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1.
Neurobiol Dis ; 163: 105603, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34954322

RESUMEN

Alzheimer's disease (AD) is the most common form of dementia, which is neuropathologically characterized by extracellular senile plaques containing amyloid-ß and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. Previous studies have suggested a role for septin (SEPTIN) protein family members in AD-associated cellular processes. Here, we elucidated the potential role of presynaptic SEPTIN5 protein and its post-translational modifications in the molecular pathogenesis of AD. RNA and protein levels of SEPTIN5 showed a significant decrease in human temporal cortex in relation to the increasing degree of AD-related neurofibrillary pathology. Conversely, an increase in the phosphorylation of the functionally relevant SEPTIN5 phosphorylation site S327 was observed already in the early phases of AD-related neurofibrillary pathology, but not in the cerebrospinal fluid of individuals fulfilling the criteria for mild cognitive impairment due to AD. According to the mechanistic assessments, a link between SEPTIN5 S327 phosphorylation status and the effects of SEPTIN5 on amyloid precursor protein processing and markers of autophagy was discovered in mouse primary cortical neurons transduced with lentiviral constructs encoding wild type SEPTIN5 or SEPTIN5 phosphomutants (S327A and S327D). C57BL/6 J mice intrahippocampally injected with lentiviral wild type SEPTIN5 or phosphomutant constructs did not show changes in cognitive performance after five to six weeks from the start of injections. However, SEPTIN5 S327 phosphorylation status was linked to changes in short-term synaptic plasticity ex vivo at the CA3-CA1 synapse. Collectively, these data suggest that SEPTIN5 and its S327 phosphorylation status play a pivotal role in several cellular processes relevant for AD.


Asunto(s)
Hipocampo/metabolismo , Ovillos Neurofibrilares/metabolismo , Septinas/metabolismo , Sinapsis/metabolismo , Animales , Autofagia/fisiología , Modelos Animales de Enfermedad , Hipocampo/patología , Humanos , Ratones , Ovillos Neurofibrilares/patología , Neuronas/metabolismo , Neuronas/patología , Fosforilación , Sinapsis/patología
2.
Mol Psychiatry ; 25(8): 1876-1900, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-29950682

RESUMEN

Synaptic dysfunction plays a central role in Alzheimer's disease (AD), since it drives the cognitive decline. An association between a polymorphism of the adenosine A2A receptor (A2AR) encoding gene-ADORA2A, and hippocampal volume in AD patients was recently described. In this study, we explore the synaptic function of A2AR in age-related conditions. We report, for the first time, a significant overexpression of A2AR in hippocampal neurons of aged humans, which is aggravated in AD patients. A similar profile of A2AR overexpression in rats was sufficient to drive age-like memory impairments in young animals and to uncover a hippocampal LTD-to-LTP shift. This was accompanied by increased NMDA receptor gating, dependent on mGluR5 and linked to enhanced Ca2+ influx. We confirmed the same plasticity shift in memory-impaired aged rats and APP/PS1 mice modeling AD, which was rescued upon A2AR blockade. This A2AR/mGluR5/NMDAR interaction might prove a suitable alternative for regulating aberrant mGluR5/NMDAR signaling in AD without disrupting their constitutive activity.


Asunto(s)
Envejecimiento/metabolismo , Depresión Sináptica a Largo Plazo , Neuronas/metabolismo , Receptor de Adenosina A2A/metabolismo , Receptor del Glutamato Metabotropico 5/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Adenosina/metabolismo , Enfermedad de Alzheimer/metabolismo , Animales , Células Cultivadas , Hipocampo/metabolismo , Humanos , Ratones , Ratas , Ratas Sprague-Dawley , Memoria Espacial
3.
Brain ; 142(11): 3636-3654, 2019 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-31599329

RESUMEN

Accumulating data support the role of tau pathology in cognitive decline in ageing and Alzheimer's disease, but underlying mechanisms remain ill-defined. Interestingly, ageing and Alzheimer's disease have been associated with an abnormal upregulation of adenosine A2A receptor (A2AR), a fine tuner of synaptic plasticity. However, the link between A2AR signalling and tau pathology has remained largely unexplored. In the present study, we report for the first time a significant upregulation of A2AR in patients suffering from frontotemporal lobar degeneration with the MAPT P301L mutation. To model these alterations, we induced neuronal A2AR upregulation in a tauopathy mouse model (THY-Tau22) using a new conditional strain allowing forebrain overexpression of the receptor. We found that neuronal A2AR upregulation increases tau hyperphosphorylation, potentiating the onset of tau-induced memory deficits. This detrimental effect was linked to a singular microglial signature as revealed by RNA sequencing analysis. In particular, we found that A2AR overexpression in THY-Tau22 mice led to the hippocampal upregulation of C1q complement protein-also observed in patients with frontotemporal lobar degeneration-and correlated with the loss of glutamatergic synapses, likely underlying the observed memory deficits. These data reveal a key impact of overactive neuronal A2AR in the onset of synaptic loss in tauopathies, paving the way for new therapeutic approaches.


