Neuroactive steroids alphaxalone and CDNC24 are effective hypnotics and potentiators of GABAA currents, but are not neurotoxic to the developing rat brain. (May 2020)

• Record Type: Journal Article
• Authors: Tesic, Vesna; Joksimovic, Srdjan M.; Quillinan, Nidia; Krishnan, Kathiresan; Covey, Douglas F.; Todorovic, Slobodan M.; Jevtovic-Todorovic, Vesna
• Is Part Of: British journal of anaesthesia. Volume 124:Number 5(2020)
• Page Start: 603
• Page End: 613
• Publication Date: 2020-05
• Subjects: general anaesthetic -- prefrontal cortex -- presynaptic -- subiculum -- synaptic transmission -- synaptogenesis; Anesthesiology -- Periodicals; Anesthesia -- Periodicals; 617.9605
• DOI: 10.1016/j.bja.2020.01.013
• Languages: English
• ISSNs: 0007-0912

Abstract

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.