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We sought to determine the preventive effects of curcumin and its highly bioavailable preparation on noise-induced hearing loss in a novel murine model of permanent hearing loss developed by repeated exposure to noise. Upon exposure to noise (8-kHz octave band noise, 90 dB sound pressure level, 1 h), hearing ability was impaired in a temporary and reversible manner. During repeated noise exposure (1-h exposure per day, 5 days), there was a progressive increase in the auditory threshold shift at 12 and 20 kHz. The threshold shift persisted for at least 6 days after noise exposure. Oral administration of curcumin for 3 days before and each day during noise exposure significantly alleviated the hearing loss induced by repeated noise exposure. Curcumin abolished intranuclear translocation of nuclear factor-κB-p65 and generation of 4-hydroxynonenal-adducted proteins found in the cochlea after noise exposure. Theracurmin®, a highly absorbable and bioavailable preparation of curcumin, had strong preventive effects on hearing loss induced by repeated noise exposure. Together, these data suggest that curcumin exerts a preventive effect on noise-induced hearing loss and is therefore a good therapeutic candidate for preventing sensorineural hearing loss.

Thrombin-activated protease-activated receptor (PAR)-1 regulates the proliferation of neural cells following brain injury. To elucidate the involvement of PAR-1 in the neurogenesis that occurs in the adult hippocampus, we examined whether PAR-1 regulated the proliferation of neural stem/progenitor cells (NPCs) derived from the murine hippocampal dentate gyrus. NPC cultures expressed PAR-1 protein and mRNA encoding all subtypes of PAR. Direct exposure of the cells to thrombin dramatically attenuated the cell proliferation without causing cell damage. This thrombin-induced attenuation was almost completely abolished by the PAR antagonist RWJ 56110, as well as by dabigatran and 4-(2-aminoethyl)benzenesulfonyl fluoride (AEBSF), which are selective and non-selective thrombin inhibitors, respectively. Expectedly, the PAR-1 agonist peptide (AP) SFLLR-NH2also attenuated the cell proliferation. The cell proliferation was not affected by the PAR-1 negative control peptide RLLFT-NH2, which is an inactive peptide for PAR-1. Independently, we determined the effect of in vivotreatment with AEBSF or AP on hippocampal neurogenesis in the adult mouse. The administration of AEBSF, but not that of AP, significantly increased the number of newly-generated cells in the hippocampal subgranular zone. These data suggest that PAR-1 negatively regulated adult neurogenesis in the hippocampus by inhibiting the proliferative activity of the NPCs.

The endocochlear potential in the inner ear is essential for hearing ability, and maintained by various K+transport apparatuses including Na+, K+-ATPase and gap junction-mediated intercellular communication (GJ-IC) in the lateral wall structures of the cochlea. Noise-induced hearing loss is known at least in part due to disruption of GJ-IC resulting from an oxidative stress-induced decrease in connexins (Cxs) level in the lateral wall structures. The purpose of this study was to investigate, using primary cultures of fibrocytes from the cochlear spiral ligament of mice, the mechanism underlying GJ-IC disruption induced by 4-hydroxynonenal (4-HNE), which is formed as a mediator of oxidative stress. An exposure to 4-HNE produced the following events: i.e., an increase in 4-HNE-adducted proteins; a decrease in the protein levels of Cx43, β-catenin, and Cx43/β-catenin complex along with intracellular translocation of this complex from the cell membrane to the cytoplasm; enhanced calpain-dependent degradation of endogenous α-fodrin; and disruption of GJ-IC. The 4-HNE-induced decrease in these protein levels and disruption of GJ-IC were most completely abolished by the calpain inhibitor PD150606. Taken together, our data suggest that 4-HNE disrupted GJ-IC through calpain-mediated degradation of Cx43 and β-catenin in primary cultures of fibrocytes derived from the cochlear spiral ligament.

