Anesthesia by alfaxalone associated with neuroprotection and preservation of cognition: Study

"Currently used anaesthetics compromise the natural m-BDNF-mediated neuroprotection, whereas alfaxalone can support it," the researchers wrote in their study.

Alfaxalone is a fast-acting IV anaesthetic with a high therapeutic index. It is an analogue of Allopregnanolone, the naturally-occurring neurosteroid responsible for the maintenance of neuroprotection and cognition by activating brain pregnancy X receptors and consequent increased production of m-BDNF. The researchers reported two studies: an in vitro study examined whether alfaxalone activates h-PXR (human pregnane X receptors) as effectively as Allopregnanolone; the clinical research measured postoperative changes in serum m-BDNF and cognition in patients after anesthesia with alfaxalone compared with sevoflurane and propofol.

For this purpose, Juliet M. Serrao & Colin S. Goodchild from Australia measured in vitro Activation of h-PXR by alfaxalone and allopregnanolone solutions (206 - 50,000 nM) using human embryonic kidney cells linked to the firefly luciferase gene and expressing h-PXR hybridized. They also measured light emission by luciferase stimulated to each ligand binding with h-PXR.

For the clinical study, a double-blind prospective randomized study was conducted of patients undergoing hip arthroplasty and anesthesia with propofol TIVA (n = 3) or alfaxalone TIVA (n = 8) or propofol plus sevoflurane inhalational anaesthesia (n = 4).

Anaesthetic doses were titrated to the same depth of anaesthesia (BIS 40-60). The cognitive performance of the participants was assessed using the Mini-Mental State Examination (MMSE), Digit Symbol Substitution Test (DSST), and Grooved Pegboard Test for seven days postoperatively. Serum m-BDNF concentrations were measured for seven postoperative days.

The study led to the following findings:

• In vitro, both, allopregnanolone and alfaxalone activated h-PXR, alfaxalone being more effective comapred to Allopregnanolone: 50,000 nM, p = 0.0019; 5600 nM, p = 0.0031; 16,700 nM, p = 0.0472.
• In the cognition tests, Alfaxalone-treated subjects scored better than propofol and sevoflurane anaesthetized patients: (MMSE p = 0.0251; Grooved Pegboard test dominant hand pre v post anaesthesia scores p = 0.8438 for alfaxalone and p = 0.0156 for propofol and combined propofol/sevoflurane).
• More elevated serum m-BDNF levels in the alfaxalone anaesthetized patients accompanied the higher cognition scores.

"The findings indicate the anaesthesia and sedation induced by alfaxalone may be accompanied by effects caused normally by physiological actions of allopregnanolone at PXR, increased m-BDNF secretion and consequent neuroprotection and preservation of cognition," the authors conclude.

Reference:

Serrao, J.M., Goodchild, C.S. Alfaxalone anaesthesia increases brain derived neurotrophic factor levels and preserves postoperative cognition by activating pregnane-X receptors: an in vitro study and a double blind randomized controlled trial. BMC Anesthesiol 22, 401 (2022). https://doi.org/10.1186/s12871-022-01940-x