RESUMEN
Mucopolysaccharidoses (MPSs) make up a group of lysosomal storage diseases characterized by the aberrant accumulation of glycosaminoglycans throughout the body. Patients with MPSs display various signs and symptoms, such as retinopathy, which is also observed in patients with MPS II. Unfortunately, retinal disorders in MPS II are resistant to conventional intravenous enzyme-replacement therapy because the blood-retinal barrier (BRB) impedes drug penetration. In this study, we show that a fusion protein, designated pabinafusp alfa, consisting of an antihuman transferrin receptor antibody and iduronate-2-sulfatase (IDS), crosses the BRB and reaches the retina in a murine model of MPS II. We found that retinal function, as assessed by electroretinography (ERG) in MPS II mice, deteriorated with age. Early intervention with repeated intravenous treatment of pabinafusp alfa decreased heparan sulfate deposition in the retina, optic nerve, and visual cortex, thus preserving or even improving the ERG response in MPS II mice. Histological analysis further revealed that pabinafusp alfa mitigated the loss of the photoreceptor layer observed in diseased mice. In contrast, recombinant nonfused IDS failed to reach the retina and hardly affected the retinal disease. These results support the hypothesis that transferrin receptor-targeted IDS can penetrate the BRB, thereby ameliorating retinal dysfunction in MPS II.
Asunto(s)
Iduronato Sulfatasa , Mucopolisacaridosis II , Enfermedades de la Retina , Animales , Ratones , Barrera Hematorretinal/metabolismo , Glicosaminoglicanos , Iduronato Sulfatasa/metabolismo , Iduronato Sulfatasa/uso terapéutico , Ácido Idurónico , Mucopolisacaridosis II/tratamiento farmacológico , Mucopolisacaridosis II/diagnóstico , Receptores de Transferrina , Enfermedades de la Retina/tratamiento farmacológicoRESUMEN
Heparan sulfate (HS) is an essential glycosaminoglycan (GAG) as a component of proteoglycans, which are present on the cell surface and in the extracellular matrix. HS-containing proteoglycans not only function as structural constituents of the basal lamina but also play versatile roles in various physiological processes, including cell signaling and organ development. Thus, inherited mutations of genes associated with the biosynthesis or degradation of HS can cause various diseases, particularly those involving the bones and central nervous system (CNS). Mucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders involving GAG accumulation throughout the body caused by a deficiency of GAG-degrading enzymes. GAGs are stored differently in different types of MPSs. Particularly, HS deposition is observed in patients with MPS types I, II, III, and VII, all which involve progressive neuropathy with multiple CNS system symptoms. While therapies are available for certain symptoms in some types of MPSs, significant unmet medical needs remain, such as neurocognitive impairment. This review presents recent knowledge on the pathophysiological roles of HS focusing on the pathogenesis of MPSs. We also discuss the possible use and significance of HS as a biomarker for disease severity and therapeutic response in MPSs.
Asunto(s)
Mucopolisacaridosis , Mucopolisacaridosis I , Biomarcadores , Glicosaminoglicanos , Proteoglicanos de Heparán Sulfato , Heparitina Sulfato/metabolismo , Humanos , Mucopolisacaridosis/patologíaRESUMEN
Deposition of heparan sulfate (HS) in the brain of patients with mucopolysaccharidosis II (MPS II) is believed to be the leading cause of neurodegeneration, resulting in several neurological signs and symptoms, including neurocognitive impairment. We recently showed that pabinafusp alfa, a blood-brain-barrier-penetrating fusion protein consisting of iduronate-2-sulfatase and anti-human transferrin receptor antibody, stabilized learning ability by preventing the deposition of HS in the CNS of MPS II mice. We further examined the dose-dependent effect of pabinafusp alfa on neurological function in relation to its HS-reducing efficacy in a mouse model of MPS II. Long-term intravenous treatment with low (0.1 mg/kg), middle (0.5 mg/kg), and high (2.0 mg/kg) doses of the drug dose-dependently decreased HS concentration in the brain and cerebrospinal fluid (CSF). A comparable dose-dependent effect in the prevention of neuronal damage in the CNS, and dose-dependent improvements in neurobehavioral performance tests, such as gait analysis, pole test, Y maze, and Morris water maze, were also observed. Notably, the water maze test performance was inversely correlated with the HS levels in the brain and CSF. This study provides nonclinical evidence substantiating a quantitative dose-dependent relationship between HS reduction in the CNS and neurological improvements in MPS II.
