RESUMEN
Amyotrophic lateral sclerosis (ALS) is a rare progressive motor neuron disease that, due to its high complexity, still lacks effective treatments. Development of a new drug is a highly costly and time-consuming process, and the repositioning of approved drugs can represent an efficient strategy to provide therapeutic opportunities. This is particularly true for rare diseases, which are characterised by small patient populations and therefore attract little commercial interest. Based on the overlap between the biological background of cancer and neurodegeneration, the repurposing of antineoplastic drugs for ALS has been suggested. The objective of this narrative review was to summarise the current experimental evidence on the use of approved anticancer drugs in ALS. Specifically, anticancer drugs belonging to different classes were found to act on mechanisms involved in the ALS pathogenesis, and some of them proved to exert beneficial effects in ALS models. However, additional studies are necessary to confirm the real therapeutic potential of anticancer drugs for repositioning in ALS treatment.
Asunto(s)
Esclerosis Amiotrófica Lateral , Antineoplásicos , Enfermedad de la Neurona Motora , Humanos , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
To clarify the role of gut mucosal immunity in ASD, we evaluated, in the early-life immune activation (EIA) mouse model, the effects of administration of a monoclonal antibody directed against the integrin alpha4 beta7 (α4ß7 mAb), blocking the leukocyte homing into the gut mucosa. EIA is a double-hit variant of the maternal immune-activation (MIA) model, including both prenatal (Poly I:C) and postnatal (LPS) immune challenges. In C57BL6/J EIA male adult offspring mice, IL-1ß and IL-17A mRNA colonic tissue content increased when compared with controls. Cytofluorimetric analyses of lymphocytes isolated from mesenteric lymph-nodes (MLN) and spleens of EIA mice show increased percentage of total and CD4+α4ß7+, unstimulated and stimulated IL-17A+ and stimulated IFN-γ+ lymphocytes in MLN and CD4+α4ß7+ unstimulated and stimulated IL-17A+ and stimulated IFN-γ+ lymphocytes in the spleen. Treatment with anti-α4ß7 mAb in EIA male mice was associated with colonic tissue IL-1ß, and IL-17A mRNA content and percentage of CD4+ IL-17A+ and IFN-γ+ lymphocytes in MLN and spleens comparable to control mice. The anti-α4ß7 mAb treatment rescue social novelty deficit showed in the three-chamber test by EIA male mice. Increased levels of IL-6 and IL-1ß and decreased CD68 and TGF-ß mRNAs were also observed in hippocampus and prefrontal cortex of EIA male mice together with a reduction of BDNF mRNA levels in all brain regions examined. Anti-α4ß7 mAb treatment restored the expression of BDNF, TGF-ß and CD68 in hippocampus and prefrontal cortex. Improvement of the gut inflammatory status, obtained by a pharmacological agent acting exclusively at gut level, ameliorates some ASD behavioral features and the neuroinflammatory status. Data provide the first preclinical indication for a therapeutic strategy against gut-immune activation in ASD subjects with peripheral increase of gut-derived (α4ß7+) lymphocytes expressing IL-17A.
Asunto(s)
Trastorno del Espectro Autista , Interleucina-17 , Humanos , Adulto , Embarazo , Femenino , Masculino , Ratones , Animales , Factor Neurotrófico Derivado del Encéfalo , Integrinas/metabolismo , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Factor de Crecimiento Transformador beta , ARN MensajeroRESUMEN
Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease for which effective treatment options are still lacking. ALS occurs in sporadic and familial forms which are clinically indistinguishable; about 20% of familial ALS cases are linked to mutations of the superoxide dismutase 1 (SOD1) gene. Fenretinide (FEN), a cancer chemopreventive and antiproliferative agent currently used in several clinical trials, is a multi-target drug which also exhibits redox regulation activities. We analyzed the effects of FEN on mutant SOD1 (mSOD1) toxicity in motoneuronal (NSC34) and a muscle (C2C12) cell lines and evaluated the impacts of chronic administration of a new nanomicellar fenretinide formulation (NanoMFen) on ALS disease progression in the SOD1G93A mouse model. The results showed that FEN significantly prevents the toxicity of mSOD1 expression in NSC34 motor neuron; furthermore, FEN is able to partially overcome the toxic effect of mSOD1 on the myogenic program of C2C12 muscle cells. Administration of NanoMFen ameliorates the disease progression and increases median survival of mSOD1G93A ALS mice, even when given after disease onset; beneficial effects in ALS mice, however, is restricted to female sex. Our data support the therapeutic potential of FEN against ALS-associated SOD1G93A mutant protein toxicity and promote further studies to elucidate specific cellular targets of the drug in ALS. Furthermore, the sex-related efficacy of NanoMFen in mSOD1G93A ALS mice strengthens the importance, in the perspective of a precision medicine approach, of gender pharmacology in ALS research.