Adult neurogenesis is the process of generating new neurons that become integrated into existing circuits after fetal and early postnatal development has ceased. In most mammalian species, adult neurogenesis only appears to occur in the olfactory bulb and the hippocampus, where neural stem/progenitor cells (NPCs) exist to create new neurons. In adult neurogenesis, microenviromental change is thought to provide a specific modulation for maintaining the multi-potent state of these NPCs. Neurodegeneration is driven by the activation of resident microglia, astrocytes, and infiltrating peripheral macrophages, which release a plethora of cytokines, chemokines, neurotransmitters, and reactive oxygen species. These endogenous factors cause further bystander damage to neurons and produces both detrimental and favorable conditions for neurogenesis. Interestingly, these endogenous factors also affect the proliferation, migration, differentiation, and survival of the NPCs, as well as regulate the incorporation of newly formed neurons into the brain circuitry. The unique profile of the endogenous factors released can vary the degree of neuroregeneration after neurodegeneration. This current review summarizes recent knowledge in the emerging field that is showing that adult neurogenesis is regulated by endogenous factors produced during neurodegeneration.

Nitric oxide (NO) activates the cyclic GMP (cGMP) / protein kinase G (PKG) pathway during physiological processes in numerous types of cells. Here, we evaluated whether this NO/cGMP/PKG pathway is involved in the proliferation of neural stem/progenitor cells (NPCs) derived from the hippocampus of embryonic mice. In culture, the exposure to the NO synthase inhibitor Nω-nitro-l-arginine methyl ester (l-NAME) significantly decreased the number of viable cells and 5-bromo-2′-deoxyuridine (BrdU) incorporation into the cells, as well as the levels of intracellular reactive oxygen species, extracellular NO2, and intracellular cGMP. Like l-NAME, the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and PKG inhibitor KT5823 also decreased cell viability and BrdU incorporation. The membrane-permeable cGMP analogue 8-bromo-cGMP partially abolished the l-NAME–induced decrease in the BrdU incorporation. BrdU incorporation was decreased by Ca2+-channel blockers, including dantrolene, MK-801, ifenprodil, and nifedipine. Interestingly, the NO2level was decreased by dantrolene, but not by the other 3 blockers. l-NAME and ODQ attenuated phosphorylation of Akt, but not that of extracellular signal-regulated kinases or epidermal growth factor receptors. Our data suggest that endogenous NO generation linked to dantrolene-sensitive ryanodine receptors activates the cGMP/PKG signaling pathway for positive regulation of proliferation of hippocampal NPCs derived from embryonic mice.

We investigated the effects of treatment with trimethyltin (TMT) on the expression of glutathione-related enzymes in mouse hippocampus. TMT promoted the expression of glutathione S-transferase (GST) Ya/Yc mRNA, and GSTA2 protein, but not that of glutamate-cysteine ligase catalytic subunit mRNA, 1 day after injection. TMT produced a slight but significant elevation of GST activity during the period from day 1 to 7 post-treatment. No significant change was seen in the activity of glutathione peroxidase at anytime post-TMT treatment. Our data suggest the prolonged elevation of GST activity in the hippocampus following TMT treatment through enhanced expression of the GST Ya/Yc.

The organotin trimethyltin (TMT) is known to cause neuronal degeneration in the central nervous system. A systemic injection of TMT produced neuronal damage in the cerebral frontal cortex of mice. To elucidate the mechanism(s) underlying the toxicity of TMT toward neurons, we prepared primary cultures of neurons from the cerebral cortex of mouse embryos for use in this study. Microscopic observations revealed that a continuous exposure to TMT produced neuronal damage with nuclear condensation in an incubation time–dependent manner up to 48 h. The neuronal damage induced by TMT was not blocked by N-methyl-D-aspartate receptor channel–blocker MK-801. The exposure to TMT produced an elevation of the phosphorylation level of c-Jun N-terminal kinase (JNK)p46, but not JNKp54, prior to neuronal death. Under the same conditions, a significant elevation was seen in the phosphorylation level of stress-activated protein kinase 1, which activates JNKs. Furthermore, TMT enhanced the expression and phosphorylation of c-Jun during a continuous exposure. The JNK inhibitor SP600125 was effective in significantly but only partially attenuating the TMT-induced nuclear condensation and accumulation of lactate dehydrogenase in the culture medium. Taken together, our data suggest that the neuronal damage induced by TMT was independent of excitotoxicity but that at least some of it was dependent on the JNK cascades in primary cultures of cortical neurons.