Asunto(s)
Complemento C1q/metabolismo , Neuronas/metabolismo , Receptor de Adenosina A2A/genética , Receptor de Adenosina A2A/metabolismo , Sinapsis/patología , Tauopatías/genética , Tauopatías/patología , Animales , Autopsia , Degeneración Lobar Frontotemporal/genética , Degeneración Lobar Frontotemporal/metabolismo , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Trastornos de la Memoria/etiología , Trastornos de la Memoria/psicología , Ratones , Ratones Transgénicos , Mutación , Aprendizaje Espacial , Tauopatías/psicología , Proteínas tau/genética
4.
Cereb Cortex ; 27(1): 718-730, 2017 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-26534909

RESUMEN

Abnormal accumulation of aggregated α-synuclein (aSyn) is a hallmark of sporadic and familial Parkinson's disease (PD) and related synucleinopathies. Recent studies suggest a neuroprotective role of adenosine A2A receptor (A2AR) antagonists in PD. Nevertheless, the precise molecular mechanisms underlying this neuroprotection remain unclear. We assessed the impact of A2AR blockade or genetic deletion (A2AR KO) on synaptic plasticity and neuronal cell death induced by aSyn oligomers. We found that impairment of LTP associated with aSyn exposure was rescued in A2AR KO mice or upon A2AR blockade, through an NMDA receptor-dependent mechanism. The mechanisms underlying these effects were evaluated in SH-SY5Y cells overexpressing aSyn and rat primary neuronal cultures exposed to aSyn. Cell death in both conditions was prevented by selective A2AR antagonists. Interestingly, blockade of these receptors did not interfere with aSyn oligomerization but, instead, reduced the percentage of cells displaying aSyn inclusions. Altogether, our data raise the possibility that the well-documented effects of A2AR antagonists involve the control of the latter stages of aSyn aggregation, thereby preventing the associated neurotoxicity. These findings suggest that A2AR represent an important target for the development of effective drugs for the treatment of PD and related synucleinopathies.


Asunto(s)
Neuronas/metabolismo , Receptor de Adenosina A2A/metabolismo , alfa-Sinucleína/metabolismo , Antagonistas del Receptor de Adenosina A2/toxicidad , Animales , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Línea Celular Tumoral , Potenciales Postsinápticos Excitadores , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas/efectos de los fármacos , Neuronas/patología , Ratas Wistar , Receptor de Adenosina A2A/genética , Proteínas Recombinantes/metabolismo , Técnicas de Cultivo de Tejidos , alfa-Sinucleína/genética
5.
Hum Mol Genet ; 24(5): 1441-56, 2015 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-25480889

RESUMEN

To investigate epigenetic contributions to Huntington's disease (HD) pathogenesis, we carried out genome-wide mapping of the transcriptional mark, trimethyl-histone H3-lysine 4 (H3K4me3) in neuronal nuclei extracted from prefrontal cortex of HD cases and controls using chromatin immunoprecipitation followed by deep-sequencing. Neuron-specific mapping of the genome-wide distribution of H3K4me3 revealed 136 differentially enriched loci associated with genes implicated in neuronal development and neurodegeneration, including GPR3, TMEM106B, PDIA6 and the Notch signaling genes hairy and enhancer of split 4 (HES4) and JAGGED2, supporting the view that the neuronal epigenome is affected in HD. Importantly, loss of H3K4me3 at CpG-rich sequences on the HES4 promoter was associated with excessive DNA methylation, reduced binding of nuclear proteins to the methylated region and altered expression of HES4 and HES4 targeted genes MASH1 and P21 involved in striatal development. Moreover, hypermethylation of HES4 promoter sequences was strikingly correlated with measures of striatal degeneration and age-of-onset in a cohort of 25 HD brains (r = 0.56, P = 0.006). Lastly, shRNA knockdown of HES4 in human neuroblastoma cells altered MASH1 and P21 mRNA expression and markedly increased mutated HTT-induced aggregates and cell death. These findings, taken together, suggest that epigenetic dysregulation of HES4 could play a critical role in modifying HD disease pathogenesis and severity.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Epigénesis Genética , Proteínas de Homeodominio/metabolismo , Enfermedad de Huntington/genética , Neostriado/patología , Adulto , Autopsia , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Estudios de Casos y Controles , Línea Celular Tumoral , Inmunoprecipitación de Cromatina , Metilación de ADN , Femenino , Sitios Genéticos , Marcadores Genéticos , Estudio de Asociación del Genoma Completo , Secuenciación de Nucleótidos de Alto Rendimiento , Proteínas de Homeodominio/genética , Humanos , Masculino , Neostriado/metabolismo , Neuronas/citología , Neuronas/metabolismo , Filogenia , Regiones Promotoras Genéticas , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Factor de Transcripción HES-1
6.
Biochem Soc Trans ; 42(2): 587-92, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24646282