RESUMEN
Parkinson's disease is characterized by a selective death of nigrostriatal dopaminergic neurons, while the difference in the vulnerability to the death between the substantia nigra pars compacta (SNpc) and the striatum is poorly understood. Here we tested the difference focused on paraquat (PQ)-induced intracellular Zn2+ toxicity via extracellular glutamate accumulation. When PQ was locally injected into the SNpc and the striatum, dopaminergic degeneration was observed in the SNpc, but not in the striatum. Intracellular hydrogen peroxide (H2O2) produced by PQ was increased in both the SNpc and the striatum. In contrast, extracellular glutamate accumulation was observed only in the SNpc and rescued in the presence of N-(p-amylcinnamoyl)anthranilic acid (ACA), a blocker of the transient receptor potential melastatin 2 (TRPM2) cation channels. PQ increased intracellular Zn2+ level in the SNpc, but not in the striatum. The increase was rescued by 1-naphthyl acetyl spermine (NASPM), a selective blocker of Ca2+- and Zn2+-permeable GluR2-lacking AMPA receptors. PQ-induced dopaminergic degeneration in the SNpc was rescued by ACA, NASPM, and GBR, a dopamine reuptake inhibitor. The present study indicates intracellular H2O2 produced by PQ, which is taken up through dopamine transporters, is retrogradely transported to presynaptic glutamatergic terminals, activates TRPM2 channels, accumulates glutamate in the extracellular compartment, and induces intracellular Zn2+ dysregulation via Ca2+- and Zn2+-permeable GluR2-lacking AMPA receptor activation, resulting in dopaminergic degeneration in the SNpc. However, H2O2 signaling is not the case in the striatum. Paraquat-induced Zn2+ dysregulation plays a key role for neurodegeneration in the SNpc, but not in the striatum.
Asunto(s)
Paraquat , Canales Catiónicos TRPM , Cuerpo Estriado/metabolismo , Dopamina , Neuronas Dopaminérgicas/metabolismo , Ácido Glutámico , Peróxido de Hidrógeno , Paraquat/toxicidad , Sustancia Negra/metabolismo , Zinc/metabolismo , Zinc/toxicidadRESUMEN
To elucidate the mechanism and significance of 6-hydroxydopamine (6-OHDA)-induced Zn2+ toxicity, which is involved in neurodegeneration in the substantia nigra pars compacta (SNpc) of rats, we postulated that intracellular hydrogen peroxide (H2O2) produced by 6-OHDA is a trigger for intracellular Zn2+ dysregulation in the SNpc. Intracellular H2O2 level elevated by 6-OHDA in the SNpc was completely inhibited by co-injection of GBR 13069 dihydrochloride (GBR), a dopamine reuptake inhibitor, suggesting that 6-OHDA taken up through dopamine transporters produces H2O2 in the intercellular compartment of dopaminergic neurons. When the SNpc was perfused with H2O2, glutamate accumulated in the extracellular compartment and the accumulation was inhibited in the presence of N-(p-amylcinnamoyl)anthranilic acid (ACA), a blocker of the transient receptor potential melastatin 2 (TRPM2) channels. In addition to 6-OHDA, H2O2 also induced intracellular Zn2+ dysregulation via AMPA receptor activation followed by nigral dopaminergic degeneration. Furthermore, 6-OHDA-induced nigral dopaminergic degeneration was completely inhibited by co-injection of either HYDROP, an intracellular H2O2 scavenger or GBR into the SNpc. The present study indicates that H2O2 is produced by 6-OHDA taken up through dopamine transporters in the SNpc, is retrogradely transported to presynaptic glutamatergic terminals, activates TRPM2 channels, accumulates glutamate in the extracellular compartment, and induces intracellular Zn2+ dysregulation via AMPA receptor activation, resulting in nigral dopaminergic degeneration prior to movement disorder. It is likely that intracellular H2O2, but not extracellular H2O2, is a key trigger for nigral dopaminergic degeneration via intracellular Zn2+ dysregulation.
