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1.
IBRO Neurosci Rep ; 14: 264-272, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-36926592

RESUMEN

Melatonin is a hormone secreted by the pineal gland, it can be associated with circadian rhythms, aging and neuroprotection. Melatonin levels are decreased in sporadic Alzheimer's disease (sAD) patients, which suggests a relationship between the melatonergic system and sAD. Melatonin may reduce inflammation, oxidative stress, TAU protein hyperphosphorylation, and the formation of ß-amyloid (Aß) aggregates. Therefore, the objective of this work was to investigate the impact of treatment with 10 mg/kg of melatonin (i.p) in the animal model of sAD induced by the intracerebroventricular (ICV) infusion of 3 mg/kg of streptozotocin (STZ). ICV-STZ causes changes in the brain of rats similar to those found in patients with sAD. These changes include; progressive memory decline, the formation of neurofibrillary tangles, senile plaques, disturbances in glucose metabolism, insulin resistance and even reactive astrogliosis characterized by the upregulation of glucose levels and glial fibrillary acidic protein (GFAP). The results show that ICV-STZ caused short-term spatial memory impairment in rats after 30 days of STZ infusion without locomotor impairment which was evaluated on day 27 post-injury. Furthermore, we observed that a prolonged 30-day treatment with melatonin can improve the cognitive impairment of animals in the Y-maze test, but not in the object location test. Finally, we demonstrated that animals receiving ICV-STZ have high levels of Aß and GFAP in the hippocampus and that treatment with melatonin reduces Aß levels but does not reduce GFAP levels, concluding that melatonin may be useful to control the progression of amyloid pathology in the brain.

2.
Brain Res ; 1799: 148175, 2023 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-36436686

RESUMEN

Alzheimer's disease (AD) is of multifactorial origin, and still presents several gaps regarding its development and progression. Disorders of the cholinergic system are well known to be involved in the pathogenesis of AD, characterized by increased acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) and decreased acetyltransferase (ChAT) enzymatic activities. Late onset AD (LOAD) animal model induced by intracerebroventricular injection of streptozotocin (icv-STZ) showed promising results in this context, due to the similarity with the pathophysiology of human LOAD. Thus, this study aimed to assess the long-term effects of icv-STZ on the cholinergic system, through the measuring of AChE and BChE enzymatic activities in hippocampus, prefrontal cortex and liver of animals euthanized 30 and 120-days after the icv-STZ. Regarding the cholinergic response to icv-STZ, the 30-days and 120-days STZ-induced rats exhibit decreased AChE and BChE activities only in the hippocampus. The cognitive deficit was more consistent in the 30-days post icv-STZ animals, as was the weight loss. This is the first study to investigate the long-term effects (more than 60 days) of the icv-STZ on AChE and BChE activities, and our results, as well as those of a recent study, suggest that the cholinergic system may not be compromised by icv-STZ, at least in the long term, which means that this model may not be the best model for studying the cholinergic system in AD or that it is informative only for a short period.


Asunto(s)
Enfermedad de Alzheimer , Fármacos Neuroprotectores , Ratas , Humanos , Animales , Enfermedad de Alzheimer/metabolismo , Estreptozocina/farmacología , Ratas Wistar , Acetilcolinesterasa/metabolismo , Butirilcolinesterasa , Modelos Animales de Enfermedad , Fármacos Neuroprotectores/farmacología , Colinérgicos/farmacología , Aprendizaje por Laberinto
3.
Behav Pharmacol ; 33(8): 513-526, 2022 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-36094044

RESUMEN

Parkinson's disease is a neurodegenerative disease, the etiology of which remains unknown, but some likely causes include oxidative stress, mitochondrial dysfunction and neuroinflammation. Peroxisome-proliferator-activated receptor (PPAR) agonists have been studied in animal models of Parkinson's disease and have shown neuroprotective effects. In this study, we aimed to (1) confirm the neuroprotective effects of PPAR-alpha agonist fenofibrate. To this end, male rats received fenofibrate (100 mg/kg) orally for 15 days, 5 days before the intraperitoneal injections of rotenone (2.5 mg/kg for 10 days). After finishing the treatment with rotenone and fenofibrate, animals were subjected to the open field, the forced swim test and the two-way active avoidance task. Subsequently, rats were euthanized for measurement of dopamine and metabolites levels in the striatum and quantification of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra pars compacta (SNpc). In addition, we aimed to (2) evaluate the neuroprotective effects of fenofibrate on the accumulation of α-synuclein aggregates. Here, rats were treated for 5 days with fenofibrate continuing for over 28 days with rotenone. Then, animals were perfused for immunohistochemistry analysis of α-synuclein. The results showed that fenofibrate reduced depressive-like behavior and memory impairment induced by rotenone. Moreover, fenofibrate diminished the depletion of striatal dopamine and protected against dopaminergic neuronal death in the SNpc. Likewise, the administration of fenofibrate attenuated the aggregation of α-synuclein in the SNpc and striatum in the rotenone-lesioned rats. Our study confirmed that fenofibrate exerted neuroprotective effects because parkinsonian rats exhibited reduced behavioral, neurochemical and immunohistochemical changes, and importantly, a lower number of α-synuclein aggregates.


