RESUMEN

Dysfunction of the corticolimbic system, particularly at the dendritic spine level, is a recognized core mechanism in neurodevelopmental disorders such as schizophrenia. Neonatal ventral hippocampus lesion (NVHL) in Sprague-Dawley rats induces both a schizophrenia-related behavioral phenotype and dendritic spine pathology (reduced total number and mature spines) in corticolimbic areas, which is mitigated by antipsychotics. However, there is limited information on the impact of rat strain on NVHL outcomes and antipsychotic effects. We compared the behavioral performance in the open field, novel object recognition (NORT), and social interaction tests, as well as structural neuroplasticity with the Golgi-Cox stain in Wistar-Kyoto (WKY) and spontaneously hypertensive (SH) male rats with and without NVHL. Additionally, we explored the effect of the atypical antipsychotic risperidone (RISP). WKY rats with NVHL displayed motor hyperactivity without impairments in memory and social behavior, accompanied by dendritic spine pathology in the neurons of the prefrontal cortex (PFC) layer 3 and basolateral amygdala. RISP treatment reduced motor activity and had subtle and selective effects on the neuroplasticity alterations. In SH rats, NVHL increased the time spent in the border area during the open field test, impaired the short-term performance in NORT, and reduced social interaction time, deficits that were corrected after RISP administration. The NVHL caused dendritic spine pathology in the PFC layers 3 and 5 of SH rats, which RISP treatment ameliorated. Our results support the utility of the NVHL model for exploring neuroplasticity mechanisms in schizophrenia and understanding pharmacotherapy.

Asunto(s)

Antipsicóticos , Hipocampo , Animales , Ratas , Masculino , Ratas Endogámicas SHR , Ratas Sprague-Dawley , Ratas Endogámicas WKY , Animales Recién Nacidos , Corteza Prefrontal , Risperidona , Antipsicóticos/farmacología , Modelos Animales de Enfermedad

RESUMEN

The prevalence of autism spectrum disorder (ASD), a neurodevelopmental condition that impacts social interaction and sensory processing, is rising. Valproic acid (VPA) exposure during pregnancy causes autistic-like traits in offspring. Olanzapine (OLZ), an atypical antipsychotic, is used to treat ASD. We assessed the impact of OLZ on behavior, neuromorphology, and nitric oxide (NO) levels in the hippocampus using prenatal VPA treatment in rats. It is commonly known that ASD patients exhibit sensory abnormalities. As such, we utilized the tail flick test to validate the ASD model. In the novel object recognition test (NORT), VPA exposure reduces the discrimination index (DI) in the first introduction to the novel object. Moreover, OLZ and vehicle-treated rats perform differently in the second exposition to the DI of the novel object, suggesting that OLZ reverses VPA-induced deficits in recognition memory. The latency to find the hidden platform in the Morris water maze test of memory and learning improves in VPA-exposed rats after OLZ administration, indicating that OLZ improves spatial memory in these rats. Administration of prenatal VPA induces neuronal hypotrophy and reduces spine density in pyramidal neurons of the CA1 region of the hippocampus. Treatment with OLZ corrects the neuromorphological changes brought on by VPA. In the CA1 region of the hippocampus, VPA treatment increases the number of neurons, which normalizes with OLZ treatment. OLZ increases the NO levels in the dorsal hippocampus in control rats. In rats exposed to VPA, the second-generation antipsychotic OLZ reduces memory-related and neuroplastic alterations. The current findings support the use of OLZ in this illness and further validate the use of prenatal VPA as a model of ASD.

