Letters to the Editor: Letter to the Editor
To the Editor
We read with great interest the article by Liu et al1 in the July edition of Anesthesia & Analgesia in which they described in vitro experiments that show propofol-induced neurotoxicity is caused, at least in part, by a paucity of astrocyte-derived brain-derived neurotrophic factor (BDNF). The accompanying Figure summarizes our interpretation of their findings (in black) and their suggestions for the targets of novel protective strategies (shown in blue) to improve survival of developing neurons during propofol anesthesia; the latter being based on supporting downstream cell survival via pathways such as protein kinase B (Akt) / glycogen synthase kinase 3β (GSK3β) involved in neuronal death under conditions of low astrocyte counts and consequent BDNF depletion.
We propose that they manipulate a pathway upstream of BDNF and encourage them to test the hypothesis in their model. The upstream mechanism to which we refer involves neurosteroids, particularly of the 3α, 5α pregnane series, of which the most prominent is allopregnanolone. Glial cells, particularly astrocytes, possess the machinery to synthesize neurosteroids and convert them to neuroactive metabolites, so it is likely the cells in their preparation also synthesize allopregnanolone. Like BDNF, allopregnanolone is produced by glial cells and neurons and it has well-recognized roles in promoting neurogenesis and neuroplasticity.2
It has been shown that BDNF is a downstream factor produced in the hippocampus by allopregnanolone binding to the nuclear receptor known as pregnane X.3 This suggests the therapeutic possibility of using the neurosteroid/pregnane X mechanism to bolster neuroprotection during times of neural challenge (shown in green in the Figure). The fact that allopregnanolone can protect fetal neurones under stress is well established. Yawno et al4 showed that blockade of allopregnanolone production with administration of finasteride led to increased apoptosis in fetal sheep and further that a synthetic analog of allopregnanolone, alphaxalone, could replace allopregnanolone in this protective role. Pretreatment with alphaxalone did not cause significant apoptosis when administered alone and it prevented the damage caused by finasteride blockade of allopregnanolone synthesis. Alphaxalone is an intravenous anesthetic, used currently in veterinary practice and previously in human anesthetic practice.5
We suggest to Liu et al that they use finasteride (shown in red in the Figure) in their in vitro hippocampal cell neurotoxicity model to block allopregnanolone synthesis and thus test the hypothesis that allopregnanolone, and perhaps its anesthetic analog, can boost BDNF-mediated neuroprotection when the ratio of astrocytes to neurons is low; such ratios mimicking the conditions in the fetal, neonatal, and ageing brain when anesthetic neurotoxicity has been shown to occur most. We hypothesize that the results of using alphaxalone would be like those in hippocampal cultures with a relatively high astrocyte to neuron ratio where astrocyte-derived BDNF decreased neuronal cell death caused by propofol. If this proves true, one must ask the question whether alphaxalone could be used as the anesthetic to boost BDNF-mediated neuronal cell survival at times when there is a stress or insult to the developing brain.
Juliet Serrao, MBBS, PhD, FRCAColin Goodchild, MBBChir, PhD, FRCA, FANZCA, FFPMANZCADrawbridge Pharmaceuticals Pty LtdMalvern, Victoria, Australiajuliet@drawbridgepharmaceuticals.com.au
1. Liu Y, Yan Y, Inagaki Y, Logan S, Bosnjak ZJ, Bai XInsufficient astrocyte-derived brain-derived neurotrophic factor contributes to propofol-induced neuron death through Akt/glycogen synthase kinase 3β/mitochondrial fission pathway. Anesth Analg. 2017;125:241–254.
2. Irwin RW, Solinsky CM, Brinton RDFrontiers in therapeutic development of allopregnanolone for Alzheimer’s disease and other neurological disorders. Front Cell Neurosci. 2014;8:203.
3. Frye CA, Koonce CJ, Walf AAInvolvement of pregnane xenobiotic receptor in mating-induced allopregnanolone formation in the midbrain and hippocampus and brain-derived neurotrophic factor in the hippocampus among female rats. Psychopharmacology (Berl). 2014;231:3375–3390.
4. Yawno T, Hirst JJ, Castillo-Melendez M, Walker DWRole of neurosteroids in regulating cell death and proliferation in the late gestation fetal brain. Neuroscience. 2009;163:838–847.
5. Hollmann MW, Sear JWAnother steroid hypnotic: more of the same or something different? Anesth Analg. 2015;120:980–982.