In previous work, we demonstrated that general anaesthetics (GAs) impair presynaptic neurotransmission, in addition to their well-known role in enhancing inhibitory post-synaptic receptors. Using animal models (flies/nematodes) and mammalian neurosecretory cell cultures, we tested a non-anaesthetic analogue of propofol, 'propofluor,' which appears to reverse the effects of GAs. This presents a potential opportunity to identify agents that could accelerate recovery from GAs in human patients.
To explore this in a context most relevant to human patients, we are using lab-grown mini-brains (organoids) derived from human pluripotent stem cells. By 6-8 months of age, these organoids display complex patterns of electrical activity, recorded via multi-electrode arrays, which can serve as a model for assessing induction and recovery dynamics of GAs. Importantly, organoids can be grown from specific patient populations, such as vulnerable individuals with mutations that make them hypersensitive to anaesthetics (e.g., Leigh Syndrome).
In our ANZCA-funded project, we will investigate the effects of two intravenous GAs (propofol and etomidate) on network activity in cortical organoids derived from Leigh Syndrome patients and controls. After characterising anaesthetic induction and recovery, we will test whether candidate reversal agents like propofluor, can counteract the effects of these drugs and reduce the time to full recovery in both types of organoids.
Professor André van Zundert, Royal Brisbane and Women’s Hospital.
The project was awarded A$69,952 funding through the ANZCA research grants program for 2025.