Asunto(s)
Esclerosis Amiotrófica Lateral , Fenretinida , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/genética , Animales , Modelos Animales de Enfermedad , Femenino , Fenretinida/farmacología , Ratones , Ratones Transgénicos , Proteínas Mutantes , Superóxido Dismutasa/genética , Superóxido Dismutasa-1/genéticaRESUMEN
In fragile X syndrome (FXS) the lack of the fragile X mental retardation protein (FMRP) leads to exacerbated signaling through the metabotropic glutamate receptors 5 (mGlu5Rs). The adenosine A2A receptors (A2ARs), modulators of neuronal damage, could play a role in FXS. A synaptic colocalization and a strong permissive interaction between A2A and mGlu5 receptors in the hippocampus have been previously reported, suggesting that blocking A2ARs might normalize the mGlu5R-mediated effects of FXS. To study the cross-talk between A2A and mGlu5 receptors in the absence of FMRP, we performed extracellular electrophysiology experiments in hippocampal slices of Fmr1 KO mouse. The depression of field excitatory postsynaptic potential (fEPSPs) slope induced by the mGlu5R agonist CHPG was completely blocked by the A2AR antagonist ZM241385 and strongly potentiated by the A2AR agonist CGS21680, suggesting that the functional synergistic coupling between the two receptors could be increased in FXS. To verify if chronic A2AR blockade could reverse the FXS phenotypes, we treated the Fmr1 KO mice with istradefylline, an A2AR antagonist. We found that hippocampal DHPG-induced long-term depression (LTD), which is abnormally increased in FXS mice, was restored to the WT level. Furthermore, istradefylline corrected aberrant dendritic spine density, specific behavioral alterations, and overactive mTOR, TrkB, and STEP signaling in Fmr1 KO mice. Finally, we identified A2AR mRNA as a target of FMRP. Our results show that the pharmacological blockade of A2ARs partially restores some of the phenotypes of Fmr1 KO mice, both by reducing mGlu5R functioning and by acting on other A2AR-related downstream targets.
Asunto(s)
Síndrome del Cromosoma X Frágil , Receptor de Adenosina A2A , Adenosina , Animales , Cognición , Modelos Animales de Enfermedad , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/tratamiento farmacológico , Síndrome del Cromosoma X Frágil/genética , Hipocampo/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptor de Adenosina A2A/genéticaRESUMEN
Autism Spectrum Disorders (ASD) are neurodevelopmental disorders characterized by social communication deficits and repetitive/stereotyped behaviours. We evaluated the effects of a chronic treatment with the immunomodulator drug Fingolimod (FTY720 - a non-selective Sphingosine 1-Phosphate Receptor ligand) in an ASD model, the BTBR T+tf/J (BTBR) mouse strain. In adult BTBR males, chronic FTY720 treatment (4â¯weeks) increased social and vocal response during a male-female interaction and hippocampal expression of BDNF and Neuregulin 1, two trophic factors reduced in BTBR when compared to control C57 mice. FTY720 also re-established the expression of IL-1ß and MnSOD in the hippocampus, whereas it did not modify IL-6 mRNA content. In addition to its central effect, FTY720 modulated the activation state of peripheral macrophages in the BTBR model, both in basal conditions and after stimulation with an immune challenge. Furthermore, IL-6 mRNA colonic content of BTBR mice, reduced when compared with C57 mice, was normalized by chronic treatment with FTY720. Our study, while indicating FTY720 as a tool to attenuate relevant alterations of the BTBR neurobehavioural phenotype, emphasizes the importance of gut mucosal immune evaluation as an additional target that deserve to be investigated in preclinical studies of anti-inflammatory therapeutic approaches in ASD.
