Nobuko Matsumura

Teikyo University Hospital, Edo, Tōkyō, Japan

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Publications (7)23.55 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: We determined the receptor subtypes of α1-adrenoceptor, which is involved in autonomic functions induced by methamphetamine (METH) in rats. An intraperitoneal injection of METH provoked the autonomic responses piloerection, eyelid retraction, and ejaculation. Pretreatment with prazosin, a nonselective α1-adrenoceptor antagonist, completely abolished the above METH-induced responses. Prazosin also provoked eyelid ptosis in saline controls. The effects of prazosin were mimicked only by a selective α1A-adrenoceptor antagonist, silodosin, not by selective α1B or α1D antagonists. These results suggest that α1A-adrenoceptor participates in the regulation of piloerection, palpebral fissure width, and ejaculation in rats.
    Autonomic neuroscience: basic & clinical 05/2013; · 1.82 Impact Factor
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    ABSTRACT: Methamphetamine (METH) is a psychostimulant that damages nigrostriatal dopaminergic terminals, primarily by enhancing dopamine and glutamate release. α(1)-adrenergic receptor (AR) subtype involved in METH-induced neurotoxicity in rats was investigated using selective α(1)-AR antagonists. METH neurotoxicity was evaluated by (1) measuring body temperature; (2) determining tyrosine hydroxylase (TH) immunoreactivity levels; (3) examining levels of dopamine and its metabolites; and (4) assessing glial fibrillary acidic protein (GFAP) and microglial immunoreactivity in the striatum. METH caused a decrease in dopamine and TH levels and induced hyperthermia which is an exacerbating factor of METH neurotoxicity. Concurrently, METH increased GFAP expression and the number of activated microglia. Pretreatment with prazosin, a nonselective α(1)-AR antagonist, completely abolished METH-induced decrease in both dopamine and TH and caused a partial reduction in hyperthermia. Prazosin also prevented METH-induced increase in both GFAP expression and the number of activated microglia. In vivo microdialysis analysis revealed that prazosin, however, does not alter the METH-induced dopamine release in the striatum. The neuroprotective effects of prazosin could be mimicked by a selective α(1D) antagonist, BMY 7378, but not by selective α(1A) or α(1B) antagonists. These results suggest that the α(1D)-AR is involved in METH-induced hyperthermia and neurotoxicity in rats.
    Neurotoxicity Research 01/2013; · 2.87 Impact Factor
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    ABSTRACT: Here we report that indazole is characterized as a potential anticonvulsant, inhibiting pentylenetetrazole-, electroshock- and strychnine-induced convulsions in mice (ED(50)'s: 39.9, 43.2 and 82.4mg/kg, respectively) but not bicuculline- and picrotoxin-induced convulsions. The median toxic dose (TD(50)) of indazole was 52.3mg/kg by the minimal motor impairment test. Therefore, nontoxic doses produced anticonvulsant activity against pentylenetetrazole- and electroshock-induced seizures. Indazole (50mg/kg) had no effect on spontaneous activity but induced hypothermia. It also inhibited the metabolism of dopamine and 5-hydroxytryptamine in the brain in vivo and the activities of monoamine oxidase A and B in vitro, with IC(50) values of 20.6μM and 16.3μM, respectively. However, these inhibitory effects do not account for the anticonvulsant activity because treatment with typical monoamine oxidase inhibitors such as pargyline or tranylcypromine did not completely reproduce the anticonvulsant activity of indazole. In the animal seizure models tested, the anticonvulsant profile of indazole most resembled that of gabapentin and somewhat resembled those of the AMPA/kainate antagonist NBQX and the sodium channel inhibitor phenytoin, but differed from that of benzodiazepine. The isobolographic analyses showed that the interactive mode of indazole with gabapentin, NBQX or phenytoin is additive. These results suggest that indazole has anticonvulsant activity and multiple mechanisms.
    Epilepsy research 12/2012; · 2.48 Impact Factor
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    ABSTRACT: Glutathione (GSH) is an important neuroprotective molecule in the brain. The strategy to increase neuronal GSH level is a promising approach to the treatment of neurodegenerative diseases. However, the regulatory mechanism by which neuron-specific GSH synthesis is facilitated remains elusive. Glutamate transporter-associated protein 3-18 (GTRAP3-18) is an endoplasmic reticulum protein interacting with excitatory amino acid carrier 1 (EAAC1), which is a neuronal glutamate/cysteine transporter. To investigate the potential regulatory mechanism to increase neuronal GSH level in vivo, we generated GTRAP3-18-deficient (GTRAP3-18(-/-)) mice using a gene-targeting approach. Disruption of the GTRAP3-18 gene resulted in increased EAAC1 expression in the plasma membrane, increased neuronal GSH content and neuroprotection against oxidative stress. In addition, GTRAP3-18(-/-) mice performed better in motor/spatial learning and memory tests than wild-type mice. Therefore, the suppression of GTRAP3-18 increases neuronal resistance to oxidative stress by increasing GSH content and also facilitates cognitive function. The present results may provide a molecular basis for the development of treatments for neurodegenerative diseases.
