RESUMEN
Parkinson's disease (PD) is a complicated and incapacitating neurodegenerative malady that emanates following the dopaminergic (DArgic) nerve cell deprivation in the substantia nigra pars compacta (SN-PC). The etiopathogenesis of PD is still abstruse. Howbeit, PD is hypothesized to be precipitated by an amalgamation of genetic mutations and exposure to environmental toxins. The aggregation of α-synucelin within the Lewy bodies (LBs), escalated oxidative stress (OS), autophagy-lysosome system impairment, ubiquitin-proteasome system (UPS) impairment, mitochondrial abnormality, programmed cell death, and neuroinflammation are regarded as imperative events that actively participate in PD pathogenesis. The central nervous system (CNS) relies heavily on redox-active metals, particularly iron (Fe) and copper (Cu), in order to modulate pivotal operations, for instance, myelin generation, synthesis of neurotransmitters, synaptic signaling, and conveyance of oxygen (O2). The duo, namely, Fe and Cu, following their inordinate exposure, are viable of permeating across the blood-brain barrier (BBB) and moving inside the brain, thereby culminating in the escalated OS (through a reactive oxygen species (ROS)-reliant pathway), α-synuclein aggregation within the LBs, and lipid peroxidation, which consequently results in the destruction of DArgic nerve cells and facilitates PD emanation. This review delineates the metabolism of Fe and Cu in the CNS, their role and disrupted balance in PD. An in-depth investigation was carried out by utilizing the existing publications obtained from prestigious medical databases employing particular keywords mentioned in the current paper. Moreover, we also focus on decoding the role of metal complexes and chelators in PD treatment. Conclusively, metal chelators hold the aptitude to elicit the scavenging of mobile/fluctuating metal ions, which in turn culminates in the suppression of ROS generation, and thereby prelude the evolution of PD.
Asunto(s)
Metales/efectos adversos , Degeneración Nerviosa/patología , Enfermedad de Parkinson/patología , Animales , Quelantes/farmacología , Quelantes/uso terapéutico , Humanos , Degeneración Nerviosa/complicaciones , Oxidación-Reducción , Estrés Oxidativo , Enfermedad de Parkinson/complicacionesRESUMEN
Injury to the optic nerve, termed, traumatic optic neuropathy (TON) is a known comorbidity of traumatic brain injury (TBI) and is now known to cause chronic and progressive retinal thinning up to 35 years after injury. Although animal models of TBI have described the presence of optic nerve degeneration and research exploring acute mechanisms is underway, few studies in humans or animals have examined chronic TON pathophysiology outside the retina. We used a closed-head weight-drop model of TBI/TON in 6-week-old male C57BL/6 mice. Mice were euthanized 7-, 14-, 30-, 90-, and 150-days post-injury (DPI) to assess histological changes in the visual system of the brain spanning a total of 12 regions. We show chronic elevation of FluoroJade-C, indicative of neurodegeneration, throughout the time course. Intriguingly, FJ-C staining revealed a bimodal distribution of mice indicating the possibility of subpopulations that may be more or less susceptible to injury outcomes. Additionally, we show that microglia and astrocytes react to optic nerve damage in both temporally and regionally different ways. Despite these differences, astrogliosis and microglial changes were alleviated between 14-30 DPI in all regions examined, perhaps indicating a potentially critical period for intervention/recovery that may determine chronic outcomes.
Asunto(s)
Envejecimiento/patología , Degeneración Nerviosa/patología , Neuroglía/patología , Traumatismos del Nervio Óptico/patología , Heridas y Lesiones/patología , Animales , Peso Corporal , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/patología , Enfermedad Crónica , Masculino , Ratones Endogámicos C57BL , Microglía/patología , Degeneración Nerviosa/complicaciones , Nervio Óptico/patología , Traumatismos del Nervio Óptico/complicaciones , Convulsiones/complicaciones , Factores de Tiempo , Heridas y Lesiones/complicacionesRESUMEN
Sleep Disordered Breathing (SDB) and Alzheimer's Disease (AD) are strongly associated clinically, but it is unknown if they are mechanistically associated. Here, we review data covering both the cellular and molecular responses in SDB and AD with an emphasis on the overlapping neuroimmune responses in both diseases. We extensively discuss the use of animal models of both diseases and their relative utilities in modeling human disease. Data presented here from mice exposed to intermittent hypoxia indicate that microglia become more activated following exposure to hypoxia. This also supports the idea that intermittent hypoxia can activate the neuroimmune system in a manner like that seen in AD. Finally, we highlight similarities in the cellular and neuroimmune responses between SDB and AD and propose that these similarities may lead to a pathological synergy between SDB and AD.
