Microtubule-Stabilizer Epothilone B Delays Anesthetic-Induced Unconsciousness in Rats.
Sana Khan, Yixiang Huang, Derin Timuçin, Shantelle Bailey, Sophia Lee, Jessica Lopes, Emeline Gaunce, Jasmine Mosberger, Michelle Zhan, Bothina Abdelrahman, Xiran Zeng, Michael C Wiest
eNeuro August 1, 2024 DOI: 10.1523/ENEURO.0291-24.2024 via PubMed
Summary
Volatile anesthetics like isoflurane may cause unconsciousness by binding to microtubules (MTs) inside neurons and dampening their quantum optical effects. In male rats injected with the MT-stabilizing drug epothilone B (epoB), loss of righting reflex under 4% isoflurane took an average of 69 seconds longer than in rats given a placebo. The difference was statistically significant with a large effect size (Cohen's d = 1.9) and could not be explained by tolerance from repeated anesthetic exposure. This supports the idea that consciousness arises from quantum physical states in neural microtubules, as proposed in the orchestrated objective reduction (Orch OR) theory.
Study at a glance
| Characteristics | Randomized controlled trial Peer reviewed |
|---|---|
| Population | Male rats |
| Keywords | Consciousness Microtubules Neoadjuvant Orchestrated objective reduction Postoperative cognitive dysfunction |
| Citations | 23 |
| Key finding | Rats given the microtubule-stabilizing drug epothilone B took significantly longer to lose consciousness under isoflurane, suggesting that anesthetic binding to microtubules contributes to unconsciousness. |
Abstract
Volatile anesthetics are currently believed to cause unconsciousness by acting on one or more molecular targets including neural ion channels, receptors, mitochondria, synaptic proteins, and cytoskeletal proteins. Anesthetic gases including isoflurane bind to cytoskeletal microtubules (MTs) and dampen their quantum optical effects, potentially contributing to causing unconsciousness. This possibility is supported by the finding that taxane chemotherapy consisting of MT-stabilizing drugs reduces the effectiveness of anesthesia during surgery in human cancer patients. In order to experimentally assess the contribution of MTs as functionally relevant targets of volatile anesthetics, we measured latencies to loss of righting reflex (LORR) under 4% isoflurane in male rats injected subcutaneously with vehicle or 0.75 mg/kg of the brain-penetrant MT-stabilizing drug epothilone B (epoB). EpoB-treated rats took an average of 69 s longer to become unconscious as measured by latency to LORR. This was a statistically significant difference corresponding to a standardized mean difference (Cohen's d) of 1.9, indicating a "large" normalized effect size. The effect could not be accounted for by tolerance from repeated exposure to isoflurane. Our results suggest that binding of the anesthetic gas isoflurane to MTs causes unconsciousness and loss of purposeful behavior in rats (and presumably humans and other animals). This finding is predicted by models that posit consciousness as a property of a quantum physical state of neural MTs.