Asunto(s)
Trastorno del Espectro Autista , Trastorno Autístico , Animales , Trastorno del Espectro Autista/tratamiento farmacológico , Modelos Animales de Enfermedad , Femenino , Clorhidrato de Fingolimod/farmacología , Inmunidad , Masculino , Ratones , Ratones Endogámicos C57BL , Transducción de Señal , Interacción SocialRESUMEN
Amyotrophic lateral sclerosis (ALS) is a fatal progressing neurodegenerative disease; to date, despite the intense research effort, only two therapeutic options, with very limited effects, are available. The purinergic system has been indicated as a possible new therapeutic target for ALS, but the results are often contradictory and generally confused. The present study was designed to determine whether P1 adenosine receptor ligands affected disease progression in a transgenic model of ALS. SOD1G93A mice were chronically treated, from presymptomatic stage, with a selective adenosine A2A receptor agonist (CGS21680), antagonist (KW6002) or the A1 receptor antagonist DPCPX. Body weight, motor performance and survival time were evaluated. The results showed that neither the stimulation nor the blockade of adenosine A2A receptors modified the progressive loss of motor skills or survival of mSOD1G93A mice. Conversely, blockade of adenosine A1 receptors from the presymptomatic stage significantly attenuated motor disease progression and induced a non-significant increase of median survival in ALS mice. Our data confirm that the modulation of adenosine receptors can elicit very different (and even opposite) effects during the progression of ALS course, thus strengthens the importance of further studies to elucidated their real therapeutic potential in this pathology.
Asunto(s)
Adenosina/análogos & derivados , Microglía/efectos de los fármacos , Neuronas Motoras/efectos de los fármacos , Fenetilaminas/farmacología , Médula Espinal/efectos de los fármacos , Superóxido Dismutasa-1/efectos de los fármacos , Adenosina/farmacología , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/patología , Animales , Modelos Animales de Enfermedad , Ratones Transgénicos , Neuronas Motoras/patología , Receptores Purinérgicos P1/efectos de los fármacos , Médula Espinal/patología , Superóxido Dismutasa-1/genéticaRESUMEN
The A2A adenosine receptor (A2AR) is widely distributed on different cellular types in the brain, where it exerts a broad spectrum of pathophysiological functions, and for which a role in different neurodegenerative diseases has been hypothesized or demonstrated. To investigate the role of neuronal A2ARs in neurodegeneration, we evaluated in vitro and in vivo the effect of the neurotoxin 3-nitropropionic acid (3-NP) in a transgenic rat strain overexpressing A2ARs under the control of the neural-specific enolase promoter (NSEA2A rats). We recorded extracellular field potentials (FP) in corticostriatal slice and found that the synaptotoxic effect of 3-NP was significantly reduced in NSEA2A rats compared with wild-type animals (WT). In addition, after exposing corticostriatal slices to 3-NP 10 mM for 2 h, we found that striatal cell viability was significantly higher in NSEA2A rats compared to control rats. These in vitro results were confirmed by in vivo experiments: daily treatment of female rats with 3-NP 10 mg/kg for 8 days induced a selective bilateral lesion in the striatum, which was significantly reduced in NSEA2A compared to WT rats. These results demonstrate that the overexpression of the A2AR selectively at the neuronal level reduced 3-NP-induced neurodegeneration, and suggest an important function of the neuronal A2AR in the modulation of neurodegeneration.