Asunto(s)
Fenofibrato , Enfermedades Neurodegenerativas , Fármacos Neuroprotectores , Enfermedad de Parkinson , Masculino , Ratas , Animales , Rotenona/farmacología , Enfermedad de Parkinson/metabolismo , Fenofibrato/farmacología , alfa-Sinucleína , Neuroprotección , Fármacos Neuroprotectores/farmacología , Dopamina/metabolismo , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Receptores Activados del Proliferador del Peroxisoma/farmacología , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas , Sustancia Negra
4.
Neurotox Res ; 40(5): 1440-1454, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-36029454

RESUMEN

Alzheimer's disease (AD) is a neurodegenerative disorder clinically manifested by a gradual cognitive decline. Intracerebroventricular injection (ICV) of streptozotocin (STZ), a model of sporadic AD (sAD), shows many aspects of sAD abnormalities (i.e., neuroinflammation, oxidative stress, protein aggregation), resulting in memory impairment. Andrographolide (ANDRO), a natural diterpene lactone, has numerous bioactivities including anti-inflammatory and antioxidant properties. Studies in rodents revealed that ANDRO has neuroprotective properties and restores cognitive impairment. In the present study, we investigated the effects of ANDRO in the ICV-STZ model relative to short-term spatial memory (object location test (OLT) and Y maze test), short-term recognition memory (object recognition test (ORT)), locomotor activity (open field test (OFT)), expression of amyloid precursor protein (APP), and activation of astrocytes (glial fibrillary acidic protein (GFAP) expression) and microglia (ionized calcium-binding adapter molecule-1 (Iba-1) immunohistochemistry) in the prefrontal cortex (PFC) and hippocampus (HIP). Wistar rats were injected ICV with STZ (3 mg/kg) or vehicle and treated with ANDRO (2 mg/kg, i.p.; three times per week). After four weeks, ANDRO attenuated the impairments of the Y maze and ORT performances, and the increase of astrocyte activation in the PFC induced by the ICV-STZ model. In addition, ANDRO decreased the number of activated microglia cells in the HIP of STZ-injected rats. The APP expression was not altered, neither by the STZ nor ANDRO. ANDRO showed a beneficial effect on memory impairment and neuroinflammation in the STZ model of AD.


Asunto(s)
Enfermedad de Alzheimer , Diterpenos , Enfermedad de Alzheimer/inducido químicamente , Enfermedad de Alzheimer/tratamiento farmacológico , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/farmacología , Animales , Antioxidantes/farmacología , Calcio , Modelos Animales de Enfermedad , Diterpenos/farmacología , Diterpenos/uso terapéutico , Proteína Ácida Fibrilar de la Glía , Lactonas/efectos adversos , Aprendizaje por Laberinto , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/metabolismo , Enfermedades Neuroinflamatorias , Agregado de Proteínas , Ratas , Ratas Wistar , Estreptozocina/toxicidad
5.
J Alzheimers Dis Rep ; 4(1): 353-363, 2020 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-33163896

RESUMEN

BACKGROUND: It has been studied that nutrition can influence Alzheimer's disease (AD) onset and progression. Some studies on rodents using intraventricular streptozotocin (STZ) injection showed that this toxin changes cerebral glucose metabolism and insulin signaling pathways. OBJECTIVE: The aim of the present study was to evaluate whether a nutritional formulation could reduce cognitive impairment in STZ-induced animals. METHODS: The rats were randomly divided into two groups: sham and STZ. The STZ group received a single bilateral STZ-ICV injection (1 mg/kg). The sham group received a bilateral ICV injection of 0.9% saline solution. The animals were treated with AZ1 formulation (Instanth® NEO, Prodiet Medical Nutrition) (1 g/kg, PO) or its vehicle (saline solution) for 30 days, once a day starting one day after the stereotaxic surgery (n = 6-10). The rats were evaluated using the open field test to evaluate locomotor activity at day 27 after surgery. Cognitive performance was evaluated at day 28 using the object recognition test and the spatial version of the Y-maze test. At day 30, the rats were anesthetized with chloral hydrate (400 mg/kg, i.p) and euthanized in order to evaluate IBA1 in the hippocampus. The differences were analyzed using one-way ANOVA with Bonferroni's or Kruskal Wallis with Dunn's post-hoc test. RESULTS/CONCLUSION: STZ-lesioned rats present memory impairment besides the increased microglial activation. The treatment with AZ1 formulation reversed the memory impairment observed in the object recognition test and Y-maze and also reduced IBA1 in CA1 and DG.