Asunto(s)
Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/patología , Microglía/patología , Síndromes de la Apnea del Sueño/complicaciones , Síndromes de la Apnea del Sueño/patología , Animales , Humanos , Inflamación/complicaciones , Inflamación/patología , Masculino , Ratones Endogámicos C57BL , Degeneración Nerviosa/complicaciones , Degeneración Nerviosa/patología , Factores de RiesgoRESUMEN
Wolfram syndrome (WS), also known as a DIDMOAD (diabetes insipidus, early-onset diabetes mellitus, optic nerve atrophy and deafness) is a rare autosomal disorder caused by mutations in the Wolframin1 (WFS1) gene. Previous studies have revealed that glucagon-like peptide-1 receptor agonist (GLP1 RA) are effective in delaying and restoring blood glucose control in WS animal models and patients. The GLP1 RA liraglutide has also been shown to have neuroprotective properties in aged WS rats. WS is an early-onset, chronic condition. Therefore, early diagnosis and lifelong pharmacological treatment is the best solution to control disease progression. Hence, the aim of this study was to evaluate the efficacy of the long-term liraglutide treatment on the progression of WS symptoms. For this purpose, 2-month-old WS rats were treated with liraglutide up to the age of 18 months and changes in diabetes markers, visual acuity, and hearing sensitivity were monitored over the course of the treatment period. We found that treatment with liraglutide delayed the onset of diabetes and protected against vision loss in a rat model of WS. Therefore, early diagnosis and prophylactic treatment with the liraglutide may also prove to be a promising treatment option for WS patients by increasing the quality of life.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Pérdida Auditiva Sensorineural/tratamiento farmacológico , Liraglutida/uso terapéutico , Degeneración Nerviosa/tratamiento farmacológico , Vías Visuales/patología , Síndrome de Wolfram/tratamiento farmacológico , Animales , Péptido C/metabolismo , Diabetes Mellitus Experimental/complicaciones , Modelos Animales de Enfermedad , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Pérdida Auditiva Sensorineural/complicaciones , Liraglutida/farmacología , Masculino , Degeneración Nerviosa/complicaciones , Nervio Óptico/efectos de los fármacos , Nervio Óptico/patología , Nervio Óptico/ultraestructura , Fenotipo , Ratas , Vías Visuales/efectos de los fármacos , Síndrome de Wolfram/complicacionesRESUMEN
Current therapies for Alzheimer's disease seek to correct for defective cholinergic transmission by preventing the breakdown of acetylcholine through inhibition of acetylcholinesterase, these however have limited clinical efficacy. An alternative approach is to directly activate cholinergic receptors responsible for learning and memory. The M1-muscarinic acetylcholine (M1) receptor is the target of choice but has been hampered by adverse effects. Here we aimed to design the drug properties needed for a well-tolerated M1-agonist with the potential to alleviate cognitive loss by taking a stepwise translational approach from atomic structure, cell/tissue-based assays, evaluation in preclinical species, clinical safety testing, and finally establishing activity in memory centers in humans. Through this approach, we rationally designed the optimal properties, including selectivity and partial agonism, into HTL9936-a potential candidate for the treatment of memory loss in Alzheimer's disease. More broadly, this demonstrates a strategy for targeting difficult GPCR targets from structure to clinic.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Diseño de Fármacos , Receptor Muscarínico M1/agonistas , Anciano , Anciano de 80 o más Años , Envejecimiento/patología , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Secuencia de Aminoácidos , Animales , Presión Sanguínea/efectos de los fármacos , Células CHO , Inhibidores de la Colinesterasa/farmacología , Cricetulus , Cristalización , Modelos Animales de Enfermedad , Perros , Donepezilo/farmacología , Electroencefalografía , Femenino , Células HEK293 , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Ratones Endogámicos C57BL , Modelos Moleculares , Simulación de Dinámica Molecular , Degeneración Nerviosa/complicaciones , Degeneración Nerviosa/patología , Primates , Ratas , Receptor Muscarínico M1/química , Transducción de Señal , Homología Estructural de ProteínaRESUMEN
N-terminal methylation is an important posttranslational modification that regulates protein/DNA interactions and plays a role in many cellular processes, including DNA damage repair, mitosis, and transcriptional regulation. Our generation of a constitutive knockout mouse for the N-terminal methyltransferase NRMT1 demonstrated its loss results in severe developmental abnormalities and premature aging phenotypes. As premature aging is often accompanied by neurodegeneration, we more specifically examined how NRMT1 loss affects neural pathology and cognitive behaviors. Here we find that Nrmt1-/- mice exhibit postnatal enlargement of the lateral ventricles, age-dependent striatal and hippocampal neurodegeneration, memory impairments, and hyperactivity. These morphological and behavior abnormalities are preceded by alterations in neural stem cell (NSC) development. Early expansion and differentiation of the quiescent NSC pool in Nrmt1-/- mice is followed by its subsequent depletion and many of the resulting neurons remain in the cell cycle and ultimately undergo apoptosis. These cell cycle phenotypes are reminiscent to those seen with loss of the NRMT1 target retinoblastoma protein (RB). Accordingly, we find misregulation of RB phosphorylation and degradation in Nrmt1-/- mice, and significant de-repression of RB target genes involved in cell cycle. We also identify novel de-repression of Noxa, an RB target gene that promotes apoptosis. These data identify Nα-methylation as a novel regulatory modification of RB transcriptional repression during neurogenesis and indicate that NRMT1 and RB work together to promote NSC quiescence and prevent neuronal apoptosis.
