Insight into brain metallothioneins from bidirectional Zn2+ signaling in synaptic dynamics.

The basal levels as the labile Zn2+ pools in the extracellular and intracellular compartments are in the range of ∼10 nM and ∼100 pM, respectively. The influx of extracellular Zn2+ is used for memory via cognitive activity and is regulated for synaptic plasticity, a cellular mechanism of memory. When Zn2+ influx into neurons excessively occurs, however, it becomes a critical trigger for cognitive decline and neurodegeneration, resulting in acute and chronic pathogenesis.

Blockage of metallothionein synthesis via adrenaline β receptor activation invalidates dehydroeffusol-mediated prevention of amyloid β toxicity.

Dehydroeffusol, a major phenanthrene in Juncus effusus, protects neurodegeneration induced by intracellular Zn ferried by extracellular amyloid β (Aβ). Here we focused on adrenaline β receptor activation and the induction of metallothioneins (MTs), intracellular Zn-binding proteins to test the protective mechanism of dehydroeffusol. Isoproterenol, an agonist of adrenergic β receptors elevated the level of MTs in the dentate granule cell layer 1 day after intracerebroventricular (ICV) injection.

Reactive oxygen species produced by Zn influx after exposure to AMPA, but not NMDA and their capturing effect on nigral dopaminergic protection.

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.

Heated Leaf Extract of Coriandrum sativum L. Protects Nigral Dopaminergic Degeneration in Rats.

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).

Involvement of isoproterenol-induced intracellular Zn dynamics in the basolateral amygdala in conditioned fear memory.

Beta-adrenergic receptors in the basolateral amygdala play an essential role in fear memory, while the physiological role of intracellular Zn remains to be clarified. Intracellular Zn level was decreased 5 min after local injection of 500 μM isoproterenol (2 μl), a nonselective beta-adrenergic receptor agonist into the basolateral amygdala, suggesting that intracellular Zn dynamic is linked with beta-adrenergic receptor signaling in the basolateral amygdala. When isoproterenol was injected into the basolateral amygdala 20 min prior to long-term potentiation (LTP) induction, LTP at perforant pathway-basolateral amygdala was enhanced and conditioned fear memory was also augmented, suggesting that isoproterenol leads to utilization of Zn to consolidate fear memory followed by lowering intracellular Zn.

Paraquat-induced intracellular Zn dysregulation causes dopaminergic degeneration in the substantia nigra, but not in the striatum.

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 Zn 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.

Isoproterenol, an adrenergic β receptor agonist, induces metallothionein synthesis followed by canceling amyloid β-induced neurodegeneration.

Adrenergic β receptor activation may ameliorate amyloid β toxicity. We examined whether isoproterenol, an adrenergic β receptor agonist reduces neurodegeneration caused by Aβ, for which intracellular Zn dysregulation is a trigger. Neurodegeneration was assessed in the dentate granule cell layer 14 days after intracerebroventricular injection of human Aβ into the mouse brain.

Intracellular hydrogen peroxide produced by 6-hydroxydopamine is a trigger for nigral dopaminergic degeneration of rats via rapid influx of extracellular Zn.

To elucidate the mechanism and significance of 6-hydroxydopamine (6-OHDA)-induced Zn toxicity, which is involved in neurodegeneration in the substantia nigra pars compacta (SNpc) of rats, we postulated that intracellular hydrogen peroxide (HO) produced by 6-OHDA is a trigger for intracellular Zn dysregulation in the SNpc. Intracellular HO 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 HO in the intercellular compartment of dopaminergic neurons. When the SNpc was perfused with HO, 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.

Isoproterenol injected into the basolateral amygdala rescues amyloid β-induced conditioned fear memory deficit via reducing intracellular Zn toxicity.

On the basis of amyloid β (Aβ) peptides as triggers in atrophy of structures in the limbic system, here we postulated that Aβ-induced intracellular Zn toxicity in the basolateral amygdala contributes to conditioned fear memory. Aβ increased intracellular Zn level in the amygdala after local injection of Aβ into the basolateral amygdala, resulting in conditioned fear memory deficit via attenuated LTP at perforant pathway-basolateral amygdala synapses. Co-injection of isoproterenol, a beta-adrenergic receptor agonist, reduced Aβ-mediated increase in intracellular Zn, resulting in rescue of the memory deficit and attenuated LTP.