6.
ACS Omega ; 5(7): 3504-3512, 2020 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-32118165

RESUMEN

The beneficial effect of polyphenols and magnesium(II) against oxidative stress motivated our research group to explore the antioxidant activity of phenMgIso, an aqueous soluble magnesium(II) complex containing 1,10-phenanthroline (phen) and isovanillic acid (Iso) as ligands. Combined electrospray ionization-mass spectrometry and DOSY-NMR techniques identified two complexes in methanolic solution: hexacoordinated [Mg(phen)2(Iso)]+ and tetracoordinated [Mg(phen)(Iso)]+. The cyclic voltammogram of phenMgIso in the anodic region showed a cyclic process that interrupts the isovanillic acid degradation, probably by stabilization of the corresponding phenoxyl radical via complexation with Mg(II), which is interesting for antioxidant applications. phenMgIso competes with 2,2,6,6-tetramethylpiperidine by 1O2 with IC50(1O2) = 15 µg m-1 and with nitrotetrazolium blue chloride by superoxide ions (IC50(O2 •-) = 3.6 µg mL-1). Exposure of both zebrafish (2 mg L-1) and wistar male rats (3 mg kg-1 day-1 dose for 21 days) to phenMgIso does not cause mortality or visual changes compared with the respective control groups, thus phenMgIso could be considered safe under the conditions of this study. Moreover, no significant changes in comparison to both control groups were observed in the biochemical parameters on the brain-acetylcholinesterase activity, digestive tract enzyme catalase, and glutathione-S-transferase. Conversely, the performance of superoxide dismutase activity in wistar male rats increased in the presence of a complex, resulting in enhanced capacity of rats for superoxide radical enzymatic scavenging. The synergistic action of phenMgIso may be explained by the strong electrostatic interaction between Mg(II) and the O,O(phenolate) group, which makes the Iso ligand easier to oxidize and deprotonate, generating a cyclic stable species under oxidative conditions.

7.
Behav Brain Res ; 371: 111981, 2019 10 03.
Artículo en Inglés | MEDLINE | ID: mdl-31141725

RESUMEN

Anxiety in Parkinson's disease may represent a physiological reaction to the development of other symptoms during disease progression. However, evidence suggests that the incidence of anxiety disorders in Parkinson's disease may be related to neurochemical changes. The present study addresses the question whether dopamine, noradrenaline and serotonin levels in brain structures related to Parkinson's disease and anxiety are responsible for anxiety-like behavior by using an animal model of parkinsonism based in the bilateral injection of the neurotoxin 6-hydroxydopamine (6-OHDA) in the substantia nigra pars compacta. For this, one day after the injection of 6-OHDA, the animals exhibited hypolocomotion and a lower frequency of rearings in the open field test, which was spontaneously reversed on the last day of motor assessment (day 21). The 6-OHDA injection also induced anxiety-like behavior in the elevated plus maze and contextual fear conditioning test (day 21 and 24, respectively). Neurochemical analysis showed a reduction of dopamine and norepinephrine levels in the striatum, prefrontal cortex, and amygdala. In addition, while the serotonin levels were reduced in the striatum and prefrontal cortex, it was increased in the amygdala. The present study indicates that the model of 6-OHDA-induced parkinsonism in rats induced an anxiety-like behavior that may be related to a dysregulation of neurotransmitter systems in brain areas involved with anxiety such as the amygdala, prefrontal cortex and striatum.


Asunto(s)
Ansiedad/metabolismo , Neurotransmisores/metabolismo , Oxidopamina/farmacología , Adrenérgicos , Amígdala del Cerebelo/metabolismo , Animales , Trastornos de Ansiedad/metabolismo , Conducta Animal , Encéfalo/metabolismo , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Dopamina/metabolismo , Masculino , Norepinefrina/metabolismo , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/psicología , Corteza Prefrontal/metabolismo , Ratas , Ratas Wistar , Serotonina/metabolismo , Sustancia Negra/metabolismo
8.
J Pharm Pharmacol ; 70(8): 1059-1068, 2018 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-29766510

RESUMEN

OBJECTIVES: To determine whether the drug saxagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor which is utilized for the treatment of Diabetes Mellitus, has neuroprotective effects in the animal model of Parkinson's disease (PD) induced by 6-hydroxydopamine (6-OHDA) in rats. METHODS: Male Wistar rats (weighing 280-300 g) received a bilateral infusion of 6-OHDA in the substantia nigra. Twenty-four hours later, they were treated with saxagliptin (1 mg/kg, p.o) once daily, for 21 days. The motor function was evaluated using the open field and rotarod (RT) tests. In addition, cognition was assessed with the novel object recognition test (ORT). After the evaluation of the behavioural tests, the animals were transcardially perfused to perform immunohistochemistry staining for tyrosine hydroxylase (TH) in the substantia nigra pars compacta (SNpc). KEY FINDINGS: Saxagliptin impaired the memory of animals in the sham group. CONCLUSIONS: Saxagliptin treatment did not exhibit neuroprotection and it did not improve the cognitive and motor deficits in the 6-OHDA model of PD. Interestingly, when saxagliptin was administered to the sham animals, a cognitive decline was observed. Therefore, this drug should be investigated as a possible treatment for PTSD.