Asunto(s)

Antipsicóticos , Trastorno del Espectro Autista , Trastorno Autístico , Efectos Tardíos de la Exposición Prenatal , Embarazo , Femenino , Ratas , Masculino , Animales , Humanos , Trastorno Autístico/inducido químicamente , Trastorno Autístico/tratamiento farmacológico , Antipsicóticos/farmacología , Antipsicóticos/uso terapéutico , Olanzapina/efectos adversos , Trastorno del Espectro Autista/inducido químicamente , Ácido Valproico/farmacología , Ácido Valproico/uso terapéutico , Neuronas , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/tratamiento farmacológico , Modelos Animales de Enfermedad , Efectos Tardíos de la Exposición Prenatal/tratamiento farmacológico , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Conducta Animal , Conducta Social

RESUMEN

Aging induces cognitive decline, reduces of synaptic plasticity and increases oxidative reactive species (ROS) in the central nervous system. Traditional medicine has long benefitted from naturally occurring molecules such as curcumin (diferuloymethane). Curcumin is extracted from the plant Curcuma longa and is known for its synaptic and antioxidant-related benefits. In this study, we tested the hypothesis that chronic curcumin treatment reduces cognitive and cellular effects of aging. Curcumin-treated mice showed improved learning and memory using the Morris Water Maze and novel object recognition task. In addition, using the Golgi-Cox stain, curcumin treatment increased spine density in all evaluated regions and increased dendritic arborization in the prefrontal cortex (PFC) layer 3 and CA3 subregion of the hippocampus. Moreover, chronic curcumin exposure increased synaptophysin and actin expression and reduced glial fibrillary acidic protein expression, a marker of astrocytes, in the hippocampus (CA1 and CA3 subregions), while simultaneously reducing the ROS-related molecule, metallothionein 3 expression in the PFC and hippocampus. Collectively, these novel findings suggest that curcumin reduces cognitive, neuronal and astrocytic signs of aging in mice.

Asunto(s)

Curcumina , Animales , Curcumina/farmacología , Hipocampo/metabolismo , Ratones , Plasticidad Neuronal/fisiología , Neuronas , Especies Reactivas de Oxígeno/metabolismo

RESUMEN

Hypertension is a risk factor for vascular dementia, which is the second most prevalent type of dementia, just behind Alzheimer's disease. This highlights the brain vulnerability due to hypertension, which may increase with aging. Thus, studying how hypertension affects neural cells and behavior, as well as the effects of antihypertensives on these alterations, it's important to understand the hypertension consequences in the brain. The spontaneously hypertensive rat (SHR) has been useful for the study of hypertension alterations in diverse organs, including the brain. Thus, we studied the losartan effects on cognitive and structural neuroplasticity impairments in SHR of 10 months of age. In the first instance, we evaluated the losartan effects on exploratory behavior and novel object recognition test (NORT) in the SHR. Then, we assessed the density and morphology of dendritic spines of pyramidal neurons from the prefrontal cortex (PFC) layers 3 and 5, and CA1 of the dorsal Hp (dHp). Our results indicate that in SHR, losartan treatment (2 months, 15 mg/Kg/day) reduces high blood pressure to age-matched vehicle-treated Wistar-Kyoto (WKY) rat levels. Moreover, losartan improved long-term memory in SHR compared with age-matched vehicle-treated WKY rats, without affecting the locomotor and anxiety behaviors. The behavioral improvement of the SHR can be associated with the increase in the number of dendritic spines and the mushroom spine population in the PFC and the dHp. In conclusion, losartan enhances cognitive impairments by controlling the high blood pressure and improving neuroplasticity in animals with chronic hypertension.

Asunto(s)

Losartán , Plasticidad Neuronal , Animales , Presión Sanguínea , Cognición , Losartán/farmacología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY

