Dexmedetomidine and propofol-induced neurotoxicity: Promise,but caution warranted

We read with great interest the recent article by Xu et al. (2025), “Protective effects of dexmedetomidine against propofol-induced memory impairment in developing rat involved Src and RARα,” published in Human and Experimental Toxicology. This study presents compelling findings regarding the potential neuroprotective role of dexmedetomidine against propofol-induced cognitive deficits in developing rats. The investigation into neuroprotective strategies for anesthetic-induced cognitive impairment in early development is a topic of significant clinical importance and novelty, addressing a critical concern in pediatric anesthesia. The authors’ exploration of Src and RARα pathways provides valuable mechanistic insights into this complex issue.

While the study offers valuable insights, we would like to provide some critical commentary on the experimental model employed. The use of 7-day-old Sprague Dawley rats as a model for neonatal human brain development warrants careful consideration. Rodent brain development, particularly synaptogenesis, occurs at a significantly accelerated rate compared to humans. ¹ For instance, the critical period of synaptogenesis in rodents peaks during the first three postnatal weeks, with some studies suggesting that postnatal day 1 (PND1) to PND10 in rats approximates the last trimester of human pregnancy.^2,3 This temporal disparity raises questions about the direct translational relevance of findings from PND7 rats to human neonates, especially concerning the timing of vulnerability to anesthetic neurotoxicity. Future studies could benefit from models that more closely align with human developmental timelines or provide a more detailed justification for the chosen developmental stage.

Furthermore, the interpretation of autophagy and apoptosis in the context of neuroprotection warrants deeper discussion. Autophagy, often considered a cell survival mechanism, can also contribute to cell death under certain conditions, exhibiting a complex dual role in neurodegeneration and neuroprotection.^4,5 The interplay between autophagy and apoptosis is intricate, with significant crosstalk influencing neuronal fate, especially under stress conditions like anesthetic exposure.^6,7 While the study by Xu et al. implicates Src and RARα, a more comprehensive discussion on how these pathways specifically modulate the balance between pro-survival and pro-death roles of autophagy, and its interaction with apoptosis, would strengthen the mechanistic interpretation. For instance, some studies suggest propofol can induce neuronal cell damage by regulating autophagy, leading to cognitive dysfunction, ⁸ while dexmedetomidine’s neuroprotective effects have been linked to the inhibition of inflammatory reactions, reduction of apoptosis, and modulation of autophagy. ⁹ Clarifying the precise nature of this interplay in their model would enhance the study’s contribution.

Concerns also arise regarding the behavioral testing methods. The eight-arm radial maze and passive avoidance test are commonly used to assess spatial learning and memory in rodents.^10,11 While valuable, these methods primarily evaluate specific aspects of memory (e.g., working and reference memory for the radial maze, and fear-motivated associative memory for passive avoidance).^12,13 However, assessing complex cognitive outcomes, which might be affected by anesthetic exposure, often requires a broader battery of tests to capture the full spectrum of potential deficits. ¹⁴ For instance, the Morris water maze is frequently cited for its robust assessment of spatial learning and memory. ¹⁵ A more comprehensive neurobehavioral assessment, potentially including tests for executive function, social cognition, or affective behaviors, would provide a more holistic understanding of the long-term impact of propofol and the neuroprotective effects of dexmedetomidine. The sensitivity and specificity of these tests in detecting subtle or multifaceted memory impairments, especially in a developing brain, should be thoroughly discussed.

The translational relevance of the study to pediatric anesthesia also warrants careful consideration. The experimental doses and regimens of dexmedetomidine and propofol used in rodent models may not always accurately reflect clinical practice in human infants. ¹⁶ For instance, typical maintenance infusions of dexmedetomidine in pediatric patients range from 0.2 to 1.5 mcg/kg/hour, and propofol induction doses can be around 2.5-3.5 mg/kg in children.^17,18 While animal models are invaluable for understanding neurotoxicity, direct extrapolation to human pediatric populations requires careful validation, as species-specific differences in drug metabolism, brain development, and vulnerability to neurotoxic insults can significantly impact outcomes.^19,20 Future research should strive to bridge this gap by employing clinically relevant dosing strategies and considering the unique physiological characteristics of the developing human brain.

Finally, the exclusive use of male rats in this study raises concerns about potential sex bias in preclinical research. There is growing evidence of sex differences in neurodevelopment and response to anesthetic agents.^21,22 Historically, preclinical research has shown a significant male bias, particularly in neuroscience, which can limit the generalizability of findings to both sexes.^23,24 The National Institutes of Health (NIH) now mandates the inclusion of both sexes in preclinical studies to enhance reproducibility and translational potential.^25,26 Discussing how the findings might differ in female subjects, or justifying the exclusion of one sex, is crucial for adherence to best practices and for ensuring the broad applicability of research outcomes.

Conclusion

In conclusion, while Xu et al. provide a valuable contribution to the understanding of neuroprotective strategies against anesthetic-induced neurotoxicity, addressing the aforementioned methodological and translational considerations would further strengthen the impact and generalizability of their findings. We encourage future studies to employ more clinically relevant animal models, conduct longer-term behavioral assessments, and consider in vitro human neuronal models or genetic manipulation techniques (e.g., CRISPR knockdown of RARα/Src) as complementary approaches to elucidate the complex mechanisms underlying anesthetic neurotoxicity and neuroprotection.