Asunto(s)
Envejecimiento/patología , Disfunción Cognitiva/complicaciones , Metiltransferasas/metabolismo , Degeneración Nerviosa/complicaciones , Células-Madre Neurales/metabolismo , Proteína de Retinoblastoma/genética , Animales , Animales Recién Nacidos , Apoptosis , Conducta Animal , Ciclo Celular , Ventrículos Cerebrales/patología , Disfunción Cognitiva/genética , Disfunción Cognitiva/patología , Regulación de la Expresión Génica , Proteína Ácida Fibrilar de la Glía/metabolismo , Hipocampo/patología , Antígeno Ki-67/metabolismo , Aprendizaje por Laberinto , Trastornos de la Memoria/complicaciones , Ratones Endogámicos C57BL , Ratones Noqueados , Degeneración Nerviosa/genética , Degeneración Nerviosa/patología , Células-Madre Neurales/patología , Neuronas/metabolismo , Neuronas/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteína de Retinoblastoma/metabolismo , Memoria Espacial , Nicho de Células MadreRESUMEN
BACKGROUND: There is a growing realization that the gut-brain axis signaling is critical for maintaining the health and homeostasis of the Central Nervous System (CNS) and the intestinal environment. The role of Short-Chain Fatty Acids (SCFAs), such as Sodium Propionate (SP) and Sodium Butyrate (SB), has been reported to counteract inflammation activation in the central and Enteric Nervous System (ENS). METHODS: In this study, we evaluated the role of the SCFAs in regulating the pathophysiology of migraine and correlated dysregulations in the gut environment in a mouse model of Nitroglycerine (NTG)-induced migraine. RESULTS: We showed that, following behavioral tests evaluating pain and photophobia, the SP and SB treatments attenuated pain attacks provoked by NTG. Moreover, treatments with both SCFAs reduced histological damage in the trigeminal nerve nucleus and decreased the expression of proinflammatory mediators. Ileum evaluation following NTG injection reported that SCFA treatments importantly restored intestinal mucosa alterations, as well as the release of neurotransmitters in the ENS. CONCLUSIONS: Taken together, these results provide evidence that SCFAs exert powerful effects, preventing inflammation through the gut-brain axis, suggesting a new insight into the potential application of SCFAs as novel supportive therapies for migraine and correlated intestinal alterations.
Asunto(s)
Ácidos Grasos Volátiles/uso terapéutico , Intestinos/patología , Trastornos Migrañosos/inducido químicamente , Trastornos Migrañosos/tratamiento farmacológico , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Citocinas/metabolismo , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Ácidos Grasos Volátiles/administración & dosificación , Ácidos Grasos Volátiles/farmacología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Hiperalgesia/inducido químicamente , Hiperalgesia/complicaciones , Hiperalgesia/tratamiento farmacológico , Mediadores de Inflamación/metabolismo , Intestinos/efectos de los fármacos , Ratones , Trastornos Migrañosos/genética , Degeneración Nerviosa/inducido químicamente , Degeneración Nerviosa/complicaciones , Degeneración Nerviosa/tratamiento farmacológico , Factores de Crecimiento Nervioso/metabolismo , Neuronas/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo I/metabolismo , Nitroglicerina/administración & dosificación , Dolor/inducido químicamente , Dolor/complicaciones , Dolor/tratamiento farmacológico , ARN Mensajero/genética , ARN Mensajero/metabolismo , Núcleos del Trigémino/patologíaRESUMEN
Axonal degeneration of retinal ganglion cells (RGCs) causes blindness in glaucoma. Currently, there are no therapies that target axons to prevent them from degenerating. Activation of the BAX protein has been shown to be the determining step in the intrinsic apoptotic pathway that causes RGCs to die in glaucoma. A putative role for BAX in axonal degeneration is less well elucidated. BCLXL (BCL2L1) is the primary antagonist of BAX in RGCs. We developed a mCherry-BCLXL fusion protein, which prevented BAX recruitment and activation to the mitochondria in tissue culture cells exposed to staurosporine. This fusion protein was then packaged into adeno-associated virus serotype 2, which was used to transduce RGCs after intravitreal injection and force its overexpression. Transduced RGCs express mCherry-BCLXL throughout their somas and axons along the entire optic tract. In a model of acute optic nerve crush, the transgene prevented the recruitment of a GFP-BAX fusion protein to mitochondria and provided long-term somal protection up to 12 weeks post injury. To test the efficacy in glaucoma, DBA/2J mice were transduced at 5 months of age, just prior to the time they begin to exhibit ocular hypertension. Gene therapy with mCherry-BCLXL did not affect the longitudinal history of intraocular pressure elevation compared to naive mice but did robustly attenuate both RGC soma pathology and axonal degeneration in the optic nerve at both 10.5 and 12 months of age. BCLXL gene therapy is a promising candidate for glaucoma therapy.