The organotin trimethyltin (TMT) is known to cause neuronal degeneration in the murine brain. Earlier studies indicate that TMT-induced neuronal degeneration is enhanced by adrenalectomy. However, no evaluation has been attempted to determine the mechanism underlying the enhancement of TMT neurotoxicity by adrenalectomy and its implications in neuronal degeneration. To assess the implications and determine the mechanism of adrenalectomy-elicited enhancement of TMT neurotoxicity, we examined neuronal degeneration and associated signaling pathways in adrenalectomized mice. Adrenalectomy dramatically enhanced the TMT-induced neuronal damage in certain brain regions including the dentate gyrus, olfactory bulb, and anterior olfactory nucleus, in addition to exacerbating the behavioral abnormalities. TMT-induced activation of caspase-3 and calpain was also enhanced by adrenalectomy. The above events elicited by TMT were almost entirely prevented by treatment with dexamethasone. In addition to the above events, adrenalectomy clearly enhanced the activation of c-Jun-N-terminal kinases and the formation of 4-hydroxynonenal in the dentate gyrus following TMT treatment. The dentate granule cell damage induced by TMT was exacerbated by mifepristone, a glucocorticoid-receptor antagonist. Taken together, our data suggest that endogenous and exogenous glucocorticoids prevent neurodegeneration induced by TMT in the central nervous system by attenuating intensive oxidative stress and associated signaling pathways.

Mitochondrial injury is induced by a decline in mitochondrial function as well as by damaged mitochondrial DNA. In this study, we evaluate the effects of glutamate exposure on the level of mitochondrial mRNA in cultured cortical neurons of mice. Glutamate exposure for 15 min significantly reduced cell viability 24 h later. Under these experimental conditions, glutamate was effective in reducing the level of mitochondrial mRNAs, especially the mRNAs of NADH–ubiquinone oxidoreductase subunits (nd1 and nd6), 6 h after the exposure. Southern blot analysis, however, revealed no significant change in that of the mitochondrial DNA at any time after glutamate exposure. These results suggest that the activation of glutamate signals negatively regulated the expression of mitochondrial mRNA, without affecting the level of mitochondrial DNA.

Endoplasmic reticulum (ER) dysfunction is known to activate the unfolded protein response, which is characterized by the activation of two divergent processes, i.e., suppression of the initiation process in global protein synthesis and expression of glucose-regulated protein 78 (Bip/Grp78) and the C/EBP homologous transcription factor CHOP/Gadd153. In this study, we examined the expression of CHOP/Gadd153 and Bip/Grp78 in human neuroblastoma SH-SY5Y cells treated with 6-hydroxydopamine (6-OHDA), which is used to prepare animal models of Parkinson’s disease. 6-OHDA treatment induced cell death, in a concentration-dependent manner, which was inhibited by co-treatment with an antioxidant N-acetylcysteine. 6-OHDA was also effective in decreasing proteasome activity and in increasing the levels of high molecular ubiquitin-conjugated proteins. Furthermore, 6-OHDA induced a marked increase in the expression of both CHOP/Gadd153 and Bip/Grp78. This increase was prevented by N-acetylcysteine. Taken together, our data indicate that ER dysfunction is at least in part involved in the mechanisms underlying cell death induced by 6-OHDA in SH-SY5Y cells.Endoplasmic reticulum (ER) dysfunction is known to activate the unfolded protein response, which is characterized by the activation of two divergent processes, i.e., suppression of the initiation process in global protein synthesis and expression of glucose-regulated protein 78 (Bip/Grp78) and the C/EBP homologous transcription factor CHOP/Gadd153. In this study, we examined the expression of CHOP/Gadd153 and Bip/Grp78 in human neuroblastoma SH-SY5Y cells treated with 6-hydroxydopamine (6-OHDA), which is used to prepare animal models of Parkinson’s disease. 6-OHDA treatment induced cell death, in a concentration-dependent manner, which was inhibited by co-treatment with an antioxidant N-acetylcysteine. 6-OHDA was also effective in decreasing proteasome activity and in increasing the levels of high molecular ubiquitin-conjugated proteins. Furthermore, 6-OHDA induced a marked increase in the expression of both CHOP/Gadd153 and Bip/Grp78. This increase was prevented by N-acetylcysteine. Taken together, our data indicate that ER dysfunction is at least in part involved in the mechanisms underlying cell death induced by 6-OHDA in SH-SY5Y cells.