Preventive effect of Ninjin-yoei-to, a Kampo medicine, on amyloid β-induced neurodegeneration via intracellular Zn toxicity in the dentate gyrus.

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 β (Aβ)-induced neurodegeneration in the dentate gyrus. A diet containing 3% NYT was administered to mice for 2 weeks and human Aβ was intracerebroventricularly injected.

Dehydroeffusol Pprevents Amyloid β-mediated Hippocampal Neurodegeneration via Reducing Intracellular Zn Toxicity.

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 β (Aβ)-mediated hippocampal neurodegeneration. Dehydroeffusol (15 mg/kg body weight) was orally administered to mice once a day for 6 days and then human Aβ was injected intracerebroventricularly followed by oral administration for 12 days.

[Alzheimer's disease pathogenesis focused on intracellular Zn toxicity and its defense strategy].

The basal levels of intracellular Zn and extracellular Zn are in the range of ~100 pM and ~10 nM, respectively, in the hippocampus. Extracellular Zn dynamics, which serves bidirectionally and involved in cognitive activity and cognitive decline, is modified by extracellular glutamate signaling and the presence of amyloid-β (Aβ), a causative peptide in Alzheimer's disease (AD) pathogenesis. When human Aβ reaches 100-500 pM in the extracellular compartment of the rat hippocampus, Zn-Aβ complexes are produced and readily taken up into dentate granule cells in a synaptic activity-independent manner.

Age-related vulnerability to nigral dopaminergic degeneration in rats via Zn-permeable GluR2-lacking AMPA receptor activation.

On the basis of the evidence that extracellular Zn 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 Zn level in the substantia nigra pars compacta (SNpc) of young adult rats, and tested whether intracellular Zn 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 Zn level was increased in the SNpc of aged rats followed by increase in turning behavior in response to apomorphine and nigral dopaminergic degeneration.

Retention Period of Amyloid β in the Brain Extracellular Fluid as the Toxicological Determinant in Freely Moving Rats.

The pathological significance of amyloid-β (Aβ) dynamics is poorly understood in the brain extracellular compartment. Here we test which of the concentration or the retention is critical for Aβ toxicity after injection of equal dose into dentate granule cell layer of freely moving rats. The toxicity of Aβ (25 µM) was compared between injections at the rate of 0.

Alzheimer risk factors age and female sex induce cortical Aβ aggregation by raising extracellular zinc.

Aging and female sex are the major risk factors for Alzheimer's disease and its associated brain amyloid-β (Aβ) neuropathology, but the mechanisms mediating these risk factors remain uncertain. Evidence indicates that Aβ aggregation by Zn released from glutamatergic neurons contributes to amyloid neuropathology, so we tested whether aging and sex adversely influences this neurophysiology. Using acute hippocampal slices, we found that extracellular Zn-elevation induced by high K stimulation was significantly greater with older (65 weeks vs 10 weeks old) rats, and was exaggerated in females.

Adrenergic β receptor activation reduces amyloid β-mediated intracellular Zn toxicity in dentate granule cells followed by rescuing impairment of dentate gyrus LTP.

Adrenergic β receptor activation prevents human soluble amyloid β (Aβ)-induced impairment of long-term potentiation (LTP) in slices. On the basis of the evidence that human Aβ-induced impairment of LTP is due to Aβ-mediated Zn toxicity, we postulated that adrenergic β receptor activation reduces Aβ-mediated intracellular Zn toxicity followed by rescuing Aβ toxicity. To test the effect of adrenergic β receptor activation, LTP was recorded at perforant pathway-dentate granule cell synapses of anesthetized rats 60 min after Aβ injection into the dentate granule cell layer.

New insight into Parkinson's disease pathogenesis from reactive oxygen species-mediated extracellular Zn influx.

Background: Parkinson's disease (PD) is the common neurodegenerative disorder in the elderly characterized by motor symptoms such as tremors, which is caused by selective loss of nigral dopaminergic neurons. Oxidative stress induced by the auto-oxidation of dopamine has been implicated as a key cause of the selective loss of dopaminergic neurons.

