognitive and emotional impairments, attenuated hippocampal neurodegeneration and white matter (WM) injury, and reduced glial response that were induced by BCCAO. In addition, ischemic mice treated with CBD exhibited an increase in the hippocampal brain derived neurotrophic factor (BDNF) protein levels. CBD also stimulated neurogenesis and promoted dendritic restructuring in the hippocampus of BCCAO animals. Collectively, the present results demonstrate that short-term CBD treatment results in global functional recovery in ischemic mice and impacts multiple and distinct targets involved in the pathophysiology of brain ischemic injury.
Asunto(s)
Isquemia Encefálica/complicaciones , Cannabidiol/farmacología , Cannabidiol/uso terapéutico , Encefalitis/tratamiento farmacológico , Encefalitis/etiología , Plasticidad Neuronal/efectos de los fármacos , Recuperación de la Función/efectos de los fármacos , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Proteínas de Unión al Calcio/metabolismo , Modelos Animales de Enfermedad , Proteínas de Dominio Doblecortina , Conducta Exploratoria/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/metabolismo , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Proteínas de Microfilamentos/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Neuropéptidos/metabolismo , Reconocimiento en Psicología/efectos de los fármacos , Natación/psicología , Factores de TiempoRESUMEN
Evidence suggests that idiopathic Parkinson's disease (PD) is the consequence of a neurodevelopmental disruption, rather than strictly a consequence of aging. Thus, we hypothesized that maternal supplement of omega-3 polyunsaturated fatty acids (ω-3 PUFA) may be associated with neuroprotection mechanisms in a self-sustaining cycle of neuroinflammation and neurodegeneration in lipopolysaccharide (LPS)-model of PD. To test this hypothesis, behavioral and neurochemical assay were performed in prenatally LPS-exposed offspring at postnatal day 21. To further determine whether prenatal LPS exposure and maternal ω-3 PUFAs supplementation had persisting effects, brain injury was induced on PN 90 rats, following bilateral intranigral LPS injection. Pre- and postnatal inflammation damage not only affected dopaminergic neurons directly, but it also modified critical features, such as activated microglia and astrocyte cells, disrupting the support provided by the microenvironment. Unexpectedly, our results failed to show any involvement of caspase-dependent and independent apoptosis pathway in neuronal death mechanisms. On the other hand, learning and memory deficits detected with a second toxic exposure were significantly attenuated in maternal ω-3 PUFAs supplementation group. In addition, ω-3 PUFAs promote beneficial effect on synaptic function, maintaining the neurochemical integrity in remaining neurons, without necessarily protect them from neuronal death. Thus, our results suggest that ω-3 PUFAs affect the functional ability of the central nervous system in a complex way in a multiple inflammation-induced neurotoxicity animal model of PD and they disclose new ways of understanding how these fatty acids control responses of the brain to different challenges.
Asunto(s)
Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/metabolismo , Ácidos Grasos Omega-3/administración & dosificación , Enfermedad de Parkinson/dietoterapia , Enfermedad de Parkinson/metabolismo , Fenómenos Fisiologicos de la Nutrición Prenatal/fisiología , Animales , Animales Recién Nacidos , Suplementos Dietéticos , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Femenino , Inflamación/dietoterapia , Inflamación/metabolismo , Inflamación/patología , Masculino , Fármacos Neuroprotectores/administración & dosificación , Enfermedad de Parkinson/patología , Embarazo , Fenómenos Fisiologicos de la Nutrición Prenatal/efectos de los fármacos , Distribución Aleatoria , Ratas , Ratas WistarRESUMEN
Myricitrin (MYR) is a natural flavonoid that inhibits nitric oxide (NO) transmission and has an atypical antipsychotic-like profile in animal models. Considering that several NO inhibitors exert antidepressant-like effects, the present study evaluated the antidepressant-like effect of MYR (3-30mg/kg) in the tail suspension test (TST). Because of the putative relationship between adult neurogenesis and antidepressant activity, we also assessed cell proliferation, survival, and differentiation in adult neurogenic niches, including the subgranular zone (SGZ) and subventricular zone (SVZ). Similar to the positive control imipramine (IMI; 10mg/kg), repeated treatment with 10mg/kg MIR but not acute treatment reduced immobility time in the TST, indicating an antidepressant-like effect. No effect on general motor activity was observed. Myricitrin also facilitated cell proliferation in the SGZ of the hippocampal dentate gyrus and SVZ. In the SGZ, MYR increased the number of doublecortin- and 5-bromo-2'-deoxyuridine/neuronal nuclei-positive cells. Our results suggest that MYR facilitates hippocampal neurogenesis, which might contribute to its antidepressant-like effect and atypical antipsychotic-like profile.