Asunto(s)
Terapia Genética , Glaucoma/terapia , Neuronas/patología , Proteína bcl-X/genética , Proteína bcl-X/uso terapéutico , Envejecimiento/patología , Animales , Dependovirus , Modelos Animales de Enfermedad , Glaucoma/complicaciones , Glaucoma/fisiopatología , Proteínas Fluorescentes Verdes/metabolismo , Presión Intraocular , Ratones Endogámicos DBA , Mitocondrias/metabolismo , Compresión Nerviosa , Degeneración Nerviosa/complicaciones , Degeneración Nerviosa/patología , Nervio Óptico/metabolismo , Nervio Óptico/patología , Transporte de Proteínas , ARN Mensajero/genética , ARN Mensajero/metabolismo , Células Ganglionares de la Retina/metabolismoRESUMEN
Parkinson's disease (PD) is a currently incurable neurodegenerative disorder characterized by the loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta and α-synuclein aggregation. Accumulated evidence indicates that the saponins, especially from ginseng, have neuroprotective effects against neurodegenerative disorders. Interestingly, saponin can also be found in marine organisms such as the sea cucumber, but little is known about its effect in neurodegenerative disease, including PD. In this study, we investigated the anti-Parkinson effects of frondoside A (FA) from Cucumaria frondosa and ginsenoside Rg3 (Rg3) from Panax notoginseng in C. elegans PD model. Both saponins were tested for toxicity and optimal concentration by food clearance assay and used to treat 6-OHDA-induced BZ555 and transgenic α-synuclein NL5901 strains in C. elegans. Treatment with FA and Rg3 significantly attenuated DAergic neurodegeneration induced by 6-OHDA in BZ555 strain, improved basal slowing rate, and prolonged lifespan in the 6-OHDA-induced wild-type strain with downregulation of the apoptosis mediators, egl-1 and ced-3, and upregulation of sod-3 and cat-2. Interestingly, only FA reduced α-synuclein aggregation, rescued lifespan in NL5901, and upregulated the protein degradation regulators, including ubh-4, hsf-1, hsp-16.1 and hsp-16.2. This study indicates that both FA and Rg3 possess beneficial effects in rescuing DAergic neurodegeneration in the 6-OHDA-induced C. elegans model through suppressing apoptosis mediators and stimulating antioxidant enzymes. In addition, FA could attenuate α-synuclein aggregation through the protein degradation process.
Asunto(s)
Caenorhabditis elegans/fisiología , Ginsenósidos/farmacología , Glicósidos/farmacología , Enfermedad de Parkinson/patología , Triterpenos/farmacología , Animales , Animales Modificados Genéticamente , Apoptosis/efectos de los fármacos , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Regulación de la Expresión Génica/efectos de los fármacos , Ginsenósidos/química , Ginsenósidos/toxicidad , Glicósidos/química , Glicósidos/toxicidad , Longevidad/efectos de los fármacos , Degeneración Nerviosa/complicaciones , Degeneración Nerviosa/patología , Oxidopamina , Enfermedad de Parkinson/complicaciones , Proteolisis/efectos de los fármacos , Triterpenos/química , Triterpenos/toxicidad , alfa-Sinucleína/metabolismoRESUMEN
Although extracellular vesicles (EVs) were initially relegated to a waste disposal role, nowadays, they have gained multiple fundamental functions working as messengers in intercellular communication as well as exerting active roles in physiological and pathological processes. Accumulating evidence proves the involvement of EVs in many diseases, including those of the central nervous system (CNS), such as multiple sclerosis (MS). Indeed, these membrane-bound particles, produced in any type of cell, carry and release a vast range of bioactive molecules (nucleic acids, proteins, and lipids), conferring genotypic and phenotypic changes to the recipient cell. This means that not only EVs per se but their content, especially, could reveal new candidate disease biomarkers and/or therapeutic agents. This review is intended to provide an overview regarding current knowledge about EVs' involvement in MS, analyzing the potential versatility of EVs as a new therapeutic tool and source of biomarkers.