RESUMEN

Attention deficit hyperactivity disorder (ADHAD) is a neurobehavioral disorder that affects children and adolescents with a high prevalence. Despite its prevalence and an unclear etiology, previous reports suggest that it is closely related to homocysteine metabolism. Male Sprague Dawley rats were administered with homocysteine from postnatal day (PD) 2 to PD 16. Locomotor activity was evaluated at 35 PD (prepuberal age) and 60 PD (adult age) before and after amphetamine administration. In rats evaluated at both ages, homocysteine induced hyperactivity, and the amphetamine administration reduced hyperactivity significantly at 35 PD, but not at 60 PD. In the social interaction test, homocysteine reduced the number of contacts and increased the latency to the first contact only in rats at 35 PD. Homocysteine also had an effect on short term memory at 35D and 60 PD and long-term memory at 60 PD. Morphological changes were found mainly in the shape of dendritic spines in the prefrontal cortex (PFC-3), dorsal hippocampus (CA1), dentate gyrus (DG) and nucleus accumbens (NAcc), in rats administered neonatally with homocysteine at both ages studied. In prepuberal and adult rats, there was an increase in dendritic length in DG and NAcc, respectively. The dendritic spine morphology also was altered at both ages, mainly decreasing the number of mushroom spines in NAcc and CA1 at 30 PD and in all the areas studied at 60 PD rats. Those areas are associated with the processes of attention, learning and memory that were studied, and those alterations are possibly related to changes observed in the behavioral tests. These behavioral and morphological changes in rats at 35 PD administered with homocysteine could be similar to changes found in children diagnosed with ADHD. Moreover, half to two thirds of children diagnosed with ADHD reach adulthood with this disorder. In this study we found similarities with ADHD, finding alterations in both rats at 35 PD and 60 PD. So, this may be proposed as an animal model to study this disorder present in children, adolescents and adults.

Asunto(s)

Trastorno por Déficit de Atención con Hiperactividad , Animales , Espinas Dendríticas , Modelos Animales de Enfermedad , Homocisteína/farmacología , Masculino , Neuronas , Corteza Prefrontal , Ratas , Ratas Sprague-Dawley

RESUMEN

Neurodegenerative diseases called tauopathies, such as Alzheimer's disease (AD), frontotemporal dementia, progressive supranuclear palsy, and Parkinson's disease, among others, are characterized by the pathological processing and accumulation of tau protein. AD is the most prevalent neurodegenerative disease and is characterized by two lesions: neurofibrillary tangles (NFTs) and neuritic plaques. The presence of NFTs in the hippocampus and neocortex in early and advanced stages, respectively, correlates with the patient's cognitive deterioration. So far, no drugs can prevent, decrease, or limit neuronal death due to abnormal pathological tau accumulation. Among potential non-pharmacological treatments, physical exercise has been shown to stimulate the development of stem cells (SCs) and may be useful in early stages. However, this does not prevent neuronal death from the massive accumulation of NFTs. In recent years, SCs therapies have emerged as a promising tool to repopulate areas involved in cognition in neurodegenerative diseases. Unfortunately, protocols for SCs therapy are still being developed and the mechanism of action of such therapy remains unclear. In this review, we show the advances and limitations of SCs therapy. Finally, we provide a critical analysis of its clinical use for AD.

Asunto(s)

Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/terapia , Ovillos Neurofibrilares/patología , Placa Amiloide/patología , Células Madre/metabolismo , Proteínas tau/metabolismo , Enfermedad de Alzheimer/patología , Amiloide/metabolismo , Regulación Gubernamental , Hipocampo/patología , Humanos , Neocórtex/patología

RESUMEN

Alzheimer's disease (AD) is a neurodegenerative disease, characterized histopathologically by intra-neuronal tau-related lesions and by the accumulation of amyloid ß-peptide (Aß) in the brain parenchyma and around cerebral blood vessels. According to the vascular hypothesis of AD, an alteration in the neurovascular unit (NVU) could lead to Aß vascular accumulation and promote neuronal dysfunction, accelerating neurodegeneration and dementia. To date, the effects of insoluble vascular Aß deposits on the NVU and the blood-brain barrier (BBB) are unknown. In this study, we analyze different Aß species and their association with the cells that make up the NVU. We evaluated post-mortem AD brain tissue. Multiple immunofluorescence assays were performed against different species of Aß and the main elements that constitute the NVU. Our results showed that there are insoluble vascular deposits of both full-length and truncated Aß species. Besides, insoluble aggregates are associated with a decrease in the phenotype of the cellular components that constitute the NVU and with BBB disruption. This approach could help identify new therapeutic targets against key molecules and receptors in the NVU that can prevent the accumulation of vascular fibrillar Aß in AD.