Differential regulation of gene expression by transcription factors is widely viewed as one of the principal mechanisms guiding development. Although numerous DNA binding proteins have been identified in various tissues, the role of individual transcription factors in the differentiation of specific cell groups, such as those populating the inner ear, is just beginning to be elucidated. It is known that transcription factors are induced in response to many signals that lead to cell growth, differentiation, inflammatory responses, the regulation of apoptosis, and neoplastic transformation. There are various transcription factors in the cochlea of the inner ear. These include activator protein-1 and nuclear factor-kappa B, glucocorticoid receptor, and so on. Based on recent reports and our investigation, in this article we review possible functions and expression of these transcription factors.

Radiolabeled probes for the transcription factor, activator protein-1 (AP-1), bound differentially to nuclear fractions of discrete structures of the guinea pig cochlea (organ of Corti, lateral wall tissues, and spiral ganglion). Noise exposure (4 kHz octave band, 115 dB, for 5 h) significantly increased AP-1 binding in both the organ of Corti and lateral wall tissues but not in the spiral ganglion. Supershift analysis using an antibody against c-Fos protein demonstrated that enhancement of AP-1/DNA binding was at least in part due to the expression of c-Fos protein. These results suggest that AP-1 is involved in the molecular mechanism(s) mediating noise-induced cochlear damage.

We previously isolated human MNB/DYRK1A cDNA from “the Down syndrome critical region” of human chromosome 21 (Shindoh et al.,1996, Biochem. Biophys. Res. Commun.225: 92–99). As described herein, we prepared a polyclonal anti-MNB/DYRK1A antibody and used it in a Western blot assay to assess the expression of the MNB/DYRK1A protein during rat development. The MNB/DYRK1A protein was expressed strongly not only in the brain but also in other tissues from embryonic rats. At the early postnatal stage, expression of the protein was high in the central nervous system and heart, but low in liver, lung, spleen, and kidney. The level of MNB/DYRK1A protein in all tissues studied gradually decreased with postnatal growth. Similarly, Northern blot analysis revealed that a major 6.0-kb transcript of the Mnb/Dyrk1Agene was expressed at a high level in the brain during the early postnatal period but that its level was low in the adult. The finding that the MNB/DYRK1A protein is expressed strongly in the central nervous system and heart may indicate a significant role for this protein in the development of these organs.

In four of four mice intracerebroventricularly injected with the inhibitor of glutathione synthesis l-buthionine-[S,R]-sulfoximine (BSO) 2 days before, an intraperitoneal injection of kainic acid (KA) invariably led to marked potentiation of DNA binding activity of the nuclear transcription factor activator protein-l (AP1) in the hippocampus at a dose which was ineffective in animals previously injected with vehicle alone. However, KA failed to potentiate binding in animals injected with BSO 1 day before. The intracerebroventricular injection of BSO induced marked and prolonged depletion of a total glutathione content in murine hippocampus for 1–2 days after administration. These results suggest that prolonged depletion of endogenous glutathione for a period longer than 1 day may lead to sensitization of KA signals to potentiate AP1 DNA binding in cell nuclei and thereby modulate de novo synthesis of particular proteins at the level of gene transcription in murine hippocampus.

Abstract: The addition of divalent cations such as Mg2+ and Ca2+ ions markedly reduced binding of a radiolabeled double stranded oligonucleotide probe for the transcription factor c-Myc in the presence of 100 mM KCl in nuclear extracts of the mouse whole brain. Irrespective of the addition of MgCl2, binding was selectively competed with the unlabeled probe for c-Myc having a double stranded conformation. Treatment with V8 protease differentially modulated binding of the probe for c-Myc determined in the presence and absence of added MgCl2. Introduction of irreversible covalent bonding between the radiolabeled probe and nuclear proteins led to retarded mobility of the radioactive probe/protein complex in the presence of MgCl2 on sodium dodecyl sulfate electrophoresis regardless of treatment with DNase. However, an antibody against the c-Myc protein affected neither mobility nor intensity of the radioactive band on gel retardation electrophoresis. Moreover, regional distribution was different from each other in mouse brain when determined in the presence and absence of added MgCl2. These results suggest that magnesium ions may have an ability to differentiate between nuclear c-Myc family proteins with different affinities for the consensus core nucleotide element CACGTG in murine brain.

