RESUMO
OBJECTIVE: The aim of this study was to determine whether surgery and anesthesia in the elderly may promote Alzheimer disease and related dementias (ADRD). BACKGROUND: There is a substantial conflicting literature concerning the hypothesis that surgery and anesthesia promotes ADRD. Much of the literature is confounded by indications for surgery or has small sample size. This study examines elderly patients with appendicitis, a common condition that strikes mostly at random after controlling for some known associations. METHODS: A matched natural experiment of patients undergoing appendectomy for appendicitis versus control patients without appendicitis using Medicare data from 2002 to 2017, examining 54,996 patients without previous diagnoses of ADRD, cognitive impairment, or neurological degeneration, who developed appendicitis between ages 68 through 77 years and underwent an appendectomy (the ''Appendectomy'' treated group), matching them 5:1 to 274,980 controls, examining the subsequent hazard for developing ADRD. RESULTS: The hazard ratio (HR) for developing ADRD or death was lower in the Appendectomy group than controls: HR = 0.96 [95% confidence interval (CI) 0.94-0.98], P < 0.0001, (28.2% in Appendectomy vs 29.1% in controls, at 7.5 years). The HR for death was 0.97 (95% CI 0.95-0.99), P = 0.002, (22.7% vs 23.1% at 7.5 years). The HR for developing ADRD alone was 0.89 (95% CI 0.86-0.92), P < 0.0001, (7.6% in Appendectomy vs 8.6% in controls, at 7.5 years). No subgroup analyses found significantly elevated rates of ADRD in the Appendectomy group. CONCLUSION: In this natural experiment involving 329,976 elderly patients, exposure to appendectomy surgery and anesthesia did not increase the subsequent rate of ADRD.
Assuntos
Doença de Alzheimer , Anestesia , Apendicite , Disfunção Cognitiva , Idoso , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/epidemiologia , Apendicite/cirurgia , Humanos , Medicare , Estados UnidosRESUMO
Propofol is widely used in the clinic for the induction and maintenance of general anesthesia. As with most general anesthetics, however, our understanding of its mechanism of action remains incomplete. Local and general anesthetics largely inhibit voltage-gated Na+ channels (Navs) by inducing an apparent stabilization of the inactivated state, associated in some instances with pore block. To determine the biophysical and molecular basis of propofol action in Navs, we investigated NaChBac and NavMs, two prokaryotic Navs with distinct voltage dependencies and gating kinetics, by whole-cell patch clamp electrophysiology in the absence and presence of propofol at clinically relevant concentrations (2-10 µM). In both Navs, propofol induced a hyperpolarizing shift of the pre-pulse inactivation curve without any significant effects on recovery from inactivation at strongly hyperpolarized voltages, demonstrating that propofol does not stabilize the inactivated state. Moreover, there was no evidence of fast or slow pore block by propofol in a non-inactivating NaChBac mutant (T220A). Propofol also induced hyperpolarizing shifts of the conductance-voltage relationships with negligible effects on the time constants of deactivation at hyperpolarized voltages, indicating that propofol does not stabilize the open state. Instead, propofol decreases the time constants of macroscopic activation and inactivation. Adopting a kinetic scheme of Nav gating that assumes preferential closed-state recovery from inactivation, a 1.7-fold acceleration of the rate constant of activation and a 1.4-fold acceleration of the rate constant of inactivation were sufficient to reproduce experimental observations with computer simulations. In addition, molecular dynamics simulations and molecular docking suggest that propofol binding involves interactions with gating machinery in the S4-S5 linker and external pore regions. Our findings show that propofol is primarily a positive gating modulator of prokaryotic Navs, which ultimately inhibits the channels by promoting activation-coupled inactivation.
Assuntos
Proteínas de Bactérias/efeitos dos fármacos , Hipnóticos e Sedativos/farmacologia , Propofol/farmacologia , Canais de Sódio/efeitos dos fármacos , Canais de Sódio Disparados por Voltagem/efeitos dos fármacos , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Células HEK293 , Humanos , Cinética , Mutação , Técnicas de Patch-Clamp , Canais de Sódio/genética , Canais de Sódio/metabolismo , Canais de Sódio Disparados por Voltagem/metabolismoRESUMO
Voltage-gated sodium (NaV) channels are important targets of general anesthetics, including the intravenous anesthetic propofol. Electrophysiology studies on the prokaryotic NaV channel NaChBac have demonstrated that propofol promotes channel activation and accelerates activation-coupled inactivation, but the molecular mechanisms of these effects are unclear. Here, guided by computational docking and molecular dynamics simulations, we predict several propofol-binding sites in NaChBac. We then strategically place small fluorinated probes at these putative binding sites and experimentally quantify the interaction strengths with a fluorinated propofol analogue, 4-fluoropropofol. In vitro and in vivo measurements show that 4-fluoropropofol and propofol have similar effects on NaChBac function and nearly identical anesthetizing effects on tadpole mobility. Using quantitative analysis by 19F-NMR saturation transfer difference spectroscopy, we reveal strong intermolecular cross-relaxation rate constants between 4-fluoropropofol and four different regions of NaChBac, including the activation gate and selectivity filter in the pore, the voltage sensing domain, and the S4-S5 linker. Unlike volatile anesthetics, 4-fluoropropofol does not bind to the extracellular interface of the pore domain. Collectively, our results show that propofol inhibits NaChBac at multiple sites, likely with distinct modes of action. This study provides a molecular basis for understanding the net inhibitory action of propofol on NaV channels.
Assuntos
Proteínas de Bactérias/efeitos dos fármacos , Hipnóticos e Sedativos/farmacologia , Propofol/farmacologia , Canais de Sódio/efeitos dos fármacos , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Flúor , Células HEK293 , Humanos , Larva , Espectroscopia de Ressonância Magnética , Técnicas de Patch-Clamp , Canais de Sódio/genética , Canais de Sódio/metabolismo , Xenopus laevisAssuntos
Envelhecimento , Estado Terminal/terapia , Avaliação da Deficiência , Pessoas com Deficiência , Feminino , Humanos , MasculinoRESUMO
We used a photoactive general anesthetic called meta-azi-propofol (AziPm) to test the selectivity and specificity of alkylphenol anesthetic binding in mammalian brain. Photolabeling of rat brain sections with [(3)H]AziPm revealed widespread but heterogeneous ligand distribution, with [(3)H]AziPm preferentially binding to synapse-dense areas compared to areas composed largely of cell bodies or myelin. With [(3)H]AziPm and propofol, we determined that alkylphenol general anesthetics bind selectively and specifically to multiple synaptic protein targets. In contrast, the alkylphenol anesthetics do not bind to specific sites on abundant phospholipids or cholesterol, although [(3)H]AziPm shows selectivity for photolabeling phosphatidylethanolamines. Together, our experiments suggest that alkylphenol anesthetic substrates are widespread in number and distribution, similar to those of volatile general anesthetics, and that multi-target mechanisms likely underlie their pharmacology.