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

Abstract

Background: The most currently used general anaesthetics are potent potentiators of g-aminobutyric acid A (GABA A ) receptors and are invariably neurotoxic during the early stages of brain development in preclinical animal models. As causality between GABA A 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, (3a,5a)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), which potentiates recombinant GABA A receptors, we examined whether this potentiation is the driving force in inducing neurotoxicity during development. Methods: The neurotoxic potential of CDNC24 was examined vis-a-vis propofol (2,6-diisopropylphenol) and alphaxalone (5a-pregnan-3a-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 GABA A 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.

Preemptive Analgesic Effect of Intrathecal Applications of Neuroactive Steroids in a Rodent Model of Post-Surgical Pain: Evidence for the Role of T-Type Calcium Channels

“…The neuroactive steroids were dissolved in 15% 2-Hydroxypropyl-β-cyclodextrin solution in pH-balanced saline (pH = 7.4 to avoid tissue irritation). In our published studies, using in vitro recordings, we established that the effects of these neuroactive steroids on T-channels and GABA A receptors are within the same concentration range [ 17 , 24 ]. Hence, for that reason, we used the same range of doses of neuroactive steroids for intrathecal injections in our in vivo studies.…”

Edaravone Alleviated Propofol-Induced Neurotoxicity in Developing Hippocampus by mBDNF/TrkB/PI3K Pathway

“…10 Previous studies have shown that propofol is the most effective agent to activate the tonic γaminobutyric acid type A (GABA-A) current in the immature hypothalamus. The upregulation of tonic GABA-A conductance is related to epilepsy and neurodevelopmental disorders and may also contribute to memory disorders after GA. 3 Brain-derived neurotrophic factor (BDNF) is an important member of the neuron growth factor family that is widely expressed in the central nervous hippocampal system. 12,13 Research on the effects of neurotrophins in animals was useful to understanding the role of BDNF in branching, synaptic differentiation, pruning, and structural changes.…”

“… 2 As the use of anesthesia is inevitable in the clinical environment, anesthesiologists strive to find ways to assure the safety of children and provide comfort during painful procedures. 3 To minimize risks, the effects of anesthetics on the neurological system need to be understood. 4 The development of the neurological system requires a series of elaborately complicated processes.…”

“… 10 Previous studies have shown that propofol is the most effective agent to activate the tonic γ-aminobutyric acid type A (GABA-A) current in the immature hypothalamus. The upregulation of tonic GABA-A conductance is related to epilepsy and neurodevelopmental disorders and may also contribute to memory disorders after GA. 3 …”

Alfaxalone activates Human Pregnane-X Receptors with greater efficacy than Allopregnanolone: an in-vitro study with implications for neuroprotection during anesthesia

“…An aqueous formulation of alfaxalone (Phaxan™) has been developed for use as an intravenous sedative and anesthetic 12;13 . This development occurs at a time when most commonly-used anesthetics are under investigation for neurotoxic effects [14][15][16] . Alfaxalone differs from those commonly used anesthetics in that it is a structural analogue of a naturally occurring neuroprotective hormone, allopregnanolone.…”