Asunto(s)

Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Astrocitos/patología , Vasos Sanguíneos/patología , Encéfalo/patología , Microglía/patología , Actinas/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Vasos Sanguíneos/metabolismo , Encéfalo/irrigación sanguínea , Encéfalo/metabolismo , Estudios de Casos y Controles , Caspasas/metabolismo , Humanos , Uniones Estrechas/patología

RESUMEN

Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide. Histopathologically, AD presents with two hallmarks: neurofibrillary tangles (NFTs), and aggregates of amyloid ß peptide (Aß) both in the brain parenchyma as neuritic plaques, and around blood vessels as cerebral amyloid angiopathy (CAA). According to the vascular hypothesis of AD, vascular risk factors can result in dysregulation of the neurovascular unit (NVU) and hypoxia. Hypoxia may reduce Aß clearance from the brain and increase its production, leading to both parenchymal and vascular accumulation of Aß. An increase in Aß amplifies neuronal dysfunction, NFT formation, and accelerates neurodegeneration, resulting in dementia. In recent decades, therapeutic approaches have attempted to decrease the levels of abnormal Aß or tau levels in the AD brain. However, several of these approaches have either been associated with an inappropriate immune response triggering inflammation, or have failed to improve cognition. Here, we review the pathogenesis and potential therapeutic targets associated with dysfunction of the NVU in AD.

Asunto(s)

Enfermedad de Alzheimer/fisiopatología , Encéfalo/irrigación sanguínea , Encéfalo/fisiopatología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Amiloide/metabolismo , Animales , Barrera Hematoencefálica/patología , Barrera Hematoencefálica/fisiopatología , Encéfalo/patología , Humanos , Terapia Molecular Dirigida

RESUMEN

Chronic consumption of ß-sitosterol-ß-D-glucoside (BSSG), a neurotoxin contained in cycad seeds, leads to Parkinson's disease in humans and rodents. Here, we explored whether a single intranigral administration of BSSG triggers neuroinflammation and neurotoxic A1 reactive astrocytes besides dopaminergic neurodegeneration. We injected 6 µg BSSG/1 µL DMSO or vehicle into the left substantia nigra and immunostained with antibodies against tyrosine hydroxylase (TH) together with markers of microglia (OX42), astrocytes (GFAP, S100ß, C3), and leukocytes (CD45). We also measured nitric oxide (NO), lipid peroxidation (LPX), and proinflammatory cytokines (TNF-α, IL-1ß, IL-6). The Evans blue assay was used to explore the blood-brain barrier (BBB) permeability. We found that BSSG activates NO production on days 15 and 30 and LPX on day 120. Throughout the study, high levels of TNF-α were present in BSSG-treated animals, whereas IL-1ß was induced until day 60 and IL-6 until day 30. Immunoreactivity of activated microglia (899.0 ± 80.20%) and reactive astrocytes (651.50 ± 11.28%) progressively increased until day 30 and then decreased to remain 251.2 ± 48.8% (microglia) and 91.02 ± 39.8 (astrocytes) higher over controls on day 120. C3(+) cells were also GFAP and S100ß immunoreactive, showing they were neurotoxic A1 reactive astrocytes. BBB remained permeable until day 15 when immune cell infiltration was maximum. TH immunoreactivity progressively declined, reaching 83.6 ± 1.8% reduction on day 120. Our data show that BSSG acute administration causes chronic neuroinflammation mediated by activated microglia, neurotoxic A1 reactive astrocytes, and infiltrated immune cells. The severe neuroinflammation might trigger Parkinson's disease in BSSG intoxication.

