Neuropsychopharmaka verändern den intrazellulären pH-Wert von zentralen Neuronen

Zusammenfassung

Ähnlich wie die Elektrolyt-Homöostase ist auch der intrazelluläre pH-Wert (pHi) von Neuronen besonders intensiv kontrolliert. Dieses geschieht beispielsweise durch spezielle membranständige Systeme, die Säureäquivalente in die Zelle hinein und wieder heraus transportieren können. Die Regulation des pHi dient unter anderem der Steuerung der neuronalen Erregbarkeit, da eine Erregbarkeitssteigerung in den meisten Neuronen den pHi senkt und vice versa eine intrazelluläre Azidose im Sinne einer negativen Rückkopplungs-Schleife die Erregbarkeit wieder senkt. Änderungen des pHi haben darüber hinaus Einflüsse auf beinahe jede Zellfunktion. Da über die Wirkung von Neuropsychopharmaka auf die H ⁺ -Homöostase wenig bekannt ist, untersuchten wir diesbezüglich mehrere Antipsychotika, Antidepressiva, Antikonvulsiva und Lithium. Als Modell wurden hippocampale CA 3-Neurone in Gewebeschnitten (vom Meerschweinchen) eingesetzt, die mit dem intrazellulären pHi-Indikator BCECF gefärbt worden waren. In therapeutischen und supratherapeutischen Konzentrationen veränderten alle gemessenen Antipsychotika, die meisten Antidepressiva und gut die Hälfte aller untersuchten Antikonvulsiva reversibel den pHi dieser Neurone. Obwohl diesbezüglich noch bestätigende In-vivo-Experimente fehlen, möchten wir auf die mögliche pHi-Aktivität von Neuropsychopharmaka aufmerksam machen, insbesondere, wenn deren therapeutische oder toxische Wirkungen diskutiert werden.

Abstract

The intracellular pH (pHi) of neurons is tightly regulated, mainly by membrane-bound transporters acting as acid extruders or acid loaders. Regulation of pHi helps to control neuronal excitability, as increased bioelectric activity moderately lowers pHi and, in the sense of a negative feedback loop, intracellular acidosis mostly reduces neuronal excitability. Moreover, a change of pHi widely influences complex cellular functions. With respect to neuropsychopharmaca, little is known about whether or not they may affect neuronal H ⁺ -homeostasis. To this aim, we tested several antipsychotics, antidepressants, anticonvulsants, and lithium for effects on neuronal pHi, using guinea pig hippocampal slice preparations in which CA 3 pyramidal neurons were loaded with the pHi-sensitive dye BCECF-AM. All antipsychotics, most antidepressants and about half of the anticonvulsants tested so far elicited reversible changes of neuronal pHi when applied at therapeutic and supratherapeutic concentrations. Although these results await confirmatory in vivo experiments, we believe that the pHi activity of neuropsychopharmaca needs further attention, especially when therapeutic mechanisms or even harmful side effects are discussed.

Schlüsselwörter

intrazellulärer pH - Neuropsychopharmaka - pH-Regulation

Keywords

intracellular pH - neuropsychopharmaca - pH regulation

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