Asunto(s)
Adamantano/análogos & derivados , Conducta Animal/efectos de los fármacos , Dipéptidos/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Adamantano/administración & dosificación , Adamantano/uso terapéutico , Animales , Dipéptidos/administración & dosificación , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Masculino , Memoria/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Fármacos Neuroprotectores/administración & dosificación , Oxidopamina , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/patología , Enfermedad de Parkinson Secundaria/fisiopatología , Ratas Wistar , Resultado del Tratamiento
9.
Physiol Behav ; 188: 298-310, 2018 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-29458117

RESUMEN

Parkinson's disease (PD) patients often suffer from circadian locomotor rhythms impairment and depression, important non-motor symptoms. It is known that toxin-based animal models of PD can reproduce these features. In a 6-hydroxydopamine (6-OHDA) intranigral model, we first investigated the possible disturbances on circadian rhythms of locomotor activity. The rats were divided into 6-OHDA and Sham groups. After a partial dopaminergic lesion, the 6-OHDA group showed slight alterations in different circadian locomotor rhythms parameters. In a second experiment, we hypothesized agomelatine, an melatoninergic antidepressant with potential to resynchronize disturbed rhythms, could prevent neuronal damage and rhythm alterations in the same 6-OHDA model. The animals were divided into four groups: 6-OHDA+vehicle, 6-OHDA+ago, Sham+vehicle and 6-OHDA+ago. However, the treated animals (agomelatine 50 mg/kg for 22 days) showed an impaired rhythm robustness, and agomelatine did not induce significant changes in the other circadian parameters nor neuroprotection. Finally, in a third experiment, we examined the effects of agomelatine in the 6-OHDA model regarding depressive-like behavior, evaluated by sucrose preference test. The animals were also divided into four groups: 6-OHDA+vehicle, 6-OHDA+ago, Sham+vehicle and 6-OHDA+ago. The toxin infused animals showed a decrease in sucrose preference in comparison with the vehicle infused animals, however, agomelatine did not prevent this decrease. Our findings indicate that agomelatine worsened circadian locomotor rhythm and was not able to reverse the depressive-like behavior of rats in the 6-OHDA PD model.


Asunto(s)
Acetamidas/uso terapéutico , Ritmo Circadiano/efectos de los fármacos , Depresión/tratamiento farmacológico , Hipnóticos y Sedantes/uso terapéutico , Locomoción/efectos de los fármacos , Animales , Depresión/inducido químicamente , Conducta Exploratoria/efectos de los fármacos , Preferencias Alimentarias/efectos de los fármacos , Masculino , Oxidopamina/toxicidad , Ratas , Ratas Wistar , Estadísticas no Paramétricas , Sacarosa/administración & dosificación , Simpaticolíticos/toxicidad , Factores de Tiempo , Tirosina 3-Monooxigenasa/metabolismo
10.
Mol Neurobiol ; 55(5): 4280-4296, 2018 May.
Artículo en Inglés | MEDLINE | ID: mdl-28623617

RESUMEN

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.


Asunto(s)
Envejecimiento/patología , Enfermedad de Alzheimer/fisiopatología , Encéfalo/patología , Encéfalo/fisiopatología , Inflamación/patología , Trastornos de la Memoria/fisiopatología , Neurogénesis , Memoria Espacial , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Animales , Astrocitos/patología , Conducta Animal , Biomarcadores/metabolismo , Modelos Animales de Enfermedad , Proteínas de Dominio Doblecortina , Miedo , Inyecciones Intraventriculares , Antígeno Ki-67/metabolismo , Masculino , Aprendizaje por Laberinto , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/patología , Microglía/patología , Proteínas Asociadas a Microtúbulos/metabolismo , Neuropéptidos/metabolismo , Ratas Wistar , Estreptozocina
11.
Behav Brain Res ; 335: 41-54, 2017 09 29.
Artículo en Inglés | MEDLINE | ID: mdl-28801114

RESUMEN

Curcumin is a natural polyphenol with evidence of antioxidant, anti-inflammatory and neuroprotective properties. Recent evidence also suggests that curcumin increases cognitive performance in animal models of dementia, and this effect would be related to its capacity to enhance adult neurogenesis. The aim of this study was to test the hypothesis that curcumin treatment would be able to preserve cognition by increasing neurogenesis and decreasing neuroinflammation in the model of dementia of Alzheimer's type induced by an intracerebroventricular injection of streptozotocin (ICV-STZ) in Wistar rats. The animals were injected with ICV-STZ or vehicle and curcumin treatments (25, 50 and 100mg/kg, gavage) were performed for 30days. Four weeks after surgery, STZ-lesioned animals exhibited impairments in short-term spatial memory (Object Location Test (OLT) and Y maze) and short-term recognition memory (Object Recognition Test - ORT), decreased cell proliferation and immature neurons (Ki-67- and doublecortin-positive cells, respectively) in the subventricular zone (SVZ) and dentate gyrus (DG) of hippocampus, and increased immunoreactivity for the glial markers GFAP and Iba-1 (neuroinflammation). Curcumin treatment in the doses of 50 and 100mg/kg prevented the deficits in recognition memory in the ORT, but not in spatial memory in the OLT and Y maze. Curcumin treatment exerted only slight improvements in neuroinflammation, resulting in no improvements in hippocampal and subventricular neurogenesis. These results suggest a positive effect of curcumin in object recognition memory which was not related to hippocampal neurogenesis.