RESUMEN

AD (Alzheimer's disease) is the most prevalent form of dementia in the aged population. Definitive diagnosis of AD is based on the presence of senile plaques and neurofibrillary tangles that are identified in post-mortem brain specimens. A third pathological component is inflammation. AD results from multiple genetic and environmental risk factors. Among other factors, epidemiological studies report beneficial effects of caffeine, a non-selective antagonist of adenosine receptors. In the present review, we discuss the impact of caffeine and the adenosinergic system in AD pathology as well as consequences in terms of pathology and therapeutics.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Cafeína/uso terapéutico , Antagonistas de Receptores Purinérgicos P1/uso terapéutico , Animales , Humanos , Receptores Purinérgicos P1/metabolismo
7.
Aging Cell ; 22(3): e13778, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36704841

RESUMEN

N-methyl-D-aspartate receptors (NMDARs) are critical for the maturation and plasticity of glutamatergic synapses. In the hippocampus, NMDARs mainly contain GluN2A and/or GluN2B regulatory subunits. The amyloid precursor protein (APP) has emerged as a putative regulator of NMDARs, but the impact of this interaction to their function is largely unknown. By combining patch-clamp electrophysiology and molecular approaches, we unravel a dual mechanism by which APP controls GluN2B-NMDARs, depending on the life stage. We show that APP is highly abundant specifically at the postnatal postsynapse. It interacts with GluN2B-NMDARs, controlling its synaptic content and mediated currents, both in infant mice and primary neuronal cultures. Upon aging, the APP amyloidogenic-derived C-terminal fragments, rather than APP full-length, contribute to aberrant GluN2B-NMDAR currents. Accordingly, we found that the APP processing is increased upon aging, both in mice and human brain. Interfering with stability or production of the APP intracellular domain normalized the GluN2B-NMDARs currents. While the first mechanism might be essential for synaptic maturation during development, the latter could contribute to age-related synaptic impairments.


Asunto(s)
Precursor de Proteína beta-Amiloide , Receptores de N-Metil-D-Aspartato , Ratones , Humanos , Animales , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transducción de Señal , Hipocampo/metabolismo , Sinapsis/metabolismo
8.
J Neurochem ; 123(6): 1030-40, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23057965

RESUMEN

In situations of hypoxia, glutamate excitotoxicity induces neuronal death. The release of extracellular adenosine is also triggered and is accompanied by an increase of the stress mediator, corticotrophin-releasing factor (CRF). Adenosine A(2A) receptors contribute to glutamate excitoxicity and their blockade is effective in stress-induced neuronal deficits, but the involvement of CRF on this effect was never explored. We now evaluated the interaction between A(2A) and CRF receptors (CRFR) function, upon glutamate insult. Primary rat cortical neuronal cultures (9 days in vitro) expressing both CRF(1)R and CRF(2)R were challenged with glutamate (20-1000 µM, 24 h). CRF(1)R was found to co-localize with neuronal markers and CRF(2)R to be present in both neuronal and glial cells. The effects of the CRF and A(2A) receptors ligands on cell viability were measured using propidium iodide and Syto-13 fluorescence staining. Glutamate decreased cell viability in a concentration-dependent manner. Urocortin (10 pM), an agonist of CRF receptors, increased cell survival in the presence of glutamate. This neuroprotective effect was abolished by blocking either CRF(1)R or CRF(2)R with antalarmin (10 nM) or anti-Sauvagine-30 (10 nM), respectively. The blockade of A(2A) receptors with a selective antagonist SCH 58261 (50 nM) improved cell viability against the glutamate insult. This effect was dependent on CRF(2)R, but not on CRF(1)R activation. Overall, these data show a protective role of CRF in cortical neurons, against glutamate-induced death. The neuroprotection achieved by A(2A) receptors blockade requires CRF(2)R activation. This interaction between the adenosine and CRF receptors can explain the beneficial effects of using A(2A) receptor antagonists against stress-induced noxious effects.