Asunto(s)
Cuerpo Estriado/metabolismo , Enfermedad de Huntington/metabolismo , Degeneración Nerviosa/metabolismo , Receptor de Adenosina A2A/metabolismo , Animales , Convulsivantes/toxicidad , Cuerpo Estriado/efectos de los fármacos , Modelos Animales de Enfermedad , Humanos , Masculino , Nitrocompuestos/toxicidad , Propionatos/toxicidad , Ratas , Ratas Sprague-Dawley , Ratas TransgénicasRESUMEN
Niemann-Pick C is a fatal neurovisceral disorder caused, in 95% of cases, by mutation of NPC1 gene. Therapeutic options are extremely limited and new "druggable" targets are highly warranted. We previously demonstrated that the stimulation of the adenosine A2A receptor (A2AR) normalized the pathological phenotype of cellular models of NPC1. Since the validation of A2ARs as a therapeutic target for NPC1 can be obtained only conducting studies in in vivo models of the disease, in the present paper, the effects of two agonists of A2ARs were evaluated in the mouse model Balb/c Npc1nih, hereafter indicated as NPC1-/-. The agonists CGS21680 (2.5 and 5mg/kg/day by intraperitoneal injection) and T1-11 (50mg/kg/day in drinking water) were administered at a presymptomatic stage of the disease of NPC1-/- mice (PN28 and PN30, respectively); the experimental groups were the following: vehicle-treated WT mice (N=16 for both CGS and T1-11 treatments); vehicle-treated NPC1-/- mice (N=14 for CGS and 12 for T1-11 treatment); CGS-treated NPC1-/- mice (N=7) and T1-11-treated NPC1-/- mice (N=11). The efficacy of the treatments was evaluated by comparing vehicle-treated and CGS or T1-11-treated NPC1-/- mice for their motor deficits (analyzed by both rotarod and footprint tests), hippocampal cognitive impairment (by Novel Object Recognition (NOR) test), cerebellar neurodegeneration (Purkinje neurons counting), and cholesterol and sphingomyelin accumulation in spleen and liver. Finally, the effect of both agonists on survival was evaluated by applying a humane late endpoint (weight loss >30% of peak weight, punched posture and reduced activity in the cage). The results demonstrated that, while CGS21680 only slightly attenuated cognitive deficits, T1-11 ameliorated motor coordination, significantly improved cognitive impairments, increased the survival of Purkinje neurons and reduced sphingomyelin accumulation in the liver. More importantly, it significantly prolonged the lifespan of NPC1-/- mice. In vitro experiments conducted in a neuronal model of NPC1 demonstrated that the ability of T1-11 to normalize cell phenotype was mediated by the selective activation of A2ARs and modulation of intracellular calcium levels. In conclusion, our results fully confirm the validity of A2ARs as a new target for NPC1 treatment. As soon as new ligands with improved pharmacokinetic characteristics (i.e. orally active, with brain bioavailability and metabolic stability) will be obtained, A2AR agonists could represent a breakthrough in the treatment of NPC.
Asunto(s)
Adenosina/análogos & derivados , Longevidad/efectos de los fármacos , Enfermedad de Niemann-Pick Tipo C/patología , Adenosina/farmacología , Animales , Cerebelo/efectos de los fármacos , Cerebelo/patología , Modelos Animales de Enfermedad , Hígado/efectos de los fármacos , Hígado/patología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Agonistas del Receptor Purinérgico P1/farmacología , Células de Purkinje/efectos de los fármacos , Receptor de Adenosina A2A/metabolismoRESUMEN
In the study of neurodegenerative diseases, rodent models provide experimentally accessible systems to study multiple pathogenetic aspects. The identification of early and robust behavioural changes is crucial to monitoring disease progression and testing potential therapeutic strategies in animals. Consistent experimental data support the translational value of rodent self-grooming as index of disturbed motor functions and perseverative behaviour patterns in different rodent models of brain disorders. Huntington's disease (HD) is a progressive neurodegenerative disorder, characterized by severe degeneration of basal ganglia, cognitive and psychiatric impairments and motor abnormalities. In the rat species, intrastriatal injection of the excitotoxin quinolinic acid (QA) mimics some of the neuroanatomical and behavioural changes found in HD, including the loss of GABAergic neurons and the appearance of motor and cognitive deficits. We show here that striatal damage induced by unilateral QA injection in dorsal striatum of rats triggers aberrant grooming behaviour as early as three weeks post-lesion in absence of other motor impairments: specifically, both quantitative (frequency and duration) and qualitative (the sequential pattern of movements) features of self-grooming behaviour were significantly altered in QA-lesioned rats placed in either the elevated plus-maze and the open-field. The consistent abnormalities in self-grooming recorded in two different experimental contexts support the use of this behavioural marker in rodent models of striatal damage such as HD, to assess the potential effects of drug and cell replacement therapy in the early stage of disease.
Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Modelos Animales de Enfermedad , Aseo Animal/efectos de los fármacos , Enfermedad de Huntington/fisiopatología , Animales , Apomorfina/administración & dosificación , Conducta Animal/efectos de los fármacos , Enfermedad de Huntington/inducido químicamente , Masculino , Ácido Quinolínico , Ratas , Ratas Sprague-DawleyRESUMEN
Fingolimod phosphate (FTY720), the first approved oral therapy for multiple sclerosis, primarily acts as an immunomodulator. Its concomitant effects in the central nervous system, however, indicate a potentially broader spectrum of activity in neurodegenerative diseases. In the present study, we investigated the possible effects of fingolimod in a mouse model of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by a strong neuroinflammatory component. Fingolimod (0.1 and 1 mg/kg i.p.) was administered to mSOD1G93A mice, a well-characterized mouse model of ALS, starting from the onset of motor symptoms to the end stage of the disease. The drug was able to improve the neurological phenotype (p < 0.05) and to extend the survival (p < 0.01) of ALS mice. The beneficial effect of fingolimod administration was associated with a significant modulation of neuroinflammatory and protective genes (CD11b, Foxp3, iNOS, Il1ß, Il10, Arg1, and Bdnf) in motor cortex and spinal cord of animals. Our data show, for the first time, that fingolimod is protective in ALS mice and that its beneficial effects are accompanied by a modulation of microglial activation and innate immunity. Considering that the treatment was started in already symptomatic mice, our data strongly support fingolimod as a potential new therapeutic approach to ALS.