Asunto(s)
Biomarcadores/metabolismo , Vesículas Extracelulares/metabolismo , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/terapia , Humanos , Esclerosis Múltiple/complicaciones , Degeneración Nerviosa/complicaciones , Degeneración Nerviosa/patología , NeuroprotecciónRESUMEN
Amyotrophic lateral sclerosis (ALS) is an intractable neurodegenerative disease. CD68-positive bone marrow (BM)-derived cells (BMDCs) accumulate in the pathological lesion in the SOD1(G93A) ALS mouse model after BM transplantation (BMT). Therefore, we investigated whether BMDCs can be applied as gene carriers for cell-based gene therapy by employing the accumulation of BMDCs. In ALS mice, YFP reporter signals were observed in 12-14% of white blood cells (WBCs) and in the spinal cord via transplantation of BM after lentiviral vector (LV) infection. After confirmation of gene transduction by LV with the CD68 promoter in 4-7% of WBCs and in the spinal cord of ALS mice, BM cells were infected with LVs expressing glutamate transporter (GLT) 1 that protects neurons from glutamate toxicity, driven by the CD68 promoter, which were transplanted into ALS mice. The treated mice showed improvement of motor behaviors and prolonged survival. Additionally, interleukin (IL)-1ß was significantly suppressed, and IL-4, arginase 1, and FIZZ were significantly increased in the mice. These results suggested that GLT1 expression by BMDCs improved the spinal cord environment. Therefore, our gene therapy strategy may be applied to treat neurodegenerative diseases such as ALS in which BMDCs accumulate in the pathological lesion by BMT.
Asunto(s)
Esclerosis Amiotrófica Lateral/fisiopatología , Células de la Médula Ósea/metabolismo , Transportador 2 de Aminoácidos Excitadores/genética , Técnicas de Transferencia de Gen , Actividad Motora/fisiología , Esclerosis Amiotrófica Lateral/complicaciones , Animales , Biomarcadores/metabolismo , Trasplante de Médula Ósea , Supervivencia Celular , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Regulación de la Expresión Génica , Terapia Genética , Gliosis/complicaciones , Gliosis/patología , Gliosis/fisiopatología , Ácido Glutámico/metabolismo , Lentivirus/metabolismo , Ratones Endogámicos C57BL , Ratones Transgénicos , Microglía/metabolismo , Neuronas Motoras/metabolismo , Atrofia Muscular/complicaciones , Atrofia Muscular/patología , Atrofia Muscular/fisiopatología , Degeneración Nerviosa/complicaciones , Degeneración Nerviosa/patología , Degeneración Nerviosa/fisiopatología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Médula Espinal/metabolismo , Superóxido Dismutasa-1/metabolismo , Análisis de SupervivenciaRESUMEN
A better understanding of white matter tract damage in patients with diffuse axonal injury (DAI) and mild traumatic brain injury (MTBI) is important to obtain an objective basis for sequelae. The purpose of this study was to clarify the characteristics of white matter tract degeneration in DAI and MTBI using automated tractography. T1-weighted and diffusion tensor imaging (DTI) was performed on seven DAI and seven MTBI patients as well as on nine healthy subjects. Automated probabilistic tractography analysis was performed using FreeSurfer and TRACULA (tracts constrained by underlying anatomy) for the reconstruction of major nerve fibers. We investigated the difference between DTI quantitative values in each white matter nerve fiber between groups and attempted to evaluate the classification accuracy of DAI and MTBI using receiver operator curve analysis. Both DAI and MTBI appeared to exhibit axonal degeneration along the nerve fiber tract in a scattered manner. The mean diffusivity of the ampulla of the corpus callosum was significantly higher in DAI than that in MTBI patients, suggesting axonal degeneration of the corpus callosum in DAI patients. Using mean diffusivity of the right cingulum-angular bundle, DAI and MTBI could be discriminated with an area under the curve of 94%. Both DAI and MTBI exhibited scattered axonal degeneration; however, DAI appeared to exhibit more pronounced axonal degeneration in the ampulla of the corpus callosum than MTBI. Our results suggest that DAI and MTBI can be accurately distinguished using DTI.
Asunto(s)
Conmoción Encefálica/diagnóstico por imagen , Lesión Axonal Difusa/diagnóstico por imagen , Imagen de Difusión Tensora/métodos , Degeneración Nerviosa/diagnóstico por imagen , Sustancia Blanca/diagnóstico por imagen , Adulto , Conmoción Encefálica/complicaciones , Cuerpo Calloso/diagnóstico por imagen , Lesión Axonal Difusa/complicaciones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Degeneración Nerviosa/complicacionesRESUMEN
Recent evidence suggests alterations in the gut microbiota-brain axis may drive cognitive impairment with aging. In the present study, we observed that prolonged administration of D-galactose to mice induced cognitive decline, gut microbial dysbiosis, peripheral inflammation, and oxidative stress. In this model of age-related cognitive decline, Cistanche deserticola polysaccharides (CDPS) improved cognitive function in D-galactose-treated mice by restoring gut microbial homeostasis, thereby reducing oxidative stress and peripheral inflammation. The beneficial effects of CDPS in these aging model mice were abolished through ablation of gut microbiota with antibiotics or immunosuppression with cyclophosphamide. Serum metabolomic profiling showed that levels of creatinine, valine, L-methionine, o-Toluidine, N-ethylaniline, uric acid and proline were all altered in the aging model mice, but were restored by CDPS. These findings demonstrated that CDPS improves cognitive function in a D-galactose-induced aging model in mice by restoring homeostasis of the gut microbiota-brain axis, which alleviated an amino acid imbalance, peripheral inflammation, and oxidative stress. CDPS thus shows therapeutic potential for patients with memory and learning disorders, especially those related to gut microbial dysbiosis.