Asunto(s)
Antagonistas del Receptor de Adenosina A2/farmacología , Hormona Liberadora de Corticotropina/fisiología , Ácido Glutámico/toxicidad , Inhibición Neural/efectos de los fármacos , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Receptor de Adenosina A2A/metabolismo , Animales , Corteza Cerebral/patología , Ácido Glutámico/metabolismo , Inhibición Neural/fisiología , Neuronas/metabolismo , Neuronas/patología , Cultivo Primario de Células , Pirimidinas/farmacología , Pirroles/farmacología , Ratas , Ratas Sprague-Dawley , Triazoles/farmacología
9.
Elife ; 112022 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-35787830

RESUMEN

Trypanosoma congolense causes a syndrome of variable severity in animals in Africa. Cerebral trypanosomiasis is a severe form, but the mechanism underlying this severity remains unknown. We developed a mouse model of acute cerebral trypanosomiasis and characterized the cellular, behavioral, and physiological consequences of this infection. We show large parasite sequestration in the brain vasculature for long periods of time (up to 8 hr) and extensive neuropathology that associate with ICAM1-mediated recruitment and accumulation of T cells in the brain parenchyma. Antibody-mediated ICAM1 blocking and lymphocyte absence reduce parasite sequestration in the brain and prevent the onset of cerebral trypanosomiasis. Here, we establish a mouse model of acute cerebral trypanosomiasis and we propose a mechanism whereby parasite sequestration, host ICAM1, and CD4+ T cells play a pivotal role.


Asunto(s)
Parásitos , Trypanosoma congolense , Tripanosomiasis Africana , Tripanosomiasis , Animales , Modelos Animales de Enfermedad , Ratones , Tripanosomiasis Africana/parasitología
10.
NPJ Parkinsons Dis ; 8(1): 51, 2022 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-35468899

RESUMEN

Alpha-synuclein (aSyn) is a central player in the pathogenesis of synucleinopathies due to its accumulation in typical protein aggregates in the brain. However, it is still unclear how it contributes to neurodegeneration. Type-2 diabetes mellitus is a risk factor for Parkinson's disease (PD). Interestingly, a common molecular alteration among these disorders is the age-associated increase in protein glycation. We hypothesized that glycation-induced neuronal dysfunction is a contributing factor in synucleinopathies. Here, we dissected the impact of methylglyoxal (MGO, a glycating agent) in mice overexpressing aSyn in the brain. We found that MGO-glycation potentiates motor, cognitive, olfactory, and colonic dysfunction in aSyn transgenic (Thy1-aSyn) mice that received a single dose of MGO via intracerebroventricular injection. aSyn accumulates in the midbrain, striatum, and prefrontal cortex, and protein glycation is increased in the cerebellum and midbrain. SWATH mass spectrometry analysis, used to quantify changes in the brain proteome, revealed that MGO mainly increase glutamatergic-associated proteins in the midbrain (NMDA, AMPA, glutaminase, VGLUT and EAAT1), but not in the prefrontal cortex, where it mainly affects the electron transport chain. The glycated proteins in the midbrain of MGO-injected Thy1-aSyn mice strongly correlate with PD and dopaminergic pathways. Overall, we demonstrated that MGO-induced glycation accelerates PD-like sensorimotor and cognitive alterations and suggest that the increase of glutamatergic signaling may underly these events. Our study sheds new light into the enhanced vulnerability of the midbrain in PD-related synaptic dysfunction and suggests that glycation suppressors and anti-glutamatergic drugs may hold promise as disease-modifying therapies for synucleinopathies.

11.
eNeuro ; 8(4)2021.
Artículo en Inglés | MEDLINE | ID: mdl-34210659

RESUMEN

Stereotaxic access to brain areas underneath the superior sagittal sinus (SSS) is notoriously challenging. As a major drainage vessel, covering the whole extension of the sagittal fissure, the SSS impedes direct bilateral access to underlying regions for recording and stimulation probes, drug-delivery cannulas, and injection devices. We now describe a new method for transection and retraction of the SSS in rats, that allows the accurate placement of microinjection devices, or chronic electrode probes, while avoiding hemorrhage and the ensuing deleterious consequences for local structures, animal health, and behavior. To demonstrate the feasibility of this approach we evaluated its consequences acutely during surgery, and thereafter during surgical survival, recovery, behavioral testing, as well as postmortem analysis of histologic impact in the related brain structures of male rats. This method provides a new approach enabling direct access for manipulation and recording of activity in brain areas previously obstructed by the SSS.