Asunto(s)
Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Clorhidrato de Fingolimod/farmacología , Clorhidrato de Fingolimod/uso terapéutico , Regulación de la Expresión Génica/efectos de los fármacos , Esclerosis Amiotrófica Lateral/complicaciones , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Animales , Peso Corporal/efectos de los fármacos , Peso Corporal/genética , Encéfalo/metabolismo , Encéfalo/patología , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Regulación de la Expresión Génica/genética , Humanos , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Trastornos del Movimiento/tratamiento farmacológico , Trastornos del Movimiento/etiología , Mutación/genética , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Médula Espinal/patología , Superóxido Dismutasa/genéticaRESUMEN
Adenosine A2A receptors (A2 A Rs) and cannabinoid CB1 receptors (CB1 Rs) are highly expressed in the striatum, where they functionally interact and form A2A /CB1 heteroreceptor complexes. We investigated the effects of CB1 R stimulation in a transgenic rat strain over-expressing A2 A Rs under the control of the neural-specific enolase promoter (NSEA2A rats) and in age-matched wild-type (WT) animals. The effects of the CB1 R agonist WIN 55,212-2 (WIN) were significantly lower in NSEA2A rats than in WT animals, as demonstrated by i) electrophysiological recordings of synaptic transmission in corticostriatal slices; ii) the measurement of glutamate outflow from striatal synaptosomes and iii) in vivo experiments on locomotor activity. Moreover, while the effects of WIN were modulated by both A2 A R agonist (CGS 21680) and antagonists (ZM 241385, KW-6002 and SCH-442416) in WT animals, the A2 A R antagonists failed to influence WIN-mediated effects in NSEA2A rats. The present results demonstrate that in rats with genetic neuronal over-expression of A2 A Rs, the effects mediated by CB1 R activation in the striatum are significantly reduced, suggesting a change in the stoichiometry of A2A and CB1 receptors and providing a strategy to dissect the involvement of A2 A R forming or not forming heteromers in the modulation of striatal functions. These findings add additional evidence for the existence of an interaction between striatal A2 A Rs and CB1 Rs, playing a fundamental role in the regulation of striatal functions. We studied A2A -CB1 receptor interaction in transgenic rats over-expressing adenosine A2A receptors under the control of the neuron-specific enolase promoter (NSEA2A ). In these rats, we demonstrated a reduced effect of the CB1 receptor agonist WIN 55,212-2 in the modulation of corticostriatal synaptic transmission and locomotor activity, while CB1 receptor expression level did not change with respect to WT rats. A reduction in the expression of A2A -CB1 receptor heteromers is postulated.
