RESUMEN
Glutamate excitotoxicity is involved in dopaminergic degeneration in the substantia nigra pars compacta (SNpc). Here we compared vulnerability to neurodegeneration after exposure to NMDA and AMPA. Apomorphine-induced movement disorder and dopaminergic degeneration in the SNpc, which are associated with Parkinson's syndrome, were induced after injection of AMPA into the SNpc of rats, but not after injection of NMDA. Co-injection of 1-naphthyl acetyl spermine (NASPM), a selective blocker of Ca2+- and Zn2+-permeable GluR2-lacking AMPA receptors rescued dopaminergic degeneration and increase in intracellular Zn2+ by AMPA. Furthermore, we tested the effect of capturing reactive oxygen species (ROS) produced by Zn2+ on neuroprotection in vivo. The levels of ROS, which were determined by HYDROP, a membrane-permeable H2O2 fluorescence probe and Aminophenyl Fluorescein (APF), a fluorescence probe for hydroxyl radical and peroxynitrite, were increased after injection of AMPA, but not after co-injection of CaEDTA, an extracellular Zn2+ chelator, suggesting that increase in Zn2+ influx by AMPA elevates the levels of intracellular ROS. AMPA-mediated dopaminergic degeneration was completely rescued by co-injection of either HYDROP or APF. The present study indicates that neurotoxic signaling of the influx of extracellular Zn2+ through Zn2+-permeable GluR2-lacking AMPA receptors is converted to ROS production and that capturing the ROS completely protects dopaminergic degeneration after exposure to AMPA, but not NMDA. It is likely that regulation of the conversion from Zn2+ influx into ROS production plays a key role to preventing Parkinson's syndrome.
Asunto(s)
Enfermedad de Parkinson , Receptores AMPA , Ratas , Animales , Especies Reactivas de Oxígeno/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/farmacología , Ratas Wistar , Peróxido de Hidrógeno , Zinc/metabolismo , Edema , Neuronas DopaminérgicasRESUMEN
Coriandrum sativum L. (coriander), which is an annual herb of the Apiaceae family, has been traditionally used as a remedy. Here we tested whether heated extract of coriander leaf protects nigral dopaminergic neurodegeneration after exposure to 6-hydroxydopamine (6-OHDA). After injection of 6-OHDA into the rat substantia nigra pars compacta (SNpc), dopaminergic degeneration, which was determined by tyrosine hydroxylase immunostaining, was rescued by co-injection of CaEDTA, an extracellular Zn2+ chelator, suggesting that extracellular Zn2+ influx is involved in neurodegeneration. Both intracellular Zn2+ dysregulation determined by ZnAF-2 fluorescence and dopaminergic degeneration in the SNpc induced by 6-OHDA were rescued by co-injection of 0.25% coriander extract, which also reduced reactive oxygen species (ROS) production in the SNpc determined by aminophenyl fluorescein fluorescence. The present study suggests that coriander leaf extract protects nigral dopaminergic neurodegeneration induced by intracellular Zn2+ dysregulation. It is likely that the nutraceutical property of coriander leaf extract contributes to the protection via reducing ROS production.
Asunto(s)
Coriandrum , Animales , Oxidopamina/farmacología , Extractos Vegetales/farmacología , Ratas , Ratas Wistar , Especies Reactivas de OxígenoRESUMEN
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
Ninjin-yoei-to (NYT), a Kampo medicine, has ameliorative effects on cognitive dysfunction via enhancing cholinergic neuron activity. To explore an efficacy of NYT administration for prevention and cure of Alzheimer's disease, here we examined the effect of NYT on amyloid ß1-42 (Aß1-42)-induced neurodegeneration in the dentate gyrus. A diet containing 3% NYT was administered to mice for 2 weeks and human Aß1-42 was intracerebroventricularly injected. Neurodegeneration in the dentate granule cell layer of the hippocampus, which was determined 2 weeks after the injection, was rescued by administration of the diet for 4 weeks. Aß staining (uptake) was not modified in the dentate granule cell layer by pre-administration of the diet for 2 weeks, while Aß1-42-induced increase in intracellular Zn2+ was reduced, suggesting that pre-administration of NYT prior to Aß injection is effective for reducing Aß1-42-induced Zn2+ toxicity in the dentate gyrus. As a matter of fact, Aß1-42-induced neurodegeneration in the dentate gyrus was rescued by pre-administration of NYT. Interestingly, the level of metallothioneins, intracellular Zn2+-binding proteins, which can capture Zn2+ from Zn-Aß1-42 complexes, was elevated in the dentate granule cell layer by pre-administration of NYT. The present study suggests that pre-administration of NYT prevents Aß1-42-mediated neurodegeneration in the dentate gyurs by induced synthesis of metallothioneins, which reduces intracellular Zn2+ toxicity induced by Aß1-42.