Asunto(s)
Roedores , Seno Sagital Superior , Animales , Encéfalo , Masculino , Ratas
12.
Cell Rep ; 36(9): 109574, 2021 08 31.
Artículo en Inglés | MEDLINE | ID: mdl-34469732

RESUMEN

Neuroinflammation in patients with Alzheimer's disease (AD) and related mouse models has been recognized for decades, but the contribution of the recently described meningeal immune population to AD pathogenesis remains to be addressed. Here, using the 3xTg-AD model, we report an accumulation of interleukin-17 (IL-17)-producing cells, mostly γδ T cells, in the brain and the meninges of female, but not male, mice, concomitant with the onset of cognitive decline. Critically, IL-17 neutralization into the ventricles is sufficient to prevent short-term memory and synaptic plasticity deficits at early stages of disease. These effects precede blood-brain barrier disruption and amyloid-beta or tau pathology, implying an early involvement of IL-17 in AD pathology. When IL-17 is neutralized at later stages of disease, the onset of short-memory deficits and amyloidosis-related splenomegaly is delayed. Altogether, our data support the idea that cognition relies on a finely regulated balance of "inflammatory" cytokines derived from the meningeal immune system.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Conducta Animal , Encéfalo/metabolismo , Cognición , Mediadores de Inflamación/metabolismo , Interleucina-17/metabolismo , Linfocitos Intraepiteliales/metabolismo , Enfermedades Neuroinflamatorias/metabolismo , Sinapsis/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/prevención & control , Enfermedad de Alzheimer/psicología , Animales , Antiinflamatorios/farmacología , Anticuerpos Monoclonales/farmacología , Anticuerpos Neutralizantes/farmacología , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/patología , Cognición/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Mediadores de Inflamación/antagonistas & inhibidores , Interleucina-17/antagonistas & inhibidores , Linfocitos Intraepiteliales/efectos de los fármacos , Masculino , Memoria a Corto Plazo , Ratones de la Cepa 129 , Ratones Transgénicos , Enfermedades Neuroinflamatorias/patología , Enfermedades Neuroinflamatorias/prevención & control , Enfermedades Neuroinflamatorias/psicología , Plasticidad Neuronal , Sinapsis/efectos de los fármacos , Sinapsis/patología
13.
Adv Biosyst ; 4(10): e2000139, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32869522

RESUMEN

Excitotoxicity is a cellular phenomenon that comprises the consequences of toxic actions of excitatory neurotransmitters, such as glutamate. This process is usually related to overproduction of reactive oxygen species (ROS) and ammonia (NH4+ ) toxicity. Platinum nanoparticle (Pt-NP)-based microreactors able to degrade hydrogen peroxide (H2 O2 ) and NH4+ , are previously described as a novel therapeutical approach against excitotoxicity, conferring protection to neuroblasts. Now, it is demonstrated that these microreactors are compatible with rat primary cortical neurons, show high levels of neuronal membrane interaction, and are able to improve cell survival and neuronal activity when neurons are exposed to H2 O2 or NH4+ . Additionally, more complex microreactors are assembled, including enzyme-loaded liposomes containing glutamate dehydrogenase and glutathione reductase, in addition to Pt-NP. The in vitro activity of these microreactors is characterized and they are compared to the Pt-NP-based microreactors in terms of biological activity, concluding that they enhance cell viability similarly or more extensively than the latter. Extracellular electrophysiological recordings demonstrate that these microreactors rescue neuronal functionality lost upon incubation with H2 O2 or NH4+ . This study provides more evidence for the potential application of these microreactors in a biomedical context with more complex cellular environments.


Asunto(s)
Supervivencia Celular/efectos de los fármacos , Neuronas , Fármacos Neuroprotectores , Estrés Oxidativo/efectos de los fármacos , Amoníaco/metabolismo , Animales , Células Cultivadas , Peróxido de Hidrógeno/metabolismo , Neuronas/citología , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/metabolismo , Fármacos Neuroprotectores/farmacología , Neurotoxinas/metabolismo , Ratas , Ratas Sprague-Dawley
14.
Neuroscience ; 424: 58-71, 2020 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-31682948