Asunto(s)
Adenosina/metabolismo , Cannabinoides/metabolismo , Cuerpo Estriado/metabolismo , Receptor de Adenosina A2A/metabolismo , Antagonistas del Receptor de Adenosina A2/farmacología , Animales , Cuerpo Estriado/efectos de los fármacos , Masculino , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/metabolismo , Transmisión Sináptica/efectos de los fármacosRESUMEN
In recent years there has been an increasing awareness of the role of P2X7, a receptor for extracellular ATP, in modulating physiopathological mechanisms in the central nervous system. In particular, P2X7 has been shown to be implicated in neuropsychiatry, chronic pain, neurodegeneration and neuroinflammation. Remarkably, P2X7 has also been shown to be a 'gene modifier' in amyotrophic lateral sclerosis (ALS): the receptor is upregulated in spinal cord microglia in human and rat at advanced stages of the disease; in vitro, activation of P2X7 exacerbates pro-inflammatory responses in microglia that have an ALS phenotype, as well as toxicity towards neuronal cells. Despite this detrimental in vitro role of P2X7, in SOD1-G93A mice lacking P2X7, the clinical onset of ALS was significantly accelerated and disease progression worsened, thus indicating that the receptor might have some beneficial effects, at least at certain stages of disease. In order to clarify this dual action of P2X7 in ALS pathogenesis, in the present work we used the antagonist Brilliant Blue G (BBG), a blood-brain barrier permeable and safe drug that has already been proven to reduce neuroinflammation in traumatic brain injury, cerebral ischemia-reperfusion, neuropathic pain and experimental autoimmune encephalitis. We tested BBG in the SOD1-G93A ALS mouse model at asymptomatic, pre-symptomatic and late pre-symptomatic phases of disease. BBG at late pre-onset significantly enhanced motor neuron survival and reduced microgliosis in lumbar spinal cord, modulating inflammatory markers such as NF-κB, NADPH oxidase 2, interleukin-1ß, interleukin-10 and brain-derived neurotrophic factor. This was accompanied by delayed onset and improved general conditions and motor performance, in both male and female mice, although survival appeared unaffected. Our results prove the twofold role of P2X7 in the course of ALS and establish that P2X7 modulation might represent a promising therapeutic strategy by interfering with the neuroinflammatory component of the disease.
Asunto(s)
Esclerosis Amiotrófica Lateral/patología , Antagonistas del Receptor Purinérgico P2X/farmacología , Colorantes de Rosanilina/farmacología , Médula Espinal/patología , Superóxido Dismutasa/genética , Esclerosis Amiotrófica Lateral/enzimología , Esclerosis Amiotrófica Lateral/metabolismo , Animales , Secuencia de Bases , Biomarcadores/metabolismo , Cartilla de ADN , Femenino , Inflamación/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Ratones Transgénicos , Microglía/patología , Neuronas Motoras/patología , Reacción en Cadena de la Polimerasa , Superóxido Dismutasa-1RESUMEN
Caffeine is a nonselective adenosine receptor antagonist; chronic consumption has proved protective toward neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. The present study was designed to determine whether caffeine intake affected survival and/or motor performance in a transgenic model of amyotrophic lateral sclerosis (ALS). SOD1(G93A) mice received caffeine through drinking water from 70 days of age until death. Body weight, motor performance and survival were evaluated. Furthermore, the expression of adenosine A(2A) receptors (A(2A) Rs), glial glutamate transporter (GLT1), and glial fibrillar acidic protein (GFAP) were evaluated by Western blotting. The results showed that caffeine intake significantly shortened the survival of SOD1(G93A) mice (log rank test, P = 0.01) and induced a nonsignificant advancing of disease onset. The expression of A(2A) R, GLT1, and GFAP was altered in the spinal cords of ALS mice, but caffeine did not influence their expression in either wild-type or SOD1(G93) mice. These data indicate that adenosine receptors may play an important role in ALS.
Asunto(s)
Esclerosis Amiotrófica Lateral/metabolismo , Cafeína/administración & dosificación , Longevidad/efectos de los fármacos , Neuronas Motoras/efectos de los fármacos , Destreza Motora/efectos de los fármacos , Médula Espinal/efectos de los fármacos , Administración Oral , Esclerosis Amiotrófica Lateral/genética , Animales , Peso Corporal/efectos de los fármacos , Peso Corporal/fisiología , Modelos Animales de Enfermedad , Ratones , Ratones Transgénicos , Neuronas Motoras/metabolismo , Receptor de Adenosina A2A/metabolismo , Prueba de Desempeño de Rotación con Aceleración Constante , Médula Espinal/metabolismo , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa-1RESUMEN
Cannabinoid CB1 receptors (CB1Rs) are known to be downregulated in patients and in animal models of Huntington's disease (HD). However, the functional meaning of this reduction, if any, is still unclear. Here, the effects of the cannabinoid receptor agonist WIN 55,212-2 (WIN) were investigated on striatal synaptic transmission and on glutamate and GABA release in symptomatic R6/2 mice, a genetic model of HD. The expression levels of CB1Rs in glutamatergic and GABAergic synapses were also evaluated. We found that in R6/2 mice, WIN effects on synaptic transmission and glutamate release were significantly increased with respect to wild type mice. On the contrary, a decrease in WIN-induced reduction of GABA release was found in R6/2 versus WT mice. The expression of CB1Rs in GABAergic neurons was drastically reduced, while CB1Rs levels in glutamatergic neurons were unchanged. These results demonstrate that the expression and functionality of CB1Rs are differentially affected in GABAergic and glutamatergic neurons in R6/2 mice. As a result, the balance between CB1Rs expressed by the two neuronal populations and, thus, the net effect of CB1R stimulation, is profoundly altered in HD mice.