Asunto(s)
Antidepresivos/farmacología , Giro Dentado/efectos de los fármacos , Flavonoides/farmacología , Neurogénesis/efectos de los fármacos , Animales , Bromodesoxiuridina/metabolismo , Relación Dosis-Respuesta a Droga , Proteínas de Dominio Doblecortina , Conducta Exploratoria/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/metabolismo , Suspensión Trasera , Antígeno Ki-67/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Proteínas Asociadas a Microtúbulos/metabolismo , Neuropéptidos/metabolismo , Fosfopiruvato Hidratasa/metabolismoRESUMEN
The pathophysiology of depression is not completely understood; nonetheless, numerous studies point to serotonergic dysfunction as a possible cause. Supplementation with fish oil rich docosahexaenoic (DHA) and eicosapentaenoic acids (EPA) during critical periods of development produces antidepressant effects by increasing serotonergic neurotransmission, particularly in the hippocampus. In a previous study, the involvement of 5-HT1A receptors was demonstrated and we hypothesized that fish oil supplementation (from conception to weaning) alters the function of post-synaptic hippocampal 5-HT1A receptors. To test this hypothesis, female rats were supplemented with fish oil during habituation, mating, gestation, and lactation. The adult male offspring was maintained without supplementation until 3 months of age, when they were subjected to the modified forced swimming test (MFST) after infusion of vehicle or the selective 5-HT1A antagonist, WAY100635, and frequency of swimming, immobility, and climbing was recorded for 5 min. After the behavioral test, the hippocampi were obtained for quantification of serotonin (5-HT) and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) and for 5-HT1A receptor expression by Western blotting analysis. Fish oil-supplemented offspring displayed less depressive-like behaviors in the MFST reflected by decreased immobility and increased swimming and higher 5-HT hippocampal levels. Although there was no difference in the expression of hippocampal 5-HT1A receptors, intra-hippocampal infusion of a sub-effective dose of 8-OH-DPAT enhanced the antidepressant effect of fish oil in supplemented animals. In summary, the present findings suggest that the antidepressant-like effects of fish oil supplementation are likely related to increased hippocampal serotonergic neurotransmission and sensitization of hippocampal 5-HT1A receptors.
Asunto(s)
Antidepresivos/farmacología , Aceites de Pescado/farmacología , Hipocampo/metabolismo , Receptor de Serotonina 5-HT1A/metabolismo , Sinapsis/metabolismo , Animales , Western Blotting , Cromatografía Líquida de Alta Presión , Femenino , Hipocampo/efectos de los fármacos , Inmovilización , Masculino , Ratas Wistar , Natación , Sinapsis/efectos de los fármacosRESUMEN
Inflammation in Parkinson's disease (PD) is a continuous process and might be implicated in the progression of neuronal degeneration. Taking this into account, we proposed a new protocol with multiple and consecutive intranigral lipopolysaccharide (LPS) administration in order to analyze its effects on cognitive behavior. Additionally, striatal concentrations of the neurotransmitters dopamine (DA) and serotonin and their respective metabolites were assessed in three different time-points with the purpose of identifying the consecutive and cumulative effects of LPS infusions. We demonstrated that with a minimum administered dose there was stabilization of neuronal damage as revealed by absence of synergic effect on DA concentration. Although the DA decrease (-43%) generates an animal model of early phase of PD, without apparent motor impairment, the LPS group exhibited deficit in episodic-like memory behavior from the first time-point until the last one, indicating persisted disturbances in memory-recognition responses. These findings provide evidence that multiple intranigral LPS infusions are not sufficient to cause cumulative and progressive damage to dopaminergic neurons, but confirm that the LPS model can be adopted as a useful tool providing insight about the cognitive impairment observed in pre-motor phase of PD.
