Targeting ALDH2 to Enhance Anesthetic Arousal: Mechanisms and Therapeutic Potential
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Project Summary: Anesthetic arousal is a complex neurological process. For some patients, arousal does not occur as planned, such as during delayed emergence or postoperative delirium, which increases the risk of postoperative complications. Aldehydes, toxic byproducts of oxidative stress, accumulate during anesthesia and disrupt synaptic function, promote neuroinflammation, and impair mitochondrial function. Aldehyde dehydrogenase 2 (ALDH2) metabolizes aldehydes, but 8% of the population carries an ALDH2*2 genetic variant, which reduces enzymatic activity. This deficiency may prolong anesthetic arousal, yet the role of ALDH2 in promoting arousal is largely unexplored. To address this knowledge gap, this basic science Research Training Plan will define how ALDH2 regulates anesthetic arousal and test whether ALDH2 pharmacological activation can accelerate arousal. The central hypothesis is that ALDH2 detoxifies reactive aldehydes, prevents aldehyde-induced protein adducts, and modulates NFκB-driven neuroinflammation to drive arousal. Key innovations include an ALDH2-specific activator (AD-9308), a genetically engineered ALDH2*2 knock-in mouse model, and targeted biochemical profiling of aldehyde-modified proteins in arousal-related brain regions. By integrating behavioral and biochemical approaches, this project will uncover metabolic mechanisms influencing anesthetic arousal. Aim 1 will determine how ALDH2 modulates anesthetic arousal in wild-type and ALDH2*2 mice, with and without ALDH2 activation using AD-9308. Aim 2 will identify aldehyde-protein adducts in arousal-related brain regions that contribute to delayed anesthetic arousal, using targeted biochemical profiling and mass spectrometry. Aim 3 will investigate how ALDH2 influences neuroinflammatory signaling, particularly NFB activation, to determine its role in arousal. The Career Development Plan is tailored to enable Dr. Goodnough to gain expertise in neuropharmacology, oxidative stress biology, and translational anesthetic research. Dr. Goodnough will train with mentor Dr. Eric Gross to gain expertise on in vivo pharmacological interventions, biochemical profiling, and neuroinflammatory signaling analyses, positioning her for an independent research career in anesthetic neuroscience. Training will occur in a collaborative environment with mentorship from experts in anesthetic pharmacology and metabolism (Dr. Morgan), neurobiology (Dr. Heifets), and aldehyde metabolism (Dr. Mochly-Rosen). The results of this study will provide critical insights into the regulation of anesthetic arousal, with broad implications for improving anesthetic recovery. By identifying aldehyde metabolism as a key modulator of anesthetic arousal and testing a targeted pharmacological intervention, this research directly aligns with the mission of NIGMS to support mechanistic insights of anesthesia that enhance patient care. Ultimately, this project represents a high-impact investment in the development of novel therapeutic strategies to optimize anesthetic arousal, particularly for individuals with impaired aldehyde metabolism.
