Barbiturates Induce Mitochondrial Depolarization and Potentiate Excitotoxic Neuronal Death

Anderson, Christopher M.; Norquist, Becky A.; Vesce, Sabino; Nicholls, David G.; Soine, William H.; Duan, Shumin; Swanson, Raymond A.

doi:10.1523/jneurosci.22-21-09203.2002

Cited by 40 publications

(27 citation statements)

References 41 publications

(53 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In cells or subcellular fractions with active glycolysis, respiratory chain inhibition at complex I to IV will therefore cause only a partial depolarization, because ATP synthase reversal at complex V can maintain a suboptimal '< m (27). In the present thesis, the finding of a considerably more depolarized mitochondrial membrane during isoflurane and sevoflurane (paper II) experiments when complex V was blocked indicates that the mitochondrial membrane was sufficiently depolarized by the anaesthetics to partly reverse the function of ATP synthase at complex V. These findings in presynaptic terminals are in coherence with the effect of barbiturates on neural mitochondria in rat cortical neural cultures (86).…”

Section: The Effects Of Volatile Anaesthetics On the Electron Transposupporting

confidence: 80%

Sevoflurane depolarizes pre‐synaptic mitochondria in the central nervous system

Moe¹,

Bains²,

Vinje³

et al. 2004

Acta Anaesthesiol Scand

View full text Add to dashboard Cite

Background: Volatile anaesthetics protect the heart from ischaemic injury by activating mitochondrial signalling pathways. The aim of this study was to test whether sevoflurane, which is increasingly used in neuroanaesthesia, affects mitochondrial function in the central nervous system by altering the mitochondrial membrane potential (ΔΨm).Methods: In order to correlate free cytosolic Ca2+ ([Ca2+]i) and ΔΨm, rat neural presynaptic terminals (synaptosomes) were loaded with the fluorescent probes fura‐2 and JC‐1. During sevoflurane exposure, 4‐aminopyridine (4‐AP) 500 µM to induce pre‐synaptic membrane depolarization or carbonylcyanide‐p‐(trifluoromethoxy)‐phenylhydrazone (FCCP) 1 µM to induce maximum mitochondrial depolarization was added. In order to block mitochondrial ATP‐regulated K+‐channels (mitoKATP), the antagonist 5‐hydroxydecanoate (5‐HD) 500 µM was added.Results: In Ca2+‐containing medium, both sevoflurane 1 and 2 MAC gradually decreased the normalized JC‐1 ratio from 0.96 ± 0.01 in control to 0.92 ± 0.01 and 0.89 ± 0.01, representing a depolarization of ΔΨm (n = 9, P < 0.05). Sevoflurane 2 MAC increased [Ca2+]i. In Ca2+‐depleted medium, sevoflurane 1 and 2