RESUMEN

The motor features in Parkinson's disease (PD) are associated with the degeneration of dopaminergic cells in the substantia nigra in the brain. Thus, the gold-standard in PD therapeutics still consists of dopamine replacement with levodopa. However, as the disease progresses, this therapeutic option becomes less effective and can be accompanied by levodopa-induced complications. On the other hand, several other neuronal pathways have been implicated in the pathological mechanisms of PD. In this context, the development of alternative therapeutic options that modulate non-dopaminergic targets is emerging as a major goal in the field. In a phenotypic-based screen in a zebrafish model of PD, we identified tapentadol as a candidate molecule for PD. The therapeutic potential of an agent that modulates the opioid and noradrenergic systems has not been explored, despite the implication of both neuronal pathways in parkinsonism. Therefore, we assessed the therapeutic properties of this µ-opioid receptor agonist and norepinephrine reuptake inhibitor in the 6-hydroxydopamine mouse model of parkinsonism. We further submitted 6-hydroxydopamine-lesioned mice to chronic treatment with levodopa and evaluated the effects of tapentadol during levodopa OFF states and on levodopa-induced dyskinesia. Importantly, we found that tapentadol halted the aggravation of dyskinesia and improved the motor impairments during levodopa OFF states. Altogether, our findings raise the hypothesis that concomitant modulation of µ-opioid receptor and norepinephrine transporter might constitute relevant intervention strategies in PD and that tapentadol holds therapeutic potential that may be translated into the clinical practice.


Asunto(s)
Inhibidores de Captación Adrenérgica/uso terapéutico , Modelos Animales de Enfermedad , Discinesia Inducida por Medicamentos/prevención & control , Trastornos Motores/prevención & control , Trastornos Parkinsonianos/prevención & control , Tapentadol/uso terapéutico , Animales , Discinesia Inducida por Medicamentos/fisiopatología , Levodopa/toxicidad , Masculino , Ratones , Trastornos Motores/inducido químicamente , Trastornos Motores/fisiopatología , Oxidopamina/toxicidad , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/fisiopatología
15.
Cells ; 9(7)2020 07 21.
Artículo en Inglés | MEDLINE | ID: mdl-32708189

RESUMEN

The pathological condition of neuroinflammation is caused by the activation of the neuroimmune cells astrocytes and microglia. The autacoid adenosine seems to be an important neuromodulator in this condition. Its main receptors involved in the neuroinflammation modulation are A1AR and A2AAR. Evidence suggests that A1AR activation produces a neuroprotective effect and A2AARs block prevents neuroinflammation. The aim of this work is to elucidate the effects of these receptors in neuroinflammation using the partial agonist 2'-dCCPA (2-chloro-N6-cyclopentyl-2'-deoxyadenosine) (C1 KiA1AR = 550 nM, KiA2AAR = 24,800 nM, and KiA3AR = 5560 nM, α = 0.70, EC50A1AR = 832 nM) and the newly synthesized in house compound 8-chloro-9-ethyl-2-phenethoxyadenine (C2 KiA2AAR = 0.75 nM; KiA1AR = 17 nM and KiA3AR = 227 nM, IC50A2AAR = 251 nM unpublished results). The experiments were performed in in vitro and in in vivo models of neuroinflammation. Results showed that C1 was able to prevent the inflammatory effect induced by cytokine cocktail (TNF-α, IL-1ß, and IFN-γ) while C2 possess both anti-inflammatory and antioxidant properties, counteracting both neuroinflammation in mixed glial cells and in an animal model of neuroinflammation. In conclusion, C2 is a potential candidate for neuroinflammation therapy.


Asunto(s)
Agonistas del Receptor de Adenosina A1/farmacología , Antagonistas del Receptor de Adenosina A2/farmacología , Inflamación/patología , Neuronas/patología , Receptores Purinérgicos P1/metabolismo , Adenosina/análogos & derivados , Animales , Células Cultivadas , Masculino , Neuroglía/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ratas Wistar , Triazinas/farmacología , Triazoles/farmacología
16.
Front Pharmacol ; 11: 985, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32733240

RESUMEN

Kyotorphin (KTP, l-tyrosyl-l-arginine) is an endogenous dipeptide initially described to have analgesic properties. Recently, KTP was suggested to be an endogenous neuroprotective agent, namely for Alzheimer's disease (AD). In fact, KTP levels were shown to be decreased in the cerebrospinal fluid of patients with AD, and recent data showed that intracerebroventricular (i.c.v.) injection of KTP ameliorates memory impairments in a sporadic rat model of AD. However, this administration route is far from being a suitable therapeutic strategy. Here, we evaluated if the blood-brain permeant KTP-derivative, KTP-NH2, when systemically administered, would be effective in preventing memory deficits in a sporadic AD animal model and if so, which would be the synaptic correlates of that action. The sporadic AD model was induced in male Wistar rats through i.c.v. injection of amyloid ß peptide (Aß). Animals were treated for 20 days with KTP-NH2 (32.3 mg/kg, intraperitoneally (i.p.), starting at day 3 after Aß administration) before memory testing (Novel object recognition (NOR) and Y-maze (YM) tests). Animals were then sacrificed, and markers for gliosis were assessed by immunohistochemistry and Western blot analysis. Synaptic correlates were assessed by evaluating theta-burst induced long term potentiation (LTP) of field excitatory synaptic potentials (fEPSPs) recorded from hippocampal slices and cortical spine density analysis. In the absence of KTP-NH2 treatment, Aß-injected rats had clear memory deficits, as assessed through NOR or YM tests. Importantly, these memory deficits were absent in Aß-injected rats that had been treated with KTP-NH2, which scored in memory tests as control (sham i.c.v. injected) rats. No signs of gliosis could be detected at the end of the treatment in any group of animals. LTP magnitude was significantly impaired in hippocampal slices that had been incubated with Aß oligomers (200 nM) in the absence of KTP-NH2. Co-incubation with KTP-NH2 (50 nM) rescued LTP toward control values. Similarly, Aß caused a significant decrease in spine density in cortical neuronal cultures, and this was prevented by co-incubation with KTP-NH2 (50 nM). In conclusion, the present data demonstrate that i.p. KTP-NH2 treatment counteracts Aß-induced memory impairments in an AD sporadic model, possibly through the rescuing of synaptic plasticity mechanisms.