Binding of [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) was significantly inhibited by the addition of several different compounds related to generation of nitric oxide (NO) at 100 μM in rat brain synaptic membranes. These included sodium nitroprusside, diphenyliodonium (DI), diphenyleneiodonium (DPI) and methylene blue. However, neither S-nitroso-N-acetyl-penicillamine nor S-nitroso-l-glutathione inhibited binding at 100 μM. Both DI and DPI inhibited binding in a concentration-dependent manner at a concentration range of over 1 μM, while further addition of spermidine (SPD) significantly attenuated the potency of DPI to inhibit binding without affecting that of DI. In contrast, SPD induced significant potentiation of the ability of unlabelled MK-801 to displace [3H]MK-801 binding in a fashion sensitive to antagonism by the novel polyamine antagonist bis-(3-aminopropyl)nonanediamine. This novel polyamine antagonist also prevented the reversing effect of SPD on inhibition by DPI of [3H]MK-801 binding. Moreover, DPI competitively exacerbated the ability of SPD to potentiate [3H]MK-801 binding in the presence of both l-glutamic acid and glycine at maximally effective concentrations. On the other hand, SPD was effective in reversing the inhibition by DPI in cerebellar, but not hippocampal, synaptic membranes. These results suggest that both DI and DPI may modulate synaptic responses mediated by the N-methyl-d-aspartate receptor through inhibition of opening processes of the ion channel in a manner irrespective of generation of NO radicals in particular situations. Possible involvement of the polyamine domain in the inhibition by DPI is also suggested. © 1997 Elsevier Science Ltd.

An attempt was made to solubilize and isolate [3H]l-glutamic acid (Glu) binding sensitive to displacement by N-methyl-d-asparticacid (NMDA) from rat brain. Brain synaptic membranes were solubilized by deoxycholic acid, followed by gel filtration with Sephadex G-25. In these turbid supernatants, significant but fragile binding was detected with a variety of radioligands related to ionotropic subclasses of receptors for excitatory amino acids. These included [3H]5-methyl-10, 11-dihydro-5H-dibenzo-[a,d]cyclohepten-5, 10-imine (MK-801), [3H]glycine, [3H]spermidine, [3H]Glu, [3H]dl-α-amino-3-hydroxy-5-methylisoxazole-4-propionic and [3H]kainic acids. Re-solubilization of turbid supernatants by Triton X-100 resulted in detection of [3H]Glu binding which was only stable for 24 h, with [3H]MK-801 binding being entirely lost. In these clear preparations after re-solubilization, Glu was exclusively effective in completely displacing [3H]Glu binding with other ligands being partially active. Furthermore, [3H]Glu binding displaceable by NMDA was eluted with 0.5 M KC1 together with [3H]Glu binding insensitive to NMDA on DEAE-Toyopearl column chromatography, while fractions eluted with 0.2 M KC1 had NMDA-insensitive [3H]Glu binding only. Chromatography on chelate (Zn)-Toyopearl resin resulted in elution of both NMDA-sensitive and NMDA-insensitive [3H]Glu binding with 10 mM EDTA. High performance liquid chromatography revealed that NMDA-sensitive [3H]Glu binding was detected at retention times of 10–20 min when eluted from an Asahipak ES-502N column with NaCl at linearly graded concentrations up to 0.5 M. In order to detect NMDA-sensitive [3H]Glu binding, however, the whole procedures needed to be completed within 24 h after re-solubilization. Accordingly, the identity of the NMDA-sensitive [3H]Glu binding partially purified here is still unclear at present. The NMDA recognition domain could be more stable than the NMDA channel domain on the NMDA receptor ionophore complex under aqueous conditions.