Asunto(s)

Astrocitos/efectos de los fármacos , Astrocitos/inmunología , Inflamación/etiología , Neurotoxinas/inmunología , Sitoesteroles/administración & dosificación , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo , Animales , Astrocitos/metabolismo , Biomarcadores , Enfermedad Crónica , Citocinas/metabolismo , Modelos Animales de Enfermedad , Humanos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Mediadores de Inflamación/metabolismo , Leucocitos/inmunología , Leucocitos/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Microglía/inmunología , Microglía/metabolismo , Neurotoxinas/efectos adversos , Estrés Oxidativo/efectos de los fármacos , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Ratas , Sustancia Negra/patología

RESUMEN

Worldwide, around 50 million people have dementia. Alzheimer's disease (AD) is the most common type of dementia and one of the major causes of disability and dependency among the elderly worldwide. Clinically, AD is characterized by impaired memory accompanied by other deficiencies in the cognitive domain. Neuritic plaques (NPs) and neurofibrillary tangles (NFTs) are histopathological lesions that define brains with AD. NFTs consist of abundant intracellular paired helical filaments (PHFs) whose main constituent is tau protein. Tau undergoes posttranslational changes including hyperphosphorylation and truncation, both of which favor conformational changes in the protein. The sequential pathological processing of tau is illustrated with the following specific markers: pT231, TG3, AT8, AT100, and Alz50. Two proteolysis sites for tau have been described-truncation at glutamate 391 and at aspartate 421-and which can be demonstrated by reactivity with the antibodies 423 and TauC-3, respectively. In this review, we describe the molecular changes in tau protein as pre-NFTs progress to extracellular NFTs and during which the formation of a minimal nucleus of the filament, as the PHF core, occurs. We also analyzed the PHF core as the initiator of PHFs and tau phosphorylation as a protective neuronal mechanism against the assembly of the PHF core.

RESUMEN

We recently developed the National Dementia Biobank in México (BioBanco Nacional de Demencias, BND) as a unit for diagnosis, research, and tissue transfer for research purposes. BND is associated with the Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de Mexico (UNAM), Mexico. The donation of fluids, brain, and other organs of deceased donors is crucial for understanding the underlying mechanisms of neurodegenerative diseases and for the development of successful treatment. Our laboratory research focuses on 1) analysis of the molecular processing of the proteins involved in those neurodegenerative diseases termed tauopathies and 2) the search for biomarkers for the non-invasive and early diagnosis of Alzheimer's disease.

Asunto(s)

Enfermedad de Alzheimer/patología , Bancos de Muestras Biológicas , Encéfalo/patología , Enfermedades Neurodegenerativas/patología , Tauopatías/patología , Bancos de Muestras Biológicas/normas , Biomarcadores/metabolismo , Encéfalo/metabolismo , Humanos , México , Proteínas tau/metabolismo

RESUMEN

The spreading and accumulation of α-synuclein and dopaminergic neurodegeneration, two hallmarks of Parkinson's disease (PD), have been faithfully reproduced in rodent brains by chronic, oral administration of ß-sitosterol ß-D-glucoside (BSSG). We investigated whether a single injection of BSSG (6 µg BSSG/µL DMSO) in the left substantia nigra of Wistar rats causes the same effects. Mock DMSO injections and untreated rats formed control groups. We performed immunostainings against the pathological α-synuclein, the dopaminergic marker tyrosine hydroxylase (TH), the neuroskeleton marker ß-III tubulin, the neurotensin receptor type 1 (NTSR1) as non-dopaminergic phenotype marker and Fluro-Jade C (F-J C) label for neurodegeneration. Using ß-galactosidase (ß-Gal) assay and active caspase-3 immunostaining, we assessed cell death mechanisms. Golgi-Cox staining was used to measure the density and types of dendritic spines of striatal medium spiny neurons. Motor and non-motor alterations were also evaluated. The study period comprised 15 to 120 days after the lesion. In the injured substantia nigra, BSSG caused a progressive α-synuclein aggregation and dopaminergic neurodegeneration caused by senescence and apoptosis. The α-synuclein immunoreactivity was also present within microglia cells. Decreased density of dopaminergic fibers and dendritic spines also occurred in the striatum. Remarkably, all the histopathological changes also appeared on the contralateral nigrostriatal system, and α-synuclein aggregates were present in other brain regions. Motor and non-motor behavioral alterations were progressive. Our data show that the stereotaxic BSSG administration reproduces PD α-synucleinopathy phenotype in the rat. This approach will aid in identifying the spread mechanism of α-synuclein pathology and validate anti-synucleinopathy therapies.