Asunto(s)
Envejecimiento/patología , Encéfalo/patología , Cistanche/química , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/microbiología , Microbioma Gastrointestinal/efectos de los fármacos , Modelos Biológicos , Polisacáridos/uso terapéutico , Aminoácidos/metabolismo , Animales , Disfunción Cognitiva/complicaciones , Disfunción Cognitiva/inmunología , Citocinas/metabolismo , Disbiosis/complicaciones , Disbiosis/microbiología , Galactosa , Homeostasis , Inflamación/patología , Mediadores de Inflamación/metabolismo , Masculino , Trastornos de la Memoria/complicaciones , Ratones , Degeneración Nerviosa/complicaciones , Degeneración Nerviosa/patología , Estrés Oxidativo/efectos de los fármacos , Polisacáridos/farmacología , Purinas/metabolismoAsunto(s)
3',5'-AMP Cíclico Fosfodiesterasas/genética , Cuerpo Estriado/patología , Degeneración Nerviosa/congénito , Temblor , Adulto , Anciano , Cuerpo Estriado/fisiopatología , Femenino , Humanos , Degeneración Nerviosa/complicaciones , Degeneración Nerviosa/diagnóstico , Degeneración Nerviosa/genética , Degeneración Nerviosa/fisiopatología , Linaje , Temblor/etiología , Temblor/genéticaRESUMEN
Primary vasopressor efficacy of epinephrine during cardiopulmonary resuscitation (CPR) is due to its α-adrenergic effects. However, epinephrine plays ß1-adrenergic actions, which increasing myocardial oxygen consumption may lead to refractory ventricular fibrillation (VF) and poor outcome. Effects of a single dose of esmolol in addition to epinephrine during CPR were investigated in a porcine model of VF with an underlying acute myocardial infarction. VF was ischemically induced in 16 pigs and left untreated for 12 min. During CPR, animals were randomized to receive epinephrine (30 µg/kg) with either esmolol (0.5 mg/kg) or saline (control). Pigs were then observed up to 96 h. Coronary perfusion pressure increased during CPR in the esmolol group compared to control (47 ± 21 vs. 24 ± 10 mmHg at min 5, p < 0.05). In both groups, 7 animals were successfully resuscitated and 4 survived up to 96 h. No significant differences were observed between groups in the total number of defibrillations delivered prior to final resuscitation. Brain histology demonstrated reductions in cortical neuronal degeneration/necrosis (score 0.3 ± 0.5 vs. 1.3 ± 0.5, p < 0.05) and hippocampal microglial activation (6 ± 3 vs. 22 ± 4%, p < 0.01) in the esmolol group compared to control. Lower circulating levels of neuron specific enolase were measured in esmolol animals compared to controls (2[1-3] vs. 21[16-52] ng/mL, p < 0.01). In this preclinical model, ß1-blockade during CPR did not facilitate VF termination but provided neuroprotection.
Asunto(s)
Reanimación Cardiopulmonar , Paro Cardíaco/tratamiento farmacológico , Neuronas/patología , Propanolaminas/uso terapéutico , Animales , Análisis de los Gases de la Sangre , Encéfalo/patología , Modelos Animales de Enfermedad , Paro Cardíaco/sangre , Paro Cardíaco/complicaciones , Paro Cardíaco/fisiopatología , Hemodinámica/efectos de los fármacos , Masculino , Degeneración Nerviosa/sangre , Degeneración Nerviosa/complicaciones , Degeneración Nerviosa/patología , Neuronas/efectos de los fármacos , Perfusión , Fosfopiruvato Hidratasa/sangre , Presión , Propanolaminas/farmacología , PorcinosRESUMEN
OBJECTIVE: To elucidate the role of Parkinson disease (PD)-related brain metabolic patterns as a biomarker in isolated REM sleep behavior disorder (iRBD) for future disease conversion. METHODS: This is a prospective cohort study consisting of 30 patients with iRBD, 25 patients with de novo PD with a premorbid history of RBD, 21 patients with longstanding PD on stable treatment, and 24 healthy controls. The iRBD group was longitudinally followed up. All participants underwent 18F-fluorodeoxyglucose (FDG) PET and were evaluated with olfaction, cognition, and the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) at baseline. From FDG-PET scans, we derived metabolic patterns from the longstanding PD group (PD-RP) and de novo PD group with RBD (dnPDRBD-RP). Subsequently, we calculated the PD-RP and dnPDRBD-RP scores in patients with iRBD. We validated the metabolic patterns in each PD group and separate iRBD cohort (n = 14). RESULTS: The 2 patterns significantly correlated with each other and were spatially overlapping yet distinct. The MDS-UPDRS motor scores significantly correlated with PD-RP (p = 0.013) but not with dnPDRBD-RP (p = 0.076). In contrast, dnPDRBD-RP correlated with olfaction in butanol threshold test (p = 0.018) in patients with iRBD, but PD-RP did not (p = 0.21). High dnPDRBD-RP in patients with iRBD predicted future phenoconversion with all cutoff ranges from 1.5 to 3 SD of the control value, whereas predictability of PD-RP was only significant in a partial range of cutoff. CONCLUSION: The dnPDRBD-RP is an efficient neuroimaging biomarker that reflects prodromal features of PD and predicts phenoconversion in iRBD that can be applied individually. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that a de novo PD pattern on FDG-PET predicts future conversion to neurodegenerative disease in patients with iRBD.