Asunto(s)
Glutamatos/metabolismo , Enfermedad de Huntington/patología , Neuronas/metabolismo , Receptor Cannabinoide CB1/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/genética , Potenciales de Acción/fisiología , Análisis de Varianza , Animales , Benzoxazinas/farmacología , Encéfalo/patología , Modelos Animales de Enfermedad , Dronabinol/análogos & derivados , Dronabinol/farmacología , Interacciones Farmacológicas , Estimulación Eléctrica , Fármacos actuantes sobre Aminoácidos Excitadores/farmacología , Humanos , Proteína Huntingtina , Enfermedad de Huntington/fisiopatología , Técnicas In Vitro , Ratones , Ratones Transgénicos , Microscopía Inmunoelectrónica , Morfolinas/farmacología , Actividad Motora/efectos de los fármacos , Actividad Motora/genética , Naftalenos/farmacología , Proteínas del Tejido Nervioso/genética , Neuronas/efectos de los fármacos , Neuronas/ultraestructura , Proteínas Nucleares/genética , Técnicas de Placa-Clamp , Piperidinas/farmacología , Potasio/farmacología , Pirazoles/farmacología , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/antagonistas & inhibidores , Estadísticas no Paramétricas , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo , Repeticiones de Trinucleótidos/genética , Tritio/metabolismo , Proteína 1 de Transporte Vesicular de Glutamato/metabolismo , Proteínas del Transporte Vesicular de Aminoácidos Inhibidores/metabolismoRESUMEN
The effect of chronic treatment with the selective adenosine A(2A) receptor agonist CGS 21680 on N-Methyl-d-Aspartate (NMDA) receptor function and expression has been studied in the striatum and cortex of R6/2 mice, a genetic mouse model of Huntington's disease (HD). Starting from 8weeks of age, R6/2 and wild type (WT) mice were treated daily with CGS 21680 (0.5mg/kg i.p.) for 3weeks and the expression levels of NMDA receptor subunits were then evaluated. In addition, to study CGS 21680-induced changes in NMDA receptor function, NMDA-induced toxicity in corticostriatal slices from both R6/2 and WT mice was investigated. We found that CGS 21680 increased NR2A subunit expression and the NR2A/NR2B ratio in the cortex of R6/2 mice, having no effect in WT mice. In the striatum, CGS 21680 reduced NR1 expression in both R6/2 and WT mice while the effect on NR2A and NR2/NR2B expression was genotype-dependent, reducing and increasing their expression in WT and R6/2 mice, respectively. On the contrary, NMDA-induced toxicity in corticostriatal slices was not modified by the treatment in WT or HD mice. These results demonstrate that in vivo activation of A(2A) receptors modulates the subunit composition of NMDA receptors in the brain of HD mice.
Asunto(s)
Adenosina/análogos & derivados , Corteza Cerebral/efectos de los fármacos , Cuerpo Estriado/efectos de los fármacos , Enfermedad de Huntington/metabolismo , Fenetilaminas/farmacología , Subunidades de Proteína/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Adenosina/farmacología , Agonistas del Receptor de Adenosina A2/farmacología , Animales , Western Blotting , Corteza Cerebral/metabolismo , Corteza Cerebral/fisiopatología , Cuerpo Estriado/metabolismo , Cuerpo Estriado/fisiopatología , Modelos Animales de Enfermedad , Electrofisiología , Femenino , Enfermedad de Huntington/fisiopatología , Masculino , Ratones , Neuronas/efectos de los fármacos , Neuronas/fisiología , Estadísticas no ParamétricasRESUMEN
Early phases of Parkinson's disease (PD) are characterized by a mild reduction of dopamine (DA) in striatum and by emergence of psychiatric disturbances that precede overt motor symptoms. In order to characterize the neurochemical re-arrangements induced by such striatal impairment, we used a mouse model in which a low dose of 6-hydroxydopamine (6-OHDA) was bilaterally injected into the dorsal striatum. These mice showed a DA reduction of about 40% that remained stable up to 12 weeks after injection. This reduction was accompanied by changes in DA metabolite levels, such as HVA, transiently reduced at 4 weeks, and DOPAC, decreased at 12 weeks. No change in the 5-hydroxytryptamine (5-HT) levels was found but the 5-hydroxyindoleacetic acid (5-HIAA)/5-HT ratio was increased at 4 weeks. In addition, at the same time-point, the levels of 15-F(2t)-IsoP, an index of oxidative stress, and of PGE(2), a major product of cyclooxygenase-2, were decreased in different brain areas while BDNF levels were increased. These neurochemical changes were accompanied by altered behavioral responses concerning the emotional reactivity. Overall, the present findings suggest that a change of 5-HT metabolism and a modification of oxidative stress levels may play a role in the early PD degeneration phases.
