Neuroprotectant minocycline depresses glutamatergic neurotransmission and Ca(2+) signalling in hippocampal neurons.
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, Ca(2+) 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 (I(Na)) by 20%, and the whole-cell Ca(2+) current (I(Ca)) by about 30%. Minocycline inhibited glutamate-evoked elevation of the cytosolic Ca(2+) concentration ([Ca(2+)](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 gamma-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 Ca(2+) overloading.
González
José Carlos
JC
Instituto Teófilo Hernando, and Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Zrzobispo Morcillo 4, E-28029 Madrid, Spain.
Egea
Javier
J
Del Carmen Godino
María
M
Fernandez-Gomez
Francisco J
FJ
Sánchez-Prieto
José
J
Gandía
Luís
L
García
Antonio G
AG
Jordán
Joaquín
J
Hernández-Guijo
Jesús M
JM
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism* / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008911:Minocycline / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018079:Receptors, GABA / Q000187:drug effects / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D013574:Synaptosomes
D000900:Anti-Bacterial Agents; D015220:Calcium Channels; D018696:Neuroprotective Agents; D018079:Receptors, GABA; D015222:Sodium Channels; D018698:Glutamic Acid; D008911:Minocycline; D002118:Calcium