Neuroactive steroids alphaxalone and CDNC24 are effective hypnotics and potentiators of GABAA currents, but are not neurotoxic to the developing rat brain.
Br J Anaesth
; 124(5): 603-613, 2020 05.
Article
en En
| MEDLINE
| ID: mdl-32151384
ABSTRACT
BACKGROUND:
The most currently used general anaesthetics are potent potentiators of γ-aminobutyric acid A (GABAA) receptors and are invariably neurotoxic during the early stages of brain development in preclinical animal models. As causality between GABAA potentiation and anaesthetic-induced developmental neurotoxicity has not been established, the question remains whether GABAergic activity is crucial for promoting/enhancing neurotoxicity. Using the neurosteroid analogue, (3α,5α)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), which potentiates recombinant GABAA receptors, we examined whether this potentiation is the driving force in inducing neurotoxicity during development.METHODS:
The neurotoxic potential of CDNC24 was examined vis-à-vis propofol (2,6-diisopropylphenol) and alphaxalone (5α-pregnan-3α-ol-11,20-dione) at the peak of rat synaptogenesis. In addition to the morphological neurotoxicity studies of the subiculum and medial prefrontal cortex (mPFC), we assessed the extra-, pre-, and postsynaptic effects of these agents on GABAergic neurotransmission in acute subicular slices from rat pups.RESULTS:
CDNC24, like alphaxalone and propofol, caused dose-dependent hypnosis in vivo, with a higher therapeutic index. CDNC24 and alphaxalone, unlike propofol, did not cause developmental neuroapoptosis in the subiculum and mPFC. Propofol potentiated post- and extrasynaptic GABAA currents as evidenced by increased spontaneous inhibitory postsynaptic current (sIPSC) decay time and prominent tonic currents, respectively. CDNC24 and alphaxalone had a similar postsynaptic effect, but also displayed a strong presynaptic effect as evidenced by decreased frequency of sIPSCs and induced moderate tonic currents.CONCLUSIONS:
The lack of neurotoxicity of CDNC24 and alphaxalone may be at least partly related to suppression of presynaptic GABA release in the developing brain.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Pregnanodionas
/
Esteroides
/
Encéfalo
/
Hipnóticos y Sedantes
Tipo de estudio:
Etiology_studies
Idioma:
En
Revista:
Br J Anaesth
Año:
2020
Tipo del documento:
Article
País de afiliación:
Estados Unidos