    Neurobiology of Disease 12/2011; 45(3):973-82. · 5.62 Impact Factor
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    ABSTRACT: Several lines of epidemiological studies have indicated that caffeine consumption and plasma uric acid (UA) level were negatively correlated with the incidence of some neurodegenerative diseases. We report here a novel mechanism by which these purine derivatives increase neuronal glutathione (GSH) synthesis. Intraperitoneal injection of caffeine or UA into male C57BL/6 mice significantly increased total GSH levels in the hippocampus. Neither SCH58261, an adenosine A2A receptor antagonist, nor rolipram, a phosphodiesterase-4 inhibitor, increased GSH levels. Pretreatment with allopurinol, a drug to inhibit UA production, did not change the GSH level in the caffeine-treated mice. Hippocampal CA1 pyramidal neurons treated with caffeine or UA were resistant to oxidant exposure in the slice culture experiments. In experiments with the SH-SY5Y cell line, cysteine uptake was sodium-dependent and pretreatment with caffeine or UA increased cysteine uptake significantly as compared with the control conditions. Slice culture experiments using the hippocampus also showed increased cysteine and GSH contents after the treatment with caffeine or UA. Immunohistochemical analysis showed increased GSH levels in the hippocampal excitatory amino acid carrier-1 (EAAC1)-positive neurons of mice treated with caffeine or UA. These findings suggest that purine derivatives caffeine and UA induce neuronal GSH synthesis by promoting cysteine uptake, leading to neuroprotection.
    Neuroscience 02/2011; 181:206-15. · 3.12 Impact Factor
  • Nobuko Matsumura, Kazue Kikuchi-Utsumi, Toshio Nakaki
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    ABSTRACT: 7-Nitroindazole (NI) is a widely used inhibitor of neuronal nitricoxide synthase (nNOS) used to study the role of the neuronal NO pathway in the nervous system. 7-NI prevents convulsions, including 2-amino-4-methylphosphinobutyric acid (glufosinate)-induced convulsions, in experimental models. Herein, we examined nNOS involvement in glufosinate-induced convulsions and the specificity of 7-NI for nNOS. Another nNOS inhibitor, 1-[2-(trifluoromethyl)phenyl]imidazole (TRIM), inhibited NOS activity in vivo, and it prevented glufosinate-induced convulsions. In contrast, an endothelial NOS inhibitor, N(5)-(1-iminoethyl)-l-ornithine, inhibited NOS activity in vivo, but it did not prevent the convulsions. These results suggest the involvement of nNOS in glufosinate-induced convulsions. However, a nonspecific NOS inhibitor, N(omega)-nitro-l-arginine methyl ester, inhibited NOS activity in vivo, but it failed to prevent glufosinate-induced convulsions. 6-NI and indazole, which did not inhibit NOS activity in vivo, suppressed glufosinate-induced convulsions. Moreover, glufosinate elicited convulsions in nNOS-deficient mice. These results suggest the anticonvulsant effects of 7-NI and TRIM on glufosinate-induced convulsions do not involve nNOS inhibition, instead possibly being related to an undefined property of nitrogen-containing chemical structures.
    Journal of Pharmacology and Experimental Therapeutics 06/2008; 325(2):357-62. · 3.89 Impact Factor
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    ABSTRACT: Excitatory amino acid carrier 1 (EAAC1) is a glutamate transporter expressed on mature neurons in the CNS, and is the primary route for uptake of the neuronal cysteine needed to produce glutathione (GSH). Parkinson's disease (PD) is a neurodegenerative disorder pathogenically related to oxidative stress and shows GSH depletion in the substantia nigra (SN). Herein, we report that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, an experimental model of PD, showed reduced motor activity, reduced GSH contents, EAAC1 translocation to the membrane and increased levels of nitrated EAAC1. These changes were reversed by pre-administration of n-acetylcysteine (NAC), a membrane-permeable cysteine precursor. Pretreatment with 7-nitroindazole, a specific neuronal nitric oxide synthase inhibitor, also prevented both GSH depletion and nitrotyrosine formation induced by MPTP. Pretreatment with hydrogen peroxide, L-aspartic acid beta-hydroxamate or 1-methyl-4-phenylpyridinium reduced the subsequent cysteine increase in midbrain slice cultures. Studies with chloromethylfluorescein diacetate, a GSH marker, demonstrated dopaminergic neurons in the SN to have increased GSH levels after NAC treatment. These findings suggest that oxidative stress induced by MPTP may reduce neuronal cysteine uptake, via EAAC1 dysfunction, leading to impaired GSH synthesis, and that NAC would exert a protective effect against MPTP neurotoxicity by maintaining GSH levels in dopaminergic neurons.
    European Journal of Neuroscience 02/2008; 27(1):20-30. · 3.75 Impact Factor