17.
J Neurosci ; 28(12): 2970-5, 2008 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-18354001

RESUMEN

The function of striatal adenosine A(2A) receptors (A(2A)Rs) is well recognized because of their high expression levels and the documented antagonistic interaction between A(2A)Rs and dopamine D(2) receptors in the striatum. However, the role of extrastriatal A(2A)Rs in modulating psychomotor activity is largely unexplored because of the low level of expression and lack of tools to distinguish A(2A)Rs in intrinsic striatal versus nonstriatal neurons. Here, we provided direct evidence for the critical role of A(2A)Rs in extrastriatal neurons in modulating psychomotor behavior using newly developed striatum-specific A(2A)R knock-out (st-A(2A)R KO) mice in comparison with forebrain-specific A(2A)R KO (fb-A(2A)R KO) mice. In contrast to fb-A(2A)R KO (deleting A(2A)Rs in the neurons of striatum as well as cerebral cortex and hippocampus), st-A(2A)R KO mice exhibited Cre-mediated selective deletion of the A(2A)R gene, mRNA, and proteins in the neurons (but not astrocytes and microglial cells) of the striatum only. Strikingly, cocaine- and phencyclidine-induced psychomotor activities were enhanced in st-A(2A)R KO but attenuated in fb-A(2A)R KO mice. Furthermore, selective inactivation of the A(2A)Rs in extrastriatal cells by administering the A(2A)R antagonist KW6002 into st-A(2A)R KO mice attenuated cocaine effects, whereas KW6002 administration into wild-type mice enhanced cocaine effects. These results identify a critical role of A(2A)Rs in extrastriatal neurons in providing a prominent excitatory effect on psychomotor activity. These results indicate that A(2A)Rs in striatal and extrastriatal neurons exert an opposing modulation of psychostimulant effects and provide the first direct demonstration of a predominant facilitatory role of extrastriatal A(2A)Rs.


Asunto(s)
Desempeño Psicomotor/fisiología , Receptor de Adenosina A2A/deficiencia , Receptor de Adenosina A2A/fisiología , Análisis de Varianza , Animales , Conducta Animal , Cocaína/farmacología , Cuerpo Estriado , Inhibidores de Captación de Dopamina/farmacología , Inhibidores Enzimáticos/farmacología , Proteínas de Homeodominio/genética , Ratones , Ratones Transgénicos , Neuronas , Fenciclidina/farmacología , Prosencéfalo , Desempeño Psicomotor/efectos de los fármacos , Purinas/farmacología
18.
Physiol Genomics ; 37(3): 199-210, 2009 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-19258493

RESUMEN

Caffeine is the most widely consumed psychoactive substance and has complex pharmacological actions in brain. In this study, we employed a novel drug target validation strategy to uncover the multiple molecular targets of caffeine using combined A(2A) receptor (A(2A)R) knockouts (KO) and microarray profiling. Caffeine (10 mg/kg) elicited a distinct profile of striatal gene expression in WT mice compared with that by A(2A)R gene deletion or by administering caffeine into A(2A)R KO mice. Thus, A(2A)Rs are required but not sufficient to elicit the striatal gene expression by caffeine (10 mg/kg). Caffeine (50 mg/kg) induced complex expression patterns with three distinct sets of striatal genes: 1) one subset overlapped with those elicited by genetic deletion of A(2A)Rs; 2) the second subset elicited by caffeine in WT as well as A(2A)R KO mice; and 3) the third subset elicited by caffeine only in A(2A)R KO mice. Furthermore, striatal gene sets elicited by the phosphodiesterase (PDE) inhibitor rolipram and the GABA(A) receptor antagonist bicucullin, overlapped with the distinct subsets of striatal genes elicited by caffeine (50 mg/kg) administered to A(2A)R KO mice. Finally, Gene Set Enrichment Analysis reveals that adipocyte differentiation/insulin signaling is highly enriched in the striatal gene sets elicited by both low and high doses of caffeine. The identification of these distinct striatal gene populations and their corresponding multiple molecular targets, including A(2A)R, non-A(2A)R (possibly A(1)Rs and pathways associated with PDE and GABA(A)R) and their interactions, and the cellular pathways affected by low and high doses of caffeine, provides molecular insights into the acute pharmacological effects of caffeine in the brain.