Asunto(s)

Modelos Animales de Enfermedad , Degeneración Nerviosa/patología , Enfermedad de Parkinson , Sitoesteroles/administración & dosificación , alfa-Sinucleína/metabolismo , Animales , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Inyecciones Intraventriculares/métodos , Degeneración Nerviosa/inducido químicamente , Ratas , Ratas Wistar , Sitoesteroles/toxicidad , Sustancia Negra/efectos de los fármacos , Sustancia Negra/patología

RESUMEN

Reduction of the dendritic arbor length and the lack of dendritic spines in the pyramidal cells of the prefrontal cortex (PFC) are prevalent pathological features in schizophrenia (SZ). Neonatal ventral hippocampus lesion (NVHL) in male rats reproduces these neuronal characteristics and here we describe how this is a consequence of BDNF/TrkB pathway disruption. Moreover, COX-2 proinflammatory state, as well as Nrf-2 antioxidant impairment, triggers oxidative/nitrosative stress, which also contributes to dendritic spine impairments in the PFC. Interestingly, oxidative/nitrosative stress was also detected in the periphery of NVHL animals. Furthermore, risperidone treatment had a neurotrophic effect on the PFC and antioxidant effects on the brain and periphery of NVHL animals; these cellular effects were related to behavioral improvement. Our data highlight the link between brain development and immune response, as well as several other factors to understand mechanisms related to the pathophysiology of SZ.SIGNIFICANCE STATEMENT Prefrontal cortex dysfunction in schizophrenia can be a consequence of morphological abnormalities and oxidative/nitrosative stress, among others. Here, we detailed how impaired plasticity-related pathways and oxidative/nitrosative stress are part of the dendritic spine pathology and their modulation by atypical antipsychotic risperidone treatment in rats with neonatal ventral hippocampus lesion. Moreover, we found that animals with neonatal ventral hippocampus lesion had oxidative/nitrosative stress in the brain as well as in the peripheral blood, an important issue for the translational approaches of this model. Then, risperidone restored plasticity and reduced oxidative/nitrosative stress of prefrontal cortex pyramidal cells, and ultimately improved the behavior of lesioned animals. Moreover, risperidone had differential effects than the brain on peripheral blood oxidative/nitrosative stress.

Asunto(s)

Antipsicóticos/uso terapéutico , Atrofia/tratamiento farmacológico , Hipocampo/patología , Estrés Nitrosativo/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Corteza Prefrontal/patología , Risperidona/uso terapéutico , Animales , Antipsicóticos/farmacología , Atrofia/metabolismo , Atrofia/patología , Espinas Dendríticas/metabolismo , Hipocampo/metabolismo , Masculino , Corteza Prefrontal/metabolismo , Ratas , Risperidona/farmacología

RESUMEN

The neonatal ventral hippocampal lesion (nVHL) has been widely used as an animal model for schizophrenia. Rats with an nVHL show several delayed behavioral alterations that mimic some symptoms of schizophrenia. Sprague-Dawley (SD) rats with an nVHL have a decrease in D3 receptors in limbic areas, but the expression of D3 receptors in Wistar (W) rats with an nVHL is unknown. The 7-Hydroxy-2-(N,N-di-n-propylamino) tetralin (7-OH-DPAT) has been reported as a D3-preferring agonist. Thus, we investigated the effect of (±)-7-OH-DPAT (0.25 mg/kg) on the motor activity in male adult W and SD rats after an nVHL. The 7-OH-DPAT caused a decrease in locomotion of W rats with an nVHL, but it did not change the locomotion of SD rats with this lesion. Our results suggest that the differential effect of 7-OH-DPAT between W and SD rats with an nVHL could be caused by a different expression of the D3 receptors. These results may have implications for modeling interactions of genetic and environmental factors involved in schizophrenia.