Asunto(s)
Curcumina/farmacología , Memoria a Corto Plazo/efectos de los fármacos , Memoria Espacial/efectos de los fármacos , Enfermedad de Alzheimer/psicología , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Cognición/efectos de los fármacos , Demencia/tratamiento farmacológico , Giro Dentado/efectos de los fármacos , Modelos Animales de Enfermedad , Proteína Doblecortina , Hipocampo/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Neuroinmunomodulación/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Ratas , Ratas Wistar
12.
Arq Neuropsiquiatr ; 73(7): 616-23, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-26200058

RESUMEN

Parkinson's disease (PD) is the second most common neurodegenerative disease affecting approximately 1.6% of the population over 60 years old. The cardinal motor symptoms are the result of progressive degeneration of substantia nigra pars compacta dopaminergic neurons which are involved in the fine motor control. Currently, there is no cure for this pathology and the cause of the neurodegeneration remains unknown. Several studies suggest the involvement of neuroinflammation in the pathophysiology of PD as well as a protective effect of anti-inflammatory drugs both in animal models and epidemiological studies, although there are controversial reports. In this review, we address evidences of involvement of inflammatory process and possible therapeutic usefulness of anti-inflammatory drugs in PD.


Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Encefalitis/tratamiento farmacológico , Encefalitis/fisiopatología , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/fisiopatología , Animales , Antiinflamatorios no Esteroideos/farmacología , Citocinas , Humanos , Degeneración Nerviosa/tratamiento farmacológico , Degeneración Nerviosa/fisiopatología , Enfermedad de Parkinson/etiología , Porción Compacta de la Sustancia Negra/fisiopatología , Reproducibilidad de los Resultados , Factores de Riesgo , Resultado del Tratamiento
13.
Arq. neuropsiquiatr ; 73(7): 616-623, 07/2015. tab
Artículo en Inglés | LILACS | ID: lil-752381

RESUMEN

Parkinson’s disease (PD) is the second most common neurodegenerative disease affecting approximately 1.6% of the population over 60 years old. The cardinal motor symptoms are the result of progressive degeneration of substantia nigra pars compacta dopaminergic neurons which are involved in the fine motor control. Currently, there is no cure for this pathology and the cause of the neurodegeneration remains unknown. Several studies suggest the involvement of neuroinflammation in the pathophysiology of PD as well as a protective effect of anti-inflammatory drugs both in animal models and epidemiological studies, although there are controversial reports. In this review, we address evidences of involvement of inflammatory process and possible therapeutic usefulness of anti-inflammatory drugs in PD.


A doença de Parkinson (DP) é a segunda doença neurodegenerativa mais comum afetando aproximadamente 1,6% da população acima de 60 anos de idade. Os sinais motores cardinais são o resultado da degeneração progressiva de neurônios dopaminérgicos da substantia nigra pars compacta (SNpc), a qual está intimamente envolvida com o controle motor. Atualmente, não há cura para esta patologia e a causa da neurodegeneração permanece desconhecida. Contudo, muitos estudos sugerem o envolvimento da neuroinflamação na patofisiologia da DP bem como um efeito protetor de drogas antiinflamatórias tanto em modelos animais quanto em estudos epidemiológicos, embora haja relatos controversos. Nesta revisão, foram abordadas evidências de envolvimento do processo inflamatório e uma possível utilidade terapêutica de drogas antiinflamatórias na DP.


Asunto(s)
Animales , Humanos , Antiinflamatorios no Esteroideos/uso terapéutico , Encefalitis/tratamiento farmacológico , Encefalitis/fisiopatología , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/fisiopatología , Antiinflamatorios no Esteroideos/farmacología , Citocinas , Degeneración Nerviosa/tratamiento farmacológico , Degeneración Nerviosa/fisiopatología , Enfermedad de Parkinson/etiología , Porción Compacta de la Sustancia Negra/fisiopatología , Reproducibilidad de los Resultados , Factores de Riesgo , Resultado del Tratamiento
14.
J Pharmacol Pharmacother ; 6(1): 7-12, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25709346