Methods: To understand the selective loss of nigral dopaminergic neurons, the PD pathogenesis is reviewed focused on paraquat (PQ) and 6-hydroxydopamine (6-OHDA)-induced PD in rats.

Dehydroeffusol Rescues Amyloid β-Induced Spatial Working Memory Deficit.

Amyloid β (Aβ) peptides produced from the amyloid precursor protein, a transmembrane protein, are neurotoxic and blocking the neurotoxicity may lead to prevention of Alzheimer's disease (AD). Here we tested whether Aβ-induced cognitive decline is rescued by treatment with dehydroeffusol, a phenanthrene isolated from Chinese medicine Juncus effusus. Dehydroeffusol (5 ~ 15 mg/kg body weight) was orally administered to mice for 6 days and Aβ (2 mM) was injected at the rate of 1 μl/min for 3 min into the lateral ventricle.

Extracellular Zn-Dependent Amyloid-β Neurotoxicity in Alzheimer's Disease Pathogenesis.

The basal level of extracellular Zn is in the range of low nanomolar (~ 10 nM) in the hippocampus. However, extracellular Zn dynamics plays a key role for not only cognitive activity but also cognitive decline. Extracellular Zn dynamics is modified by glutamatergic synapse excitation and the presence of amyloid-β (Aβ), a causative peptide in Alzheimer's disease (AD).

Preferential Neurodegeneration in the Dentate Gyrus by Amyloid β-Induced Intracellular ZnDysregulation and Its Defense Strategy.

On the basis of the evidence that rapid intracellular Zn dysregulation by amyloid β (Aβ) in the normal hippocampus transiently induces cognitive decline, here we report preferential neurodegeneration in the dentate gyrus by Aβ-induced intracellular Zn dysregulation and its defense strategy. Neurodegeneration was preferentially observed in the dentate granule cell layer in the hippocampus after a single Aβ injection into the lateral ventricle but not in the CA1 and CA3 pyramidal cell layers, while intracellular Zn dysregulation was extensively observed in the hippocampus in addition to the dentate gyrus. Neurodegeneration in the dentate granule cell layer was rescued after co-injection of extracellular and intracellular Zn chelators, i.

Age-Dependent Modification of Intracellular Zn Buffering in the Hippocampus and Its Impact.

The basal concentrations of extracellular Zn and intracellular Zn, which are approximately 10 nM and 100 pM, respectively, in the brain, are markedly lower than those of extracellular Ca (1.3 mM) and intracellular Ca (100 nM), respectively, resulting in much less attention paid to Zn than to Ca. However, intracellular Zn dysregulation, which is closely linked with glutamate- and amyloid β-mediated extracellular Zn influx, is more critical for cognitive decline and neurodegeneration than intracellular Ca dysregulation.

CA1 LTP Attenuated by Corticosterone is Canceled by Effusol via Rescuing Intracellular Zn Dysregulation.

Exposure to corticosterone attenuates hippocampal CA1 long-term potentiation (LTP) via intracellular Zn dysregulation. Here we report that effusol, a phenanthrene isolated from Chinese medicine Juncus effusus, rescues CA1 LTP attenuated by corticosterone. In vivo microdialysis experiment indicated that both increases in extracellular glutamate induced under perfusion with corticosterone and high K are suppressed in the hippocampus by co-perfusion with effusol.

Paraquat as an Environmental Risk Factor in Parkinson's Disease Accelerates Age-Related Degeneration Via Rapid Influx of Extracellular Zn into Nigral Dopaminergic Neurons.

On the basis of the evidence that paraquat (PQ)-induced extracellular Zn 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 Zn 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.

Extracellular Zn-independently attenuated LTP by human amyloid β and rat amyloid β.

Human amyloid-β (Aβ) and rat Aβ have lower affinity for extracellular Zn than human Aβ. Here we report extracellular Zn-independent attenuation of dentate gyrus long-term potentiation (LTP) by human Aβ and rat Aβ. On the basis of the data that dentate gyrus LTP is extracellular Zn-dependently attenuated after local injection of human Aβ (25 pmol, 1 μl) into the dentate gyrus, which increases intracellular Zn in the dentate gyrus, the toxicity of human Aβ and rat Aβ was compared in the in vivo system with human Aβ.