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Inhibition of astrocyte metabolism is not the primary mechanism for anaesthetic hypnosis.

Voss LJ, Harvey MG, Sleigh JW - Springerplus (2016)

Bottom Line: Subsequently, the effect of astrocyte metabolic inhibition was investigated in neocortical slices, and compared with that of the anaesthetic drugs.In vivo anaesthetic potency correlated strongly with the magnitude of reduction in SLE frequency in neocortical slices (R(2) 37.7 %, p = 0.002).The capacity of an anaesthetic agent to reduce SLE frequency in the neocortical slice is a good indicator of its in vivo hypnotic potency.

View Article: PubMed Central - PubMed

Affiliation: Anaesthesia Department, Waikato District Health Board, Pembroke St, Hamilton, 3240 New Zealand.

ABSTRACT
Astrocytes have been promoted as a possible mechanistic target for anaesthetic hypnosis. The aim of this study was to explore this using the neocortical brain slice preparation. The methods were in two parts. Firstly, multiple general anaesthetic compounds demonstrating varying in vivo hypnotic potency were analysed for their effect on "zero-magnesium" seizure-like event (SLE) activity in mouse neocortical slices. Subsequently, the effect of astrocyte metabolic inhibition was investigated in neocortical slices, and compared with that of the anaesthetic drugs. The rationale was that, if suppression of astrocytes was both necessary and sufficient to cause hypnosis in vivo, then inhibition of astrocytic metabolism in slices should mimic the anaesthetic effect. In vivo anaesthetic potency correlated strongly with the magnitude of reduction in SLE frequency in neocortical slices (R(2) 37.7 %, p = 0.002). Conversely, SLE frequency and length were significantly enhanced during exposure to both fluoroacetate (23 and 20 % increase, respectively, p < 0.01) and aminoadipate (12 and 38 % increase, respectively, p < 0.01 and p < 0.05). The capacity of an anaesthetic agent to reduce SLE frequency in the neocortical slice is a good indicator of its in vivo hypnotic potency. The results do not support the hypothesis that astrocytic metabolic inhibition is a mechanism of anaesthetic hypnosis.

No MeSH data available.


Related in: MedlinePlus

Scatterplot of the change in seizure-like event (SLE) frequency against in vivo hypnotic potency (mg/kg) for ketamine and each of the 21 ketamine analogues. Triangles are the non-ester analogues (including ketamine—circled); stars are the ester analogues. The three agents identified by arrows that were moderately potent hypnotics but did not induce a reduction in SLE frequency were either seizureogenic or had very rapid offset (<100 s)
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Fig1: Scatterplot of the change in seizure-like event (SLE) frequency against in vivo hypnotic potency (mg/kg) for ketamine and each of the 21 ketamine analogues. Triangles are the non-ester analogues (including ketamine—circled); stars are the ester analogues. The three agents identified by arrows that were moderately potent hypnotics but did not induce a reduction in SLE frequency were either seizureogenic or had very rapid offset (<100 s)

Mentions: A large range of hypnotic potencies were represented in the suite of ketamine-ester analogues, matched by equally variable slice SLE responses. Figure 1 plots the change in SLE frequency against in vivo hypnotic potency and shows a strong positive correlation (R2 37.7 %, p = 0.002)—indicating that the more potent hypnotics induced larger reductions in event frequency. The correlation was strongly driven by the non-ester analogues (R2 = 73 %, p = 0.01, n = 7), confirming that the relationship was based largely on drug pharmacodynamics, not the kinetics of ester break-down. Neither change in SLE length, nor amplitude correlated significantly with hypnotic potency (R2 5.7 and 0.3 %, respectively). The dose-dependent effect of propofol and etomidate on SLE frequency (Fig. 2) further indicates that the ability of an agent to reduce SLE frequency in the cortical slice is a good indicator of its hypnotic capacity in vivo. This is consistent with previous investigations showing that clinically used anaesthetics have in common the capacity to strongly reduce SLE frequency in cortical slices (Voss and Sleigh 2010; Voss et al. 2012). We reasoned that if inhibitory effects on astrocytes underpinned the ability of anaesthetics to induce hypnosis, then a measurable reduction in SLE frequency should be evident following blockade of astrocytic metabolism in the cortical slice.Fig. 1


Inhibition of astrocyte metabolism is not the primary mechanism for anaesthetic hypnosis.