RESUMEN

OBJECTIVE: To investigate the antidepressant-like effect of piroxicam with a focus on serotonergic neurotransmission. MATERIALS AND METHODS: Rats were randomly distributed into the following groups: 0.9% saline control; 3 mg/kg pizotifen; 10 mg/kg sertraline; 10 mg/kg piroxicam; 10 mg/kg sertraline + 10 mg/kg piroxicam; 10 mg/kg sertraline + 3 mg/kg pizotifen; and 10 mg/kg piroxicam + 3 mg/kg pizotifen. All the drugs were dissolved in 0.9% saline. Three administrations of the drugs (piroxicam and sertraline) were performed 1, 5 and 24 h before testing the animals in the open field followed by the forced swim test (FST). Piroxicam and sertraline were administered orally by gavage and pizotifen was administered intraperitoneally 30 min before gavage. Immediately after the FST, the hippocampi were rapidly dissected for neurochemical analysis in high-performance liquid chromatography. RESULTS: Acute treatment with piroxicam promoted an antidepressant-like effect in the FST, which was associated with an increase in serotonin levels in the hippocampus. This effect was potentiated in the piroxicam + sertraline group but counteracted by administration of the non-selective serotonin receptor antagonist pizotifen. CONCLUSION: These results suggest that the antidepressant-like effect of piroxicam in the FST is mediated by the serotonin system; however, by different mechanisms from those of sertraline.

15.
Brain Res ; 1593: 95-105, 2014 Dec 17.
Artículo en Inglés | MEDLINE | ID: mdl-25301688

RESUMEN

Parkinson׳s disease (PD) is a neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Systemic and intranigral exposure to rotenone in rodents reproduces many of the pathological and behavioral features of PD in humans and thus has been used as an animal model of the disease. Melatonin is a neurohormone secreted by the pineal gland, which has several important physiological functions. It has been reported to be neuroprotective in some animal models of PD. The present study investigated the effects of prolonged melatonin treatment in rats previously exposed to rotenone. The animals were intraperitoneally treated for 10 days with rotenone (2.5mg/kg) or its vehicle. 24h later, they were intraperitoneally treated with melatonin (10mg/kg) or its vehicle for 28 days. One day after the last rotenone exposure, the animals exhibited hypolocomotion in the open field test, which spontaneously reversed at the last motor evaluation. We verified that prolonged melatonin treatment after dopaminergic lesion did not alter motor function but produced antidepressant-like effects in the forced swim test, prevented the rotenone-induced reduction of striatal dopamine, and partially prevented tyrosine hydroxylase immunoreactivity loss in the SNpc. Our results indicate that melatonin exerts neuroprotective and antidepressant-like effects in the rotenone model of PD.


Asunto(s)
Antidepresivos/administración & dosificación , Melatonina/administración & dosificación , Fármacos Neuroprotectores/administración & dosificación , Trastornos Parkinsonianos/tratamiento farmacológico , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/patología , Cuerpo Estriado/fisiopatología , Dopamina/metabolismo , Masculino , Actividad Motora/efectos de los fármacos , Norepinefrina/metabolismo , Trastornos Parkinsonianos/patología , Trastornos Parkinsonianos/fisiopatología , Porción Compacta de la Sustancia Negra/efectos de los fármacos , Porción Compacta de la Sustancia Negra/patología , Porción Compacta de la Sustancia Negra/fisiopatología , Distribución Aleatoria , Ratas Wistar , Rotenona , Serotonina/metabolismo , Tirosina 3-Monooxigenasa/metabolismo
16.
Behav Brain Res ; 275: 136-45, 2014 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-25218873

RESUMEN

It has been observed that the secretion pattern of melatonin is modified in Parkinson's disease (PD). Hence, it is hypothesized that dysregulations of melatonin MT2 receptors may be involved in the installation of depression in PD patients. Together with recent evidence based on the use of the intranigral rotenone model of PD, have led to the hypothesis that modulating the striatal MT2 receptor could provide a more comprehensive understanding of the antidepressant properties triggered. To further investigate this issue, male Wistar rats were infused with intranigral rotenone (12µg/µL) and seven days later subjected to a rapid eye movement sleep deprivation (REMSD) for 24h. After, we injected within the striatum the MT2 selective agonist, 8-M-PDOT (10µg/µL), the MT2 selective antagonist, 4-P-PDOT (5µg/µL) or vehicle. Subsequently, they were tested in the forced swimming test and were allowed to perform the sleep rebound (REB). Then, the rats were re-tested, and the striatum, hippocampus and substantia nigra pars compacta (SNpc) were collected for neurochemical purposes. Results indicated substantial antidepressant effects promoted by the blockade of striatal MT2 receptors that were potentiated by REMSD. MT2 activation increased DA levels in the striatum and hippocampus, while MT2 blockade increase DA in the SNpc. 4-P-PDOT treatment of the rotenone REMSD group generated a decrement in 5-HT levels within the striatum, hippocampus and SNpc. However, increased 5-HT turnover was observed among these structures. Therefore, we demonstrated the neurochemical antidepressant effect induced by striatal MT2 blockage associated with REMSD in the rotenone model of PD.