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Adrenérgicos/toxicidad , Química Encefálica/efectos de los fármacos , Cuerpo Estriado/efectos de los fármacos , Oxidopamina/toxicidad , Enfermedad de Parkinson , Animales , Conducta Animal/efectos de los fármacos , Monoaminas Biogénicas/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Cuerpo Estriado/metabolismo , Dinoprost/análogos & derivados , Dinoprost/metabolismo , Dinoprostona/metabolismo , Modelos Animales de Enfermedad , Conducta Exploratoria/efectos de los fármacos , Locomoción/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , NataciónRESUMEN
Excitotoxicity plays a major role in the pathogenesis of Huntington disease (HD), a fatal neurodegenerative disorder. Adenosine A(2A) receptors (A(2A)Rs) modulate excitotoxicity and have been suggested to play a pathogenetic role in HD. The main aim of this study was to evaluate the effect of A(2A)R blockade on the expression and functions of NMDA receptors in the striatum of HD mice (R6/2). We found that 3 weeks' treatment with SCH 58261 (0.01 mg/kg/day i.p. from the 8th week of age) modified NR1 and NR2A/NR2B expression in the striatum of R6/2 (Western blotting) while had no effect on NMDA-induced toxicity in corticostriatal slices (electrophysiological experiments). In conclusion, in vivo A(2A)R blockade induced a remodeling of NMDA receptors in the striatum of HD mice. Even though the functional relevance of the above effect remains to be fully elucidated, these results add further evidence to the modulatory role of A(2A)Rs in HD.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Cuerpo Estriado/efectos de los fármacos , Enfermedad de Huntington/tratamiento farmacológico , Plasticidad Neuronal/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Fármacos del Sistema Nervioso Central/farmacología , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Femenino , Enfermedad de Huntington/metabolismo , Técnicas In Vitro , Masculino , Ratones , Ratones Transgénicos , N-Metilaspartato/toxicidad , Neurotoxinas/toxicidad , Pirimidinas/farmacología , Receptor de Adenosina A2A/metabolismo , Receptor trkB/metabolismo , Triazoles/farmacologíaRESUMEN
To investigate the psychiatric symptoms accompanying the early phases of Parkinson's disease (PD), we injected adult rats with 10.5 microg 6-hydroxydopamine (6-OHDA) bilaterally into the dorsal striatum. The resulting neurodegeneration led, 12 weeks after injection, to a mild (36%) reduction of striatal dopamine. We tested the behavioral response of sham and 6-OHDA-lesioned animals at different time points after injection to evaluate the onset and progression of behavioral abnormalities. The results showed that such a mild reduction of dopamine levels was associated with a decrease in anxiety-like behavior, an increase in "depression"-like behavior, and a marked change in social behavior. Learning and memory abilities were not affected. Overall, the PD rat model used here displays behavioral alterations having face validity with psychiatric symptoms of the pathology and thus appears to be a valuable tool for investigating the neural bases of the early phases of PD.
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Oxidopamina/toxicidad , Trastornos Parkinsonianos/fisiopatología , Animales , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Ratas , Ratas Wistar , NataciónRESUMEN
The aim of this study was to evaluate the possible neuroprotective effects of thymosin beta(4) in different models of excitotoxicity. The application of thymosin beta(4) significantly attenuated glutamate-induced toxicity both in primary cultures of cortical neurons and in rat hippocampal slices. In in vivo experiments, the intracerebroventricular administration of thymosin beta(4) significantly reduced hippocampal neuronal loss induced by kainic acid. These results show that thymosin beta(4) induced a protective effect in models of excitotoxicity. The mechanisms underlying such an effect, as well as the real neuroprotective potential of thymosin beta(4), are worthy of further investigations.