Asunto(s)
Trastornos del Conocimiento/inducido químicamente , Trastornos del Conocimiento/metabolismo , Cognición/efectos de los fármacos , Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Lipopolisacáridos/farmacología , Sustancia Negra/efectos de los fármacos , Animales , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Lipopolisacáridos/administración & dosificación , Masculino , Microinyecciones , Actividad Motora/efectos de los fármacos , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/metabolismo , Ratas , Reconocimiento en Psicología/efectos de los fármacos , Serotonina/metabolismoRESUMEN
We previously reported that long-term treatment with fish oil (FO) facilitates memory recovery after transient, global cerebral ischemia (TGCI), despite the presence of severe hippocampal damage. The present study tested whether this antiamnesic effect resulted from an action of FO on behavioral performance itself, or whether it resulted from an anti-ischemic action. Different treatment regimens were used that were distinguished from each other by their initiation or duration with regard to the onset of TGCI and memory assessment. Naive rats were trained in an eight-arm radial maze, subjected to TGCI (4-VO model, 15 min), and tested for memory performance up to 6 weeks after TGCI. Fish oil (docosahexaenoic acid, 300 mg/kg/day) was given orally according to one of the following regimens: regimen 1 (from 3 days prior to ischemia until 4 weeks post-ischemia), regimen 2 (from 3 days prior to ischemia until 1 week post-ischemia), and regimen 3 (from week 2 to week 5 post-ischemia). When administered according to regimens 1 and 2, FO abolished amnesia completely. This effect persisted for at least 5 weeks after discontinuing the treatment. Such an effect did not occur, however, in the group treated according to regimen 3. Hippocampal and cortical damage was not alleviated by FO. The present results demonstrate that FO-mediated memory recovery (or preservation) following TGCI is a reproducible, robust, and long-lasting effect. Moreover, such an effect was found with a relatively short period of treatment, provided it covered the first days prior to and after ischemia. This suggests that FO prevented amnesia by changing some acute, ischemia/reperfusion-triggered process and not by stimulating memory performance on its own.
Asunto(s)
Ácidos Docosahexaenoicos/uso terapéutico , Ataque Isquémico Transitorio/dietoterapia , Trastornos de la Memoria/dietoterapia , Animales , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/patología , Ácidos Docosahexaenoicos/administración & dosificación , Esquema de Medicación , Hipocampo/efectos de los fármacos , Hipocampo/patología , Ataque Isquémico Transitorio/complicaciones , Ataque Isquémico Transitorio/patología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/complicaciones , Trastornos de la Memoria/patología , Degeneración Nerviosa/dietoterapia , Degeneración Nerviosa/patología , RatasRESUMEN
This study investigated whether sensorimotor deficits measured soon after reperfusion could predict the occurrence and magnitude of cerebral infarct following middle cerebral artery occlusion (MCAO). Rats were subjected to left MCAO for 2 h according to the intraluminal thread method. At 0, 1, 2, and 3 h after reperfusion, the animals were examined for neurological deficits using an expanded scale comprising the following tests: (A) postural reflex, (B) circling motion, (C) falling to contralateral side, (D) placement of the contralateral forelimb during motion, and (E) general state of alertness or consciousness. Deficits were graded from 0 (normal) to 2 or 3 (severe), and the final neuro-score was a summation of these scores over the various time points and among the various tests. The neuro-score of the animals that survived up to 24 h after MCAO ranged from 0 to 8.2 and positively correlated with infarct size (p=0.0002-0.001). However, at least three animals with moderate neuro-scores (4.5-6.0) did not exhibit any sign of infarcted brain tissue. Other animals having a distinct neuro-score (3.2 and 8.2, respectively) exhibited cerebral infarct with the same size (235 mm³). These data indicate that the extent of neurological deficit assessed within the first 3h after reperfusion does not reliably correspond to the occurrence and magnitude of cerebral infarct. Therefore, the neuro-score, when measured acutely within the first few hours after reperfusion, does not serve as a reliable criterion for preselecting animals with similar infarct size following transient MCAO.