Asunto(s)
Monoaminas Biogénicas/metabolismo , Cuerpo Estriado/fisiología , Depresión/tratamiento farmacológico , Depresión/metabolismo , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Depresión/etiología , Modelos Animales de Enfermedad , Insecticidas/toxicidad , Masculino , Ratas , Ratas Wistar , Receptores de Melatonina/antagonistas & inhibidores , Rotenona/toxicidad , Privación de Sueño , Estadística como Asunto , Natación/psicología , Tetrahidronaftalenos/farmacología
17.
Behav Brain Res ; 274: 390-9, 2014 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-25127682

RESUMEN

A large body of evidence suggests that peroxisome proliferator-activated receptor (PPAR) agonists may improve some of the pathological features of Parkinson's disease (PD). In the present study, we evaluated the effects of the PPAR-α agonist fenofibrate (100mg/kg) and PPAR-γ agonist pioglitazone (30mg/kg) in a rat model of parkinsonism induced by intranigral 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine (MPTP). Male Wistar rats were pretreated with both drugs for 5 days and received an infusion of MPTP. The experiments were divided into two parts. First, 1, 7, 14, and 21 days after surgery, the animals were submitted to the open field test. On days 21 and 22, the rats were subjected to the forced swim test and two-way active avoidance task. In the second part of the study, 24h after neurotoxin administration, immunohistochemistry was performed to assess tyrosine hydroxylase activity. The levels of dopamine and its metabolites in the striatum were determined using high-performance liquid chromatography, and fluorescence detection was used to assess caspase-3 activation in the substantia nigra pars compacta (SNpc). Both fenofibrate as pioglitazone protected against hypolocomotion, depressive-like behavior, impairment of learning and memory, and dopaminergic neurodegeneration caused by MPTP, with dopaminergic neuron loss of approximately 33%. Fenofibrate and pioglitazone also protected against the increased activation of caspase-3, an effector enzyme of the apoptosis cascade that is considered one of the pathological features of PD. Thus, PPAR agonists may contribute to therapeutic strategies in PD.


Asunto(s)
Intoxicación por MPTP/inducido químicamente , Intoxicación por MPTP/prevención & control , Fármacos Neuroprotectores/uso terapéutico , PPAR alfa/metabolismo , PPAR gamma/metabolismo , Animales , Reacción de Prevención/efectos de los fármacos , Caspasa 3/metabolismo , Modelos Animales de Enfermedad , Dopamina/análogos & derivados , Dopamina/metabolismo , Esquema de Medicación , Interacciones Farmacológicas , Conducta Exploratoria/efectos de los fármacos , Fenofibrato/uso terapéutico , Masculino , Pioglitazona , Ratas , Ratas Wistar , Sustancia Negra/efectos de los fármacos , Natación/psicología , Tiazolidinedionas/uso terapéutico , Factores de Tiempo , Tirosina 3-Monooxigenasa/metabolismo
18.
Neurotox Res ; 26(4): 351-62, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-24740429

RESUMEN

Idiopathic Parkinson's disease is a neurodegenerative disorder that affects approximately 1 % of the population over 55 years of age. The disease manifests itself through motor and nonmotor symptoms induced mainly by the neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The possible mechanisms involved in this pathology include mitochondrial dysfunction, neuroinflammation, and oxidative stress. The present study evaluated the effects of the nonselective cyclooxygenase inhibitor ibuprofen on motor and depressive-like behavior induced by rotenone in rats. Rotenone (2.5 mg/kg, i.p., for 10 days) decreased tyrosine hydroxylase immunoreactivity in the SNpc, and ibuprofen treatment (15 mg/kg, p.o., for 22 days) blocked this impairment. We also found that rotenone-induced motor deficits (hypolocomotion) and depressive-like behavior, and ibuprofen was able to reverse these deficits. In addition to motor and nonmotor behaviors, we evaluated oxidative stress induced by rotenone. Rotenone administration depleted glutathione levels in the hippocampus and reduced catalase activity in both the hippocampus and striatum. Post treatment with ibuprofen blocked the depletion of glutathione induced by rotenone and increased the basal levels of this antioxidant in the striatum. Ibuprofen also restored catalase activity. The neuroprotective effects of ibuprofen against toxicity induced by rotenone appear to be attributable to its antioxidant properties, in addition to cyclooxygenase inhibition.