Voss LJ, Harvey MG, Sleigh JW - Springerplus (2016)

Scatterplot of the change in seizure-like event (SLE) frequency against in vivo hypnotic potency (mg/kg) for ketamine and each of the 21 ketamine analogues. Triangles are the non-ester analogues (including ketamine—circled); stars are the ester analogues. The three agents identified by arrows that were moderately potent hypnotics but did not induce a reduction in SLE frequency were either seizureogenic or had very rapid offset (<100 s)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4940352&req=5

Fig1: Scatterplot of the change in seizure-like event (SLE) frequency against in vivo hypnotic potency (mg/kg) for ketamine and each of the 21 ketamine analogues. Triangles are the non-ester analogues (including ketamine—circled); stars are the ester analogues. The three agents identified by arrows that were moderately potent hypnotics but did not induce a reduction in SLE frequency were either seizureogenic or had very rapid offset (<100 s)
Mentions: A large range of hypnotic potencies were represented in the suite of ketamine-ester analogues, matched by equally variable slice SLE responses. Figure 1 plots the change in SLE frequency against in vivo hypnotic potency and shows a strong positive correlation (R2 37.7 %, p = 0.002)—indicating that the more potent hypnotics induced larger reductions in event frequency. The correlation was strongly driven by the non-ester analogues (R2 = 73 %, p = 0.01, n = 7), confirming that the relationship was based largely on drug pharmacodynamics, not the kinetics of ester break-down. Neither change in SLE length, nor amplitude correlated significantly with hypnotic potency (R2 5.7 and 0.3 %, respectively). The dose-dependent effect of propofol and etomidate on SLE frequency (Fig. 2) further indicates that the ability of an agent to reduce SLE frequency in the cortical slice is a good indicator of its hypnotic capacity in vivo. This is consistent with previous investigations showing that clinically used anaesthetics have in common the capacity to strongly reduce SLE frequency in cortical slices (Voss and Sleigh 2010; Voss et al. 2012). We reasoned that if inhibitory effects on astrocytes underpinned the ability of anaesthetics to induce hypnosis, then a measurable reduction in SLE frequency should be evident following blockade of astrocytic metabolism in the cortical slice.Fig. 1

Bottom Line: Subsequently, the effect of astrocyte metabolic inhibition was investigated in neocortical slices, and compared with that of the anaesthetic drugs.In vivo anaesthetic potency correlated strongly with the magnitude of reduction in SLE frequency in neocortical slices (R(2) 37.7 %, p = 0.002).The capacity of an anaesthetic agent to reduce SLE frequency in the neocortical slice is a good indicator of its in vivo hypnotic potency.

View Article: PubMed Central - PubMed

Affiliation: Anaesthesia Department, Waikato District Health Board, Pembroke St, Hamilton, 3240 New Zealand.

ABSTRACT
Astrocytes have been promoted as a possible mechanistic target for anaesthetic hypnosis. The aim of this study was to explore this using the neocortical brain slice preparation. The methods were in two parts. Firstly, multiple general anaesthetic compounds demonstrating varying in vivo hypnotic potency were analysed for their effect on "zero-magnesium" seizure-like event (SLE) activity in mouse neocortical slices. Subsequently, the effect of astrocyte metabolic inhibition was investigated in neocortical slices, and compared with that of the anaesthetic drugs. The rationale was that, if suppression of astrocytes was both necessary and sufficient to cause hypnosis in vivo, then inhibition of astrocytic metabolism in slices should mimic the anaesthetic effect. In vivo anaesthetic potency correlated strongly with the magnitude of reduction in SLE frequency in neocortical slices (R(2) 37.7 %, p = 0.002). Conversely, SLE frequency and length were significantly enhanced during exposure to both fluoroacetate (23 and 20 % increase, respectively, p < 0.01) and aminoadipate (12 and 38 % increase, respectively, p < 0.01 and p < 0.05). The capacity of an anaesthetic agent to reduce SLE frequency in the neocortical slice is a good indicator of its in vivo hypnotic potency. The results do not support the hypothesis that astrocytic metabolic inhibition is a mechanism of anaesthetic hypnosis.

No MeSH data available.


Related in: MedlinePlus