Expression of ionotropic excitatory amino acid receptors was assessed by membrane binding assays using a variety of radioligands in fetal and neonatal rat brains. In fetal rat brain, receptors sensitive toN-methyl-d-aspartate (NMDA) exhibited delayed onset of expression during the last 7 days before birth as compared with those insensitive to NMDA. In addition, developmental increases in agonist-preferring sites preceded those in antagonist-preferring sites within the first 7 postnatal days in particular brain structures with respect to each domain on the NMDA receptor complex. Growth of animals led to drastic increments of [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) binding to the NMDA channel in telencephalic regions until 21 to 28 days after birth, with concomitant desensitization to inhibition by protons of [3H]MK-801 binding in cortical membranes. By contrast, three different agonists were invariably effective in more potently potentiating [3H]MK-801 binding in cortical membranes of 14- and 28-day-old rats than in those of 5-day-old rats. These results suggest that the NMDA-sensitive subclass may play more critical roles in mechanisms underlying postnatal development of rat telencephalon than do the NMDA-insensitive subclasses.

Among over 60 polyamine derivatives tested, onlyN-(3-aminopropyl)octanediamine and bis-(3-aminopropyl)nonanediamine (TE393) markedly inhibited [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) binding at equilibrium in the presence of added spermidine (SPD) in “non-washed” rat brain synaptic membranes, without affecting that in the absence of added SPD. Although TE393 significantly potentiated [3H]MK-801 binding before equilibrium in the presence ofl-glutamic acid (Glu) alone or both Glu and glycine (Gly) added in “Triton-treated” membranes, the putative polyamine antagonists 1,10-decanediamine (DA10) and arcaine invariably inhibited binding irrespective of the addition of agonists. In the absence of added SPD, in addition, TE393 markedly enhanced abilities of both Glu and Gly to potentiate [3H]MK-801 binding before equilibrium. However, TE393 induced a rightward shift of the concentration-response curve of SPD for [3H]MK-801 binding before equilibrium. Moreover, TE393 was effective in potentiating binding of an antagonist but not an agonist radioligand to the NMDA domain and in inhibiting binding of an antagonist but not an agonist radioligand to the Gly domain. The potentiation of NMDA antagonist binding by TE393 occurred in a manner sensitive to prevention by arcaine but not by DA10. These results suggest that TE393 may be a novel ligand at the polyamine domain with an ability to interact with both the NMDA and Gly recognition domains in antagonist-preferring forms.

The significance of mild hypothermia as a therapeutic measure for ischemic brain damage is presented on the basis of different experimental results. An extracellular glutamate surge, a sustained activation of N-methyl-D-aspartate (NMDA) receptors, and an enhancement of DNA binding activity to transcription factor AP-1, all being key items directly linked to excitotoxic neuronal damage, are deeply affected by slightly lowering temperature (mild hypothermia [MH]). The cellular mechanism of MH seems rather nonspecific but tends to collectively involve these key items rendering neurons resistant to ischemic damage. Clinical application of MH should be a great challenge to relieve deadly effects on central neurons.

Abstract: Strychnine‐insensitive [3H]glycine binding was detected in brain synaptic membranes treated with Triton X‐100 using a filtration assay method. The binding was a time‐dependent, inversely temperature‐dependent, and reversible process with a relatively high affinity for the neuroactive amino acid. Scatchard analysis revealed that Triton treatment doubled both the affinity and density of the binding sites, which consisted of a single component. The binding was not only displaced by structurally‐related amino acids such as D‐serine and D‐alanine, but also inhibited by some peptides containing glycine, including glycine methylester and N‐methylglycine. These ligands invariably potentiated the binding of [3H](+)‐5‐methyl‐10,11‐dihydro‐5H‐dibenzo[a,d]‐cyclohepten‐5,10‐imine ([3H]MK‐801), a noncompetitive antagonist for the N‐methyl‐D‐aspartate‐sensitive subclass of the central excitatory amino acid receptors, in a concentration‐dependent manner. Among various endogenous tryptophan metabolites, kynurenic acid significantly inhibited the strychnine‐insensitive [3H]glycine binding. The Triton treatment did not affect the pharmacological profile of [3H]MK‐801 binding sites. These results suggest that brain synaptic membranes treated with Triton X‐100 are useful in evaluating the strychnine‐insensitive and kynurenate‐sensitive binding sites of glycine, which are functionally linked to N‐methyl‐D‐aspartate‐sensitive receptor channels.

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