Asunto(s)
Encéfalo/diagnóstico por imagen , Degeneración Nerviosa/complicaciones , Enfermedad de Parkinson/complicaciones , Trastorno de la Conducta del Sueño REM/complicaciones , Anciano , Anciano de 80 o más Años , Encéfalo/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Degeneración Nerviosa/diagnóstico por imagen , Degeneración Nerviosa/metabolismo , Neuroimagen , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/metabolismo , Tomografía de Emisión de Positrones , Estudios Prospectivos , Trastorno de la Conducta del Sueño REM/diagnóstico por imagen , Trastorno de la Conducta del Sueño REM/metabolismoRESUMEN
Hypobaric hypoxia at higher altitudes usually impairs cognitive function. Previous studies suggested that epigenetic modifications are the culprits for this condition. Here, we set out to determine how hypobaric hypoxia mediates epigenetic modifications and how this condition worsens neurodegeneration and memory loss in rats. In the current study, different duration of hypobaric hypoxia exposure showed a discrete pattern of histone acetyltransferases and histone deacetylases (HDACs) gene expression in the hippocampus when compared with control rat brains. The level of acetylation sites in histone H2A, H3 and H4 was significantly decreased under hypobaric hypoxia exposure compared to the control rat's hippocampus. Additionally, inhibiting the HDAC family with sodium butyrate administration (1.2 g/kg body weight) attenuated neurodegeneration and memory loss in hypobaric hypoxia-exposed rats. Moreover, histone acetylation increased at the promoter regions of brain-derived neurotrophic factor (BDNF); thereby its protein expression was enhanced significantly in hypobaric hypoxia exposed rats treated with HDAC inhibitor compared with hypoxic rats. Thus, BDNF expression upregulated cAMP-response element binding protein (CREB) phosphorylation by stimulation of PI3K/GSK3ß/CREB axis, which counteracts hypobaric hypoxia-induced spatial memory impairment. In conclusion, these results suggested that sodium butyrate is a novel therapeutic agent for the treatment of spatial memory loss associated with hypobaric hypoxia, and also further studies are warranted to explore specific HDAC inhibitors in this condition.
Asunto(s)
Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Hipoxia/complicaciones , Trastornos de la Memoria/etiología , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal , Memoria Espacial , Acetilación/efectos de los fármacos , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Hipocampo/metabolismo , Histona Acetiltransferasas/genética , Histona Acetiltransferasas/metabolismo , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Histonas/metabolismo , Masculino , Trastornos de la Memoria/metabolismo , Modelos Biológicos , Degeneración Nerviosa/complicaciones , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuroprotección/efectos de los fármacos , Regiones Promotoras Genéticas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Memoria Espacial/efectos de los fármacosRESUMEN
Environmental triggers have important functions in multiple sclerosis (MS) susceptibility, phenotype, and trajectory. Exposure to early life trauma (ELT) has been associated with higher relapse rates in MS patients; however, the underlying mechanisms are not well-defined. Here we show ELT induces mechanistic and phenotypical alterations during experimental autoimmune encephalitis (EAE). ELT sustains downregulation of immune cell adrenergic receptors, which can be attributed to chronic norepinephrine circulation. ELT-subjected mice exhibit interferon-ß resistance and neurodegeneration driven by lymphotoxin and CXCR2 involvement. These phenotypic changes are observed in control EAE mice treated with ß1 adrenergic receptor antagonist. Conversely, ß1 adrenergic receptor agonist treatment to ELT mice abrogates phenotype changes via restoration of immune cell ß1 adrenergic receptor function. Our results indicate that ELT alters EAE phenotype via downregulation of ß1 adrenergic signaling in immune cells. These results have implications for the effect of environmental factors in provoking disease heterogeneity and might enable prediction of long-term outcomes in MS.