Asunto(s)
Dopamina , Peróxido de Hidrógeno , Animales , Neuronas Dopaminérgicas , Oxidopamina/toxicidad , Ratas , Ratas Wistar , Sustancia Negra , ZincRESUMEN
On the basis of the evidence that paraquat (PQ)-induced extracellular Zn2+ influx causes PQ-induced pathogenesis in the substantia nigra pars compacta (SNpc) of rats, we postulated that the transient receptor potential melastatin 2 (TRPM2) cation channels activated with PQ-induced reactive oxygen species (ROS) are linked with extracellular glutamate accumulation in the SNpc, followed by age-related intracellular Zn2+ dysregulation. Presynaptic activity (glutamate exocytosis), which was determined with FM4-64, was enhanced in the SNpc after exposure to PQ, and the enhancement was inhibited in the presence of N-(p-amylcinnamoyl)anthranilic acid (ACA), a blocker of TRPM2 cation channels, suggesting that PQ-induced ROS enhances presynaptic activity in the SNpc, probably via TRPM2 channel activation. Extracellular glutamate concentration in the SNpc was increased almost to the same extent under the SNpc perfusion with PQ of young and aged rats, and was suppressed by co-perfusion with ACA, suggesting that PQ-induced TRPM2 cation channel activation enhances glutamate exocytosis in the SNpc. Interestingly, PQ more markedly increased intracellular Zn2+ in the aged SNpc, which was also blocked by co-injection of ACA and CaEDTA, an extracellular Zn2+ chelator. Loss of nigrostriatal dopaminergic neurons was more severely increased in aged rats and completely blocked by co-injection of PQ and CaEDTA into the SNpc. The present study indicates that rapid influx of extracellular Zn2+ into dopaminergic neurons via PQ-induced TRPM2 cation channel activation accelerates nigrostriatal dopaminergic degeneration in aged rats. It is likely that vulnerability to PQ-induced pathogenesis in the aged SNpc is due to accelerated intracellular Zn2+ dysregulation.
Asunto(s)
Envejecimiento/patología , Neuronas Dopaminérgicas/metabolismo , Espacio Extracelular/metabolismo , Paraquat/toxicidad , Enfermedad de Parkinson/patología , Sustancia Negra/patología , Zinc/metabolismo , Animales , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Exocitosis/efectos de los fármacos , Ácido Glutámico/metabolismo , Masculino , Terminales Presinápticos/efectos de los fármacos , Terminales Presinápticos/metabolismo , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Receptores AMPA/metabolismo , Factores de Riesgo , Sustancia Negra/efectos de los fármacosRESUMEN
Coriandrum sativum (coriander) is an annual herb of the Apiaceae family and has been used as a traditional remedy. Here we examined whether heated leaf extract of coriander decreases the concentrations of heavy metals in tissues. Male ddY mice were given a drinking water containing 0.25% of heated leaf extract of coriander for 8 weeks. Eight weeks after the intake, the concentrations of zinc, iron, copper, arsenic, and cadmium were measured in the liver and kidney. The intake of coriander did not modify the concentrations of all heavy metals tested in the liver, but decreased the concentrations of iron, arsenic, and cadmium in the kidney. Because heavy metals can induce oxidative stress, the effect of coriander intake on hydrogen peroxide-induced oxidative stress was compared between slices from the kidney and liver. The slices were immersed in Ringer solution containing 100 µM hydrogen peroxide and aminophenyl fluorescein (APF), a probe for detecting reactive oxygen species (ROS). APF fluorescence was markedly increased in the control kidney slices, while the increase was completely blocked in kidney slices from coriander intake group. In contrast, APF fluorescence was also markedly increased in the control liver slices, while the increase was not blocked by coriander intake. The present study indicates that intake of coriander leaf extract contributes to powerful resistance to oxidative stress in the kidney, probably via decreased concentrations in heavy metals. It is likely that decrease in arsenic concentration to the detection limit is a major factor for the resistance.
