The metabolomic profile during isoflurane anesthesia differs from propofol anesthesia in the live rodent brain

Makaryus, Rany; Lee, Hedok; Yu, Mei; Zhang, Shaonan; Smith, Shane; Rebecchi, Mario J.; Glass, Peter S. A.; Benveniste, Helene

doi:10.1038/jcbfm.2011.1

Cited by 68 publications

(86 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent studies have also highlighted that these anesthetics produce neurotoxic effects (34). However, the exact mechanism by which these drugs induce unconsciousness or neurotoxicity is not clearly understood, and their effects on nonneuronal cells are not widely appreciated (21,23).…”

Section: Discussionmentioning

confidence: 99%

General anesthesia selectively disrupts astrocyte calcium signaling in the awake mouse cortex

Thrane

Zeppenfeld

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

268

258

View full text Add to dashboard Cite

Calcium signaling represents the principle pathway by which astrocytes respond to neuronal activity. General anesthetics are routinely used in clinical practice to induce a sleep-like state, allowing otherwise painful procedures to be performed. Anesthetic drugs are thought to mainly target neurons in the brain and act by suppressing synaptic activity. However, the direct effect of general anesthesia on astrocyte signaling in awake animals has not previously been addressed. This is a critical issue, because calcium signaling may represent an essential mechanism through which astrocytes can modulate synaptic activity. In our study, we performed calcium imaging in awake head-restrained mice and found that three commonly used anesthetic combinations (ketamine/xylazine, isoflurane, and urethane) markedly suppressed calcium transients in neocortical astrocytes. Additionally, all three anesthetics masked potentially important features of the astrocyte calcium signals, such as synchronized widespread transients that appeared to be associated with arousal in awake animals. Notably, anesthesia affected calcium transients in both processes and soma and depressed spontaneous signals, as well as calcium responses, evoked by whisker stimulation or agonist application. We show that these calcium transients are inositol 1,4,5-triphosphate type 2 receptor (IP 3 R2)-dependent but resistant to a local blockade of glutamatergic or purinergic signaling. Finally, we found that doses of anesthesia insufficient to affect neuronal responses to whisker stimulation selectively suppressed astrocyte calcium signals. Taken together, these data suggest that general anesthesia may suppress astrocyte calcium signals independently of neuronal activity. We propose that these glial effects may constitute a nonneuronal mechanism for sedative action of anesthetic drugs.

show abstract

Section: Discussionmentioning

confidence: 99%

General anesthesia selectively disrupts astrocyte calcium signaling in the awake mouse cortex

Thrane

Zeppenfeld

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

268

258

View full text Add to dashboard Cite

show abstract

“…Longitudinal exposure may impair learning and increase anxiety in subjects (Yonezaki et al, 2015). Further, neurovascular coupling in macaques was found to be compromised under isoflurane, showing reduced BOLD amplitudes and longer onset times (Li et al, 2014), along with significant alterations in the metabolic profile of the brain (Makaryus et al, 2011). Suppression of brain function likely contributed to these outcomes.…”

Section: Discussionmentioning

confidence: 99%

Two-photon imaging of cerebral hemodynamics and neural activity in awake and anesthetized marmosets

Santisakultarm

Kersbergen

Bandy

et al. 2016

Journal of Neuroscience Methods

View full text Add to dashboard Cite

Background Marmosets are a powerful, emerging model for human behavior and neurological disorders. However, longitudinal imaging modalities that visualize both cellular structure and function within the cortex are not available in this animal model. Hence, we implemented an approach to quantify vascular topology, hemodynamics, and neural activity in awake marmosets using two-photon microscopy (2PM). New method Marmosets were acclimated to a custom stereotaxic system. AAV1-GCaMP5G was injected into somatosensory cortex to optically indicate neural activity, and a cranial chamber was implanted. Results Longitudinal 2PM revealed vasculature and neurons 500 µm below the cortical surface. Vascular response and neural activity during sensory stimulation were preserved over 5 and 3 months, respectively, before optical quality deteriorated. Vascular remodeling including increased tortuosity and branching was quantified. However, capillary connectivity from arterioles to venules remained unchanged. Further, behavioral assessment before and after surgery demonstrated no impact on cognitive and motor function. Immunohistochemistry confirmed minimal astrocyte activation with no focal damage. Over 6 months, total cortical depth visualized decreased. When under anesthesia, the most prominent isoflurane-induced vasodilation occurred in capillaries and smaller arterioles. Comparison with existing method(s) These results demonstrate the capability to repeatedly observe cortical physiology in awake marmosets over months. Conclusions This work provides a novel and insightful technique to investigate critical mechanisms in neurological disorders in awake marmosets without introducing confounds from anesthesia.

show abstract

“…In addition, simulated spectra of mobile lipids (Lip20, Lip1.3a, Lip1.3b and Lip09) were also included. Spectral profiles of population averaged macromolecules (MM) from a separate group of juvenile rats 39 were also incorporated as described previously 40 . Due to the higher concentration of water in neonatal rat brains 27 , the quantitative data was linearly interpolated and the water concentrations were estimated as 48.6 mM for PND8, 48.4 for PND9, 46.7 for PND16, and 46.5 for PND17.…”

Section: Methodsmentioning

confidence: 99%

Brain Maturation in Neonatal Rodents Is Impeded by Sevoflurane Anesthesia

et al. 2015

Self Cite

View full text Add to dashboard Cite

Background A wealth of data shows neuronal demise after general anesthesia in the very young rodent brain. Here we apply proton magnetic resonance spectroscopy (1HMRS), testing the hypothesis that neurotoxic exposure during peak synaptogenesis can be tracked via changes in neuronal metabolites. Methods 1HMRS spectra was acquired in the brain (thalamus) of neonatal rat pups 24- and 48 h after sevoflurane exposure on post-natal day (PND) 7 and 15, and in unexposed, sham controls. A repeated measure ANOVA was performed to examine if changes in metabolites were different between exposed and unexposed groups. Sevoflurane-induced neurotoxicity on PND7 was confirmed by immunohistochemistry. Results In unexposed PND7 pups (N=21), concentration of NAA ([NAA]) increased by 16% from PND8 to PND9, whereas in exposed PND7 pups (N=19), [NAA] did not change and concentration of choline compounds ([GPC+PCh]) decreased by 25%. In PND15 rats, [NAA] increased from PND16 to PND17 for both the exposed (N=14) and unexposed (N=16) groups. Two-way ANOVA for PND7 pups demonstrated changes over time observed in [NAA] (p=0.031) and [GPC+PCh] (p=0.024) were different between those two groups. Conclusions We demonstrated that normal [NAA] increase from PND8 to PND9 was impeded in sevoflurane-exposed rats when exposed at PND7; however, not impeded when exposed on PND15. Furthermore, we showed that non-invasive 1HMRS is sufficiently sensitive to detect subtle differences in developmental time trajectory of [NAA]. This is potentially clinically relevant since 1HMRS can be applied across species, and may be useful in providing evidence of neurotoxicity in the human neonatal brain.

show abstract

The metabolomic profile during isoflurane anesthesia differs from propofol anesthesia in the live rodent brain

Cited by 68 publications

References 45 publications

General anesthesia selectively disrupts astrocyte calcium signaling in the awake mouse cortex

General anesthesia selectively disrupts astrocyte calcium signaling in the awake mouse cortex

Two-photon imaging of cerebral hemodynamics and neural activity in awake and anesthetized marmosets

Brain Maturation in Neonatal Rodents Is Impeded by Sevoflurane Anesthesia

Contact Info

Product

Resources

About