Synthetic neuroactive steroids as new sedatives and anaesthetics: Back to the future

Abstract

Since the 1990s, there has been waning interest in researching general anaesthetics (anaesthetics). Although currently used anaesthetics are mostly safe and effective, they are not without fault. In paediatric populations and neonatal animal models, they are associated with learning impairments and neurotoxicity. In an effort to research safer anaesthetics, we have gone back to re-examine neuroactive steroids as anaesthetics. Neuroactive steroids are steroids that have direct, local effects in the central nervous system. Since the discovery of their anaesthetic effects, neuroactive steroids have been consistently used in human or veterinary clinics as preferred anaesthetic agents. Although briefly abandoned for clinical use due to unwanted vehicle side effects, there has since been renewed interest in their therapeutic value. Neuroactive steroids are safe sedative/hypnotic and anaesthetic agents across various animal species. Importantly, unlike traditional anaesthetics, they do not cause extensive neurotoxicity in the developing rodent brain. Similar to traditional anaesthetics, neuroactive steroids are modulators of synaptic and extrasynaptic γ-aminobutyric acid type A (GABA_A ) receptors and their interactions at the GABA_A receptor are stereo- and enantioselective. Recent work has also shown that these agents act on other ion channels, such as high- and low-voltage-activated calcium channels. Through these mechanisms of action, neuroactive steroids modulate neuronal excitability, which results in characteristic burst suppression of the electroencephalogram, and a surgical plane of anaesthesia. However, in addition to their interactions with voltage and ligand gated ions channels, neuroactive steroids interact with membrane bound metabotropic receptors and xenobiotic receptors to facilitate signaling of prosurvival, antiapoptotic pathways. These pathways play a role in their neuroprotective effects in neuronal injury and may also prevent extensive apoptosis in the developing brain during anaesthesia. The current review explores the history of neuroactive steroids as anaesthetics in humans and animal models, their diverse mechanisms of action, and their neuroprotective properties.

Keywords: GABAA receptors; T-channels; anaesthesia; neuroactive steroids; neuroprotection.

Figure 1:

The anesthetic effects of the endogenous steroids are due to metabolism to their respective neuroactive metabolites. Early studies by Hans Selye (1941) found that progesterone and deoxycorticosterone could produce anesthesia. However, these agents can be further reduced by 5α-reductase to 3-keto compounds. They are further reduced by oxidoreductases, such as 3α-HSD. The final 5α-reduced, 3α-hydroxy compounds are GABA_A receptor modulators and potent endogenous anesthetic agents.

Figure 2:

Currently studied synthetic neuroactive steroids that have sedative/hypnotic and anesthetic properties and may reduce neonatal neurotoxicity in rodent models. A) alfaxalone, a synthetic analogue of allopregnanolone is one of the most widely used neuroactive steroids in research and veterinary medicine. Although it is primarily a GABA_A receptor modulator, it also partially blocks T-type calcium channels. B) Alfadolone was added into formulation with alfaxalone to aid in the solubility of CT1341. C) CDNC24 is a 5α-reduced 3α-hydroxy selective GABA_A receptor modular that unlike alfaxalone, does not block T-channels. It is a long-lasting hypnotic in neonatal rat pups. D) ACN is a potent 5α-reduced 3α-hydroxy GABA_A receptor modulator and hypnotic. Experiments with ACN helped show that GABA_A receptor modulation and hypnosis are affected by enantioselectivity. E) 3β-OH is a 5β-reduced 3β-hydroxy synthetic steroid extensively studied in our lab as a non-GABA_A receptor modulator which blocks T-channels. Use of 3β-OH has demonstrated the role of T-channels in hypnosis. F) 3α-OH is a 5β-reduced 3α-hydroxy neuroactive steroid used by our group; it is a GABA_A receptor modulator that also partially blocks T-channels. Although being 5β-reduced, 3α-OH is a strong hypnotic, and more potent than its stereoisomer, 3β-OH, indicating an important role of GABA_A receptor modulation in hypnosis.

Figure 3:

EEG activity during anesthesia induction after intravenous administration of 3β-OH in a female SD rat. A. Representative spectrograms computed from the same rat during the baseline (top) and IV bolus injection of 60 mg/kg 3β-OH (bottom). Note a characteristic pattern of frequency distribution during the baseline recording in an awake rat, with low frequencies dominating the spectrum. A sudden rise in EEG power immediately after the injection was quickly followed by a suppressed EEG activity. B. Original EEG trace depicting a typical burst suppression pattern – short periods of high amplitude oscillatory activity (burst) were followed by periods of marked EEG attenuation (suppression).