Asunto(s)
Antidepresivos/farmacología , Antioxidantes/farmacología , Encéfalo/efectos de los fármacos , Depresión/tratamiento farmacológico , Actividad Motora/efectos de los fármacos , Trastornos Parkinsonianos/tratamiento farmacológico , Animales , Encéfalo/patología , Encéfalo/fisiopatología , Catalasa/metabolismo , Depresión/patología , Depresión/fisiopatología , Relación Dosis-Respuesta a Droga , Glutatión/metabolismo , Ibuprofeno , Masculino , Actividad Motora/fisiología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Trastornos Parkinsonianos/patología , Trastornos Parkinsonianos/fisiopatología , Trastornos Parkinsonianos/psicología , Distribución Aleatoria , Ratas Wistar , Rotenona , Superóxido Dismutasa/metabolismo , Tirosina 3-Monooxigenasa/metabolismo
19.
Artículo en Inglés | MEDLINE | ID: mdl-24593945

RESUMEN

Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The etiology and pathogenesis of PD are still unknown, however, many evidences suggest a prominent role of oxidative stress, inflammation, apoptosis, mitochondrial dysfunction and proteosomal dysfunction. The peroxisome proliferator-activated receptor (PPAR) ligands, a member of the nuclear receptor family, have anti-inflammatory activity over a variety of rodent's models for acute and chronic inflammation. PPAR-α agonists, a subtype of the PPAR receptors, such as fenofibrate, have been shown a major role in the regulation of inflammatory processes. Animal models of PD have shown that neuroinflammation is one of the most important mechanisms involved in dopaminergic cell death. In addition, anti-inflammatory drugs are able to attenuate toxin-induced parkinsonism. In this study we evaluated the effects of oral administration of fenofibrate 100mg/kg 1h after infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the SNpc. First, we assessed the motor behavior in the open field for 24h, 7, 14 and 21 days after MPTP. Twenty-two days after surgery, the animals were tested for two-way active avoidance and forced swimming for evaluation regarding cognitive and depressive parameters, respectively. Twenty-three days after infusion of the toxin, we quantified DA and turnover and evaluated oxidative stress through the measurement of GSH (glutathione peroxidase), SOD (superoxide dismutase) and LOOH (hydroperoxide lipid). The data show that fenofibrate was able to decrease hypolocomotion caused by MPTP 24h after injury, depressive-like behavior 22 days after the toxin infusion, and also protected against decreased level of DA and excessive production of reactive oxygen species (ROS) 23 days after surgery. Thus, fenofibrate has shown a neuroprotective effect in the MPTP model of Parkinson's disease.


Asunto(s)
Encefalitis/etiología , Encefalitis/prevención & control , Fenofibrato/uso terapéutico , Hipolipemiantes/uso terapéutico , Intoxicación por MPTP/complicaciones , Animales , Reacción de Prevención/efectos de los fármacos , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Dopamina/metabolismo , Conducta Exploratoria/efectos de los fármacos , Glutatión/metabolismo , Peróxidos Lipídicos/metabolismo , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Superóxido Dismutasa/metabolismo , Natación , Factores de Tiempo , Tirosina 3-Monooxigenasa/metabolismo
20.
J Neural Transm (Vienna) ; 121(6): 671-82, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24463888

RESUMEN

Beyond the current hypothesis of depression, several new biological substrates have been proposed for this disorder. The present study investigated whether the anti-inflammatory drugs celecoxib and piroxicam have antidepressant activity in animal models of depression. After acute administration, we observed antidepressant-like effects of celecoxib (10 mg/kg) and piroxicam (10 mg/kg) in the modified forced swim test in rats. Piroxicam increased serotonin and norepinephrine levels in the hippocampus. Prolonged (21-day) treatment with celecoxib (10 mg/kg) and piroxicam (10 mg/kg) rescued sucrose preference in a chronic mild stress model of depression. Additionally, the chronic mild stress-induced reduction of hippocampal glutathione was prevented by treatment with celecoxib and piroxicam. Superoxide dismutase in the hippocampus was increased after chronic mild stress compared with the non-stressed saline group. The non-stressed celecoxib and piroxicam groups and stressed piroxicam group exhibited an increase in hippocampal superoxide dismutase activity compared with the stressed saline group. Lipid hydroperoxide was increased in the stressed group treated with vehicle and non-stressed group treated with imipramine but not in the stressed groups treated with celecoxib and piroxicam. These results suggest that the antidepressant-like effects of anti-inflammatory drugs might be attributable to enhanced antioxidant defenses and attenuated oxidative stress in the hippocampus.


Asunto(s)
Antidepresivos/uso terapéutico , Depresión/tratamiento farmacológico , Piroxicam/uso terapéutico , Pirazoles/uso terapéutico , Sulfonamidas/uso terapéutico , Animales , Antidepresivos/farmacología , Celecoxib , Modelos Animales de Enfermedad , Conducta Exploratoria/efectos de los fármacos , Privación de Alimentos , Glutatión/metabolismo , Peróxidos Lipídicos/metabolismo , Masculino , Norepinefrina/metabolismo , Piroxicam/farmacología , Pirazoles/farmacología , Ratas , Ratas Wistar , Estrés Fisiológico/efectos de los fármacos , Sacarosa/administración & dosificación , Sulfonamidas/farmacología , Superóxido Dismutasa/metabolismo , Natación/psicología , Factores de Tiempo , Privación de Agua
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