Asunto(s)
Cafeína/farmacología , Perfilación de la Expresión Génica , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Receptor de Adenosina A2A/fisiología , Animales , Bicuculina/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Análisis por Conglomerados , Relación Dosis-Respuesta a Droga , Femenino , Antagonistas del GABA/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Ratones , Ratones Noqueados , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Inhibidores de Fosfodiesterasa/farmacología , Receptor de Adenosina A2A/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Rolipram/farmacología
19.
Ann Neurol ; 63(3): 338-46, 2008 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-18300283

RESUMEN

OBJECTIVE: To investigate whether the motor and neuroprotective effects of adenosine A(2A) receptor (A(2A)R) antagonists are mediated by distinct cell types in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. METHODS: We used the forebrain A(2A)R knock-out mice coupled with flow cytometric analyses and intracerebroventricular injection to determine the contribution of A(2A)Rs in forebrain neurons and glial cells to A(2A)R antagonist-mediated motor and neuroprotective effects. RESULTS: The selective deletion of A(2A)Rs in forebrain neurons abolished the motor stimulant effects of the A(2A)R antagonist KW-6002 but did not affect acute MPTP neurotoxicity. Intracerebroventricular administration of KW-6002 into forebrain A(2A)R knock-out mice reinstated protection against acute MPTP-induced dopaminergic neurotoxicity and attenuated MPTP-induced striatal microglial and astroglial activation. INTERPRETATION: A(2A)R activity in forebrain neurons is critical to the control of motor activity, whereas brain cells other than forebrain neurons (likely glial cells) are important components for protection against acute MPTP toxicity.


Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Actividad Motora/fisiología , Neuronas/citología , Fármacos Neuroprotectores/farmacología , Animales , Intoxicación por MPTP/tratamiento farmacológico , Intoxicación por MPTP/prevención & control , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Actividad Motora/efectos de los fármacos , Neuroglía/citología , Neuroglía/efectos de los fármacos , Neuroglía/fisiología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Fármacos Neuroprotectores/uso terapéutico , Prosencéfalo/citología , Prosencéfalo/efectos de los fármacos , Prosencéfalo/fisiología , Purinas/farmacología , Purinas/uso terapéutico , Receptor de Adenosina A2A/deficiencia , Receptor de Adenosina A2A/fisiología
20.
J Caffeine Adenosine Res ; 9(3): 104-127, 2019 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-31559391

RESUMEN

While neuronal loss has long been considered as the main contributor to age-related cognitive decline, these alterations are currently attributed to gradual synaptic dysfunction driven by calcium dyshomeostasis and alterations in ionotropic/metabotropic receptors. Given the key role of the hippocampus in encoding, storage, and retrieval of memory, the morpho- and electrophysiological alterations that occur in the major synapse of this network-the glutamatergic-deserve special attention. We guide you through the hippocampal anatomy, circuitry, and function in physiological context and focus on alterations in neuronal morphology, calcium dynamics, and plasticity induced by aging and Alzheimer's disease (AD). We provide state-of-the art knowledge on glutamatergic transmission and discuss implications of these novel players for intervention. A link between regular consumption of caffeine-an adenosine receptor blocker-to decreased risk of AD in humans is well established, while the mechanisms responsible have only now been uncovered. We review compelling evidence from humans and animal models that implicate adenosine A2A receptors (A2AR) upsurge as a crucial mediator of age-related synaptic dysfunction. The relevance of this mechanism in patients was very recently demonstrated in the form of a significant association of the A2AR-encoding gene with hippocampal volume (synaptic loss) in mild cognitive impairment and AD. Novel pathways implicate A2AR in the control of mGluR5-dependent NMDAR activation and subsequent Ca2+ dysfunction upon aging. The nature of this receptor makes it particularly suited for long-term therapies, as an alternative for regulating aberrant mGluR5/NMDAR signaling in aging and disease, without disrupting their crucial constitutive activity.

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