Asunto(s)
Péptidos beta-Amiloides/farmacología , Disfunción Cognitiva/tratamiento farmacológico , Giro Dentado/fisiopatología , Medicina Kampo , Panax/química , Sustancias Protectoras/farmacología , Animales , Giro Dentado/efectos de los fármacos , Masculino , RatonesRESUMEN
Dehydroeffusol, a phenanthrene isolated from Juncus effusus, is a Chinese medicine. To explore an efficacy of dehydroeffusol administration for prevention and cure of Alzheimer's disease, here we examined the effect of dehydroeffusol on amyloid ß1-42 (Aß1-42)-mediated hippocampal neurodegeneration. Dehydroeffusol (15 mg/kg body weight) was orally administered to mice once a day for 6 days and then human Aß1-42 was injected intracerebroventricularly followed by oral administration for 12 days. Neurodegeneration in the dentate granule cell layer, which was determined 2 weeks after Aß1-42 injection, was rescued by dehydroeffusol administration. Aß staining (uptake) was not reduced in the dentate granule cell layer by pre-administration of dehydroeffusol for 6 days, while increase in intracellular Zn2+ induced with Aß1-42 was reduced, suggesting that pre-administration of dehydroeffusol prior to Aß1-42 injection is effective for Aß1-42-mediated neurodegeneration that was linked with intracellular Zn2+ toxicity. As a matter of fact, pre-administration of dehydroeffusol rescued Aß1-42-mediated neurodegeneration. Interestingly, pre-administration of dehydroeffusol increased synthesis of metallothioneins, intracellular Zn2+-binding proteins, in the dentate granule cell layer, which can capture Zn2+ from Zn-Aß1-42 complexes. The present study indicates that pre-administration of dehydroeffusol protects Aß1-42-mediated neurodegeneration in the hippocampus by reducing intracellular Zn2+ toxicity, which is linked with induced synthesis of metallothioneins. Dehydroeffusol, a novel inducer of metallothioneins, may protect Aß1-42-induced pathogenesis in Alzheimer's disease.
Asunto(s)
Péptidos beta-Amiloides/toxicidad , Hipocampo/efectos de los fármacos , Líquido Intracelular/efectos de los fármacos , Enfermedades Neurodegenerativas/prevención & control , Fragmentos de Péptidos/toxicidad , Fenantrenos/uso terapéutico , Zinc/toxicidad , Péptidos beta-Amiloides/administración & dosificación , Animales , Medicamentos Herbarios Chinos/aislamiento & purificación , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Hipocampo/metabolismo , Humanos , Inyecciones Intraventriculares , Líquido Intracelular/metabolismo , Masculino , Enfermedades Neurodegenerativas/inducido químicamente , Enfermedades Neurodegenerativas/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Fragmentos de Péptidos/administración & dosificación , Fenantrenos/aislamiento & purificación , Fenantrenos/farmacologíaRESUMEN
On the basis of the evidence that extracellular Zn2+ influx induced with AMPA causes Parkinson's syndrome in rats that apomorphine-induced movement disorder emerges, here we used a low dose of AMPA, which does not increase intracellular Zn2+ level in the substantia nigra pars compacta (SNpc) of young adult rats, and tested whether intracellular Zn2+ dysregulation induced with AMPA is accelerated in the SNpc of aged rats, resulting in age-related vulnerability to Parkinson's syndrome. When AMPA (1 mM) was injected at the rate of 0.05 µl/min for 20 min into the SNpc, intracellular Zn2+ level was increased in the SNpc of aged rats followed by increase in turning behavior in response to apomorphine and nigral dopaminergic degeneration. In contrast, young adult rats do not show movement disorder and nigral dopaminergic degeneration, in addition to no increase in intracellular Zn2+. In aged rats, movement disorder and nigral dopaminergic degeneration were rescued by co-injection of either extracellular (CaEDTA) or intracellular (ZnAF-2DA) Zn2+ chelators. 1-Naphthyl acetyl spermine (NASPM), a selective blocker of Ca2+- and Zn2+-permeable GluR2-lacking AMPA receptors blocked increase in intracellular Zn2+ in the SNpc of aged rats followed by rescuing nigral dopaminergic degeneration. The present study indicates that intracellular Zn2+ dysregulation is accelerated by Ca2+- and Zn2+-permeable GluR2-lacking AMPA receptor activation in the SNpc of aged rats, resulting in age-related vulnerability to Parkinson's syndrome.