Neuroprotectant minocycline depresses glutamatergic neurotransmission and Ca2+ signalling in hippocampal neurons

Authors

  • José Carlos González,

    1. Instituto Teófilo Hernando,
    2. Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Arzobispo Morcillo 4, E-28029 Madrid, Spain
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  • Javier Egea,

    1. Instituto Teófilo Hernando,
    2. Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Arzobispo Morcillo 4, E-28029 Madrid, Spain
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  • María Del Carmen Godino,

    1. Departamento de Bioquímica, Facultad de Veterinaria, Universidad Complutense, Madrid, Spain
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  • Francisco J. Fernandez-Gomez,

    1. Grupo de Neurofarmacología, Departamento de Ciencias Médicas, Facultad de Medicina, Universidad Castilla-La Mancha y Centro Regional de Investigaciones Biomédicas, Albacete, Spain
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  • José Sánchez-Prieto,

    1. Departamento de Bioquímica, Facultad de Veterinaria, Universidad Complutense, Madrid, Spain
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  • Luís Gandía,

    1. Instituto Teófilo Hernando,
    2. Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Arzobispo Morcillo 4, E-28029 Madrid, Spain
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  • Antonio G. García,

    1. Instituto Teófilo Hernando,
    2. Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Arzobispo Morcillo 4, E-28029 Madrid, Spain
    3. Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
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  • Joaquín Jordán,

    1. Grupo de Neurofarmacología, Departamento de Ciencias Médicas, Facultad de Medicina, Universidad Castilla-La Mancha y Centro Regional de Investigaciones Biomédicas, Albacete, Spain
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  • Jesús M. Hernández-Guijo

    1. Instituto Teófilo Hernando,
    2. Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Arzobispo Morcillo 4, E-28029 Madrid, Spain
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Dr J. M. Hernández-Guijo, Departamento de Farmacología y Terapéutica, as above.
E-mail: jesusmiguel.hernandez@uam.es

Abstract

The mechanism of the neuroprotective action of the tetracycline antibiotic minocycline against various neuron insults is controversial. In an attempt to clarify this mechanism, we have studied here its effects on various electrophysiological parameters, Ca2+ signalling, and glutamate release, in primary cultures of rat hippocampal neurons, and in synaptosomes. Spontaneous excitatory postsynaptic currents and action potential firing were drastically decreased by minocycline at concentrations known to afford neuroprotection. The drug also blocked whole-cell inward Na+ currents (INa) by 20%, and the whole-cell Ca2+ current (ICa) by about 30%. Minocycline inhibited glutamate-evoked elevation of the cytosolic Ca2+ concentration ([Ca2+]c) by nearly 40%, and K+-evoked glutamate release from synaptosomes by 63%. Minocycline also depressed the frequency and amplitude of spontaneous excitatory postsynaptic currents, but did not affect the whole-cell inward current elicited by γ-aminobutyric acid or glutamate. This pharmacological profile suggests that the neuroprotective effects of minocycline might be associated with the mitigation of neuronal excitability, glutamate release, and Ca2+ overloading.

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