Asunto(s)
Regulación hacia Abajo , Interferón beta/metabolismo , Esclerosis Múltiple/complicaciones , Degeneración Nerviosa/complicaciones , Receptores Adrenérgicos beta 1/metabolismo , Transducción de Señal , Estrés Psicológico/complicaciones , Agonistas de Receptores Adrenérgicos beta 1/farmacología , Antagonistas de Receptores Adrenérgicos beta 1/farmacología , Animales , Biomarcadores/metabolismo , Encéfalo/inmunología , Encéfalo/patología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/sangre , Encefalomielitis Autoinmune Experimental/patología , Femenino , Aparato de Golgi/metabolismo , Masculino , Ratones Endogámicos C57BL , Esclerosis Múltiple/sangre , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Degeneración Nerviosa/sangre , Degeneración Nerviosa/inmunología , Degeneración Nerviosa/patología , Neuronas/metabolismo , Neuronas/patología , Norepinefrina/sangre , Fenotipo , Índice de Severidad de la Enfermedad , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Lafora disease (LD; OMIM#274780) is a fatal rare neurodegenerative disorder characterized by generalized epileptic seizures and the presence of polyglucosan inclusions (PGs), called Lafora bodies (LBs), typically in the brain. LD is caused by mutations in two genes EPM2A or EPM2B, which encode respectively laforin, a glucan phosphatase, and malin, an E3-ubiquitin ligase. Much remains unknown about the molecular bases of LD and, unfortunately, appropriate treatment is still missing; therefore patients die within 10 years from the onset of the disease. Recently, we have identified neuroinflammation as one of the initial determinants in LD. In this work, we have investigated anti-inflammatory treatments as potential therapies in LD. With this aim, we have performed a preclinical study in an Epm2b-/- mouse model with propranolol, a ß-adrenergic antagonist, and epigallocatechin gallate (EGCG), an antioxidant from green tea extract, both of which displaying additional anti-inflammatory properties. In vivo motor and cognitive behavioral tests and ex vivo histopathological brain analyses were used as parameters to assess the therapeutic potential of propranolol and EGCG. After 2 months of treatment, we observed an improvement not only in attention defects but also in neuronal disorganization, astrogliosis, and microgliosis present in the hippocampus of Epm2b-/- mice. In general, propranolol intervention was more effective than EGCG in preventing the appearance of astrocyte and microglia reactivity. In summary, our results confirm the potential therapeutic effectiveness of the modulators of inflammation as novel treatments in Lafora disease.
Asunto(s)
Encéfalo/patología , Inflamación/patología , Enfermedad de Lafora/patología , Animales , Biomarcadores/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Catequina/análogos & derivados , Catequina/farmacología , Modelos Animales de Enfermedad , Gliosis/complicaciones , Gliosis/patología , Gliosis/fisiopatología , Glucanos/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Hipocampo/fisiopatología , Cuerpos de Inclusión/efectos de los fármacos , Cuerpos de Inclusión/metabolismo , Inflamación/complicaciones , Inflamación/fisiopatología , Enfermedad de Lafora/complicaciones , Enfermedad de Lafora/fisiopatología , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/patología , Actividad Motora , Degeneración Nerviosa/complicaciones , Degeneración Nerviosa/patología , Degeneración Nerviosa/fisiopatología , Neuronas/efectos de los fármacos , Neuronas/patología , Fenotipo , Propranolol/farmacología , Ubiquitina-Proteína Ligasas/deficiencia , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Wolfram syndrome (WS) is a monogenic progressive neurodegenerative disease and is characterized by various neurological symptoms, such as optic nerve atrophy, loss of vision, cognitive decline, memory impairment, and learning difficulties. GLP1 receptor agonist liraglutide and BDNF mimetic 7,8-dihydroxyflavone (7,8-DHF) have had protective effect to visual pathway and to learning and memory in different rat models of neurodegenerative disorders. Although synergistic co-treatment effect has not been reported before and therefore the aim of the current study was to investigate liraglutide, 7,8-DHF and most importantly for the first time their co-treatment effect on degenerative processes in WS rat model. We took 9 months old WS rats and their wild-type (WT) control animals and treated them daily with liraglutide, 7,8-DHF or with the combination of liraglutide and 7,8-DHF up to the age of 12.5 months (n = 47, 5-8 per group). We found that liraglutide, 7,8-DHF and their co-treatment all prevented lateral ventricle enlargement, improved learning in Morris Water maze, reduced neuronal inflammation, delayed the progression of optic nerve atrophy, had remyelinating effect on optic nerve and thereby improved visual acuity in WS rats compared to WT controls. Thus, the use of the liraglutide, 7,8-DHF and their co-treatment could potentially be used as a therapeutic intervention to induce neuroprotection or even neuronal regeneration.