Asunto(s)
Coriandrum/química , Metales Pesados/análisis , Estrés Oxidativo/efectos de los fármacos , Fitoterapia , Extractos Vegetales/farmacología , Animales , Arsénico/análisis , Arsénico/metabolismo , Cadmio/análisis , Cadmio/metabolismo , Hierro/análisis , Hierro/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Metales Pesados/metabolismo , Ratones , Extractos Vegetales/química , Hojas de la Planta/química , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Parkinson's disease (PD) is a progressive neurological disease characterized by a selective loss of nigrostriatal dopaminergic neurons. The exact cause of the neuronal loss remains unclear. Here, we report a unique mechanism of nigrostriatal dopaminergic neurodegeneration, in which extracellular Zn2+ influx plays a key role for PD pathogenesis induced with 6-hydroxydopamine (6-OHDA) in rats. 6-OHDA rapidly increased intracellular Zn2+ only in the substantia nigra pars compacta (SNpc) of brain slices and this increase was blocked in the presence of CaEDTA, an extracellular Zn2+ chelator, and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist, indicating that 6-OHDA rapidly increases extracellular Zn2+ influx via AMPA receptor activation in the SNpc. Extracellular Zn2+ concentration was decreased under in vivo SNpc perfusion with 6-OHDA and this decrease was blocked by co-perfusion with CNQX, supporting 6-OHDA-induced Zn2+ influx via AMPA receptor activation in the SNpc. Interestingly, both 6-OHDA-induced loss of nigrostriatal dopaminergic neurons and turning behavior to apomorphine were ameliorated by co-injection of intracellular Zn2+ chelators, i.e., ZnAF-2DA and N,N,N',N'-Tetrakis(2-pyridylmethyl)ethylenediamine (TPEN). Co-injection of TPEN into the SNpc blocked 6-OHDA-induced increase in intracellular Zn2+ but not in intracellular Ca2+. These results suggest that the rapid influx of extracellular Zn2+ into dopaminergic neurons via AMPA receptor activation in the SNpc induces nigrostriatal dopaminergic neurodegeneration, resulting in 6-OHDA-induced PD in rats.
Asunto(s)
Neuronas Dopaminérgicas/metabolismo , Espacio Extracelular/metabolismo , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Sustancia Negra/patología , Zinc/metabolismo , Animales , Calcio/metabolismo , Quelantes/farmacología , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Etilenodiaminas , Espacio Intracelular/metabolismo , Masculino , Degeneración Nerviosa/patología , Oxidopamina , Ratas WistarRESUMEN
The herbicide paraquat (PQ) has been reported to enhance the risk of developing Parkinson's disease (PD) from epidemiological studies. PQ-induced reactive oxygen species (ROS) are linked with a selective loss of nigrostriatal dopaminergic neurons. Here, we first report a unique mechanism of nigrostriatal dopaminergic degeneration, in which rapid intracellular Zn2+ dysregulation via PQ-induced ROS production causes PD in rats. When the substantia nigra pars compacta (SNpc) of rats was perfused with PQ, extracellular concentrations of glutamate and Zn2+ were increased and decreased, respectively, in the SNpc. These changes were ameliorated by co-perfusion with Trolox, an antioxidative agent. In in vitro slice experiments, PQ rapidly increased extracellular Zn2+ influx via AMPA receptor activation. Both loss of nigrostriatal dopaminergic neurons and increase in turning behavior in response to apomorphine were markedly reduced by coinjection of PQ and intracellular Zn2+ chelator, i.e., ZnAF-2DA into the SNpc. Furthermore, loss of nigrostriatal dopaminergic neurons induced with a low dose of PQ, which did not induce any behavioral abnormality, was completely blocked by coinjection of ZnAF-2DA. The present study indicates that rapid influx of extracellular Zn2+ into dopaminergic neurons via AMPA receptor activation, which is initially induced by PQ-mediated ROS production in the SNpc, induces nigrostriatal dopaminergic degeneration, resulting in PQ-induced PD in rats. Intracellular Zn2+ dysregulation in dopaminergic neurons is the cause of PQ-induced pathogenesis in the SNpc, and the block of intracellular Zn2+ toxicity leads to defending PQ-induced pathogenesis.
Asunto(s)
Neuronas Dopaminérgicas/metabolismo , Espacio Extracelular/metabolismo , Paraquat/toxicidad , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Sustancia Negra/patología , Zinc/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Quelantes/farmacología , Quelantes/uso terapéutico , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Ácido Glutámico/metabolismo , Masculino , Modelos Biológicos , Trastornos del Movimiento/complicaciones , Trastornos del Movimiento/tratamiento farmacológico , Degeneración Nerviosa/tratamiento farmacológico , Degeneración Nerviosa/patología , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/tratamiento farmacológico , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Sustancia Negra/efectos de los fármacosRESUMEN
On the basis of the findings that the rapid influx of extracellular Zn2+ into nigral dopaminergic neurons causes dopaminergic neurodegeneration, here we report that AMPA causes movement disorder in rats. AMPA markedly increased turning behavior in response to apomorphine 1 and 2 weeks after AMPA injection into the substantia nigra pars compacta (SNpc), while AMPA-induced movement disorder was suppressed by co-injection of intracellular Zn2+ chelators, i.e., ZnAF-2DA and TPEN, suggesting that AMPA-induced movement disorder is due to intracellular Zn2+ dysregulation. Furthermore, AMPA markedly induced loss of nigrostriatal dopaminergic neurons 2 weeks after AMPA injection into the SNpc, while AMPA-induced neurodegeneration was also suppressed in the SNpc and the striatum by co-injection of ZnAF-2DA and TPEN. AMPA rapidly increased nigral intracellular Zn2+ after AMPA injection into the SNpc and this increase was blocked by co-injection of TPEN. These results indicate that AMPA receptor activation rapidly increases influx of extracellular Zn2+ into nigral dopaminergic neurons and causes nigrostriatal dopaminergic neurodegeneration, resulting in movement disorder in rats. The evidence that AMPA-induced intracellular Zn2+ dysregulation causes movement disorder via nigrostriatal dopaminergic neurodegeneration suggests that AMPA receptors, probably Ca2+- and Zn2+-permeable GluR2-lacking AMPA receptors are potential targets for overcoming Parkinson's syndrome.
Asunto(s)
Neuronas Dopaminérgicas/metabolismo , Discinesia Inducida por Medicamentos/metabolismo , Líquido Extracelular/metabolismo , Sustancia Negra/metabolismo , Zinc/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/toxicidad , Animales , Quelantes/administración & dosificación , Neuronas Dopaminérgicas/efectos de los fármacos , Discinesia Inducida por Medicamentos/prevención & control , Líquido Extracelular/efectos de los fármacos , Inyecciones Intraventriculares , Masculino , Ratas , Ratas Wistar , Sustancia Negra/efectos de los fármacos , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/administración & dosificaciónRESUMEN
On the basis of the data that yokukansan (YKS), a herbal medicine, ameliorates aggressive behavior and abnormal glucocorticoid secretion of socially isolated mice under zinc deficiency, we tested whether YKS preventively buffers crowding stress-induced attenuations of glucocorticoid secretion response and long-term potentiation (LTP), an index of cognition. YKS-containing water was administered during the period of exposure to social crowding stress for 3 weeks. Serum corticosterone level was not significantly modified by administration of YKS-containing water and was also not increased after social-crowding stress. When vasopressin was injected into crowding-stressed rats to assess corticosterone secretion via pituitary-adorenocortical axis activation, vasopressin-induced increase in serum corticosterone was significantly attenuated compared to non-stressed control rats, indicating that the pituitary-adrenocortical response to vasopressin is affected after exposure to crowding stress. Interestingly, administration of YKS-containing water rescued attenuation of vasopressin-induced increase in serum corticosterone. LTP at Schaffer collateral-CA1 pyramidal cells synapses was attenuated in the hippocampal slices from crowding-stressed rats, while administration of YKS-containing water rescued the attenuation. The present study demonstrates that intake of YKS rescues crowding stress-induced impairments of glucocorticoid secretion response to vasopressin and hippocampal LTP. The intake of YKS may be benefit to buffering chronic stress.
Asunto(s)
Medicamentos Herbarios Chinos/uso terapéutico , Estrés Psicológico/tratamiento farmacológico , Animales , Corticosterona/sangre , Medicamentos Herbarios Chinos/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Japón , Potenciación a Largo Plazo/efectos de los fármacos , Masculino , Fitoterapia , Ratas Wistar , Vasopresinas/farmacologíaRESUMEN
Here, we present the complete genome sequence of Rothia aeria type strain JCM 11412, isolated from air in the Russian space laboratory Mir. Recently, there has been an increasing number of reports on infections caused by R. aeria The genomic information will enable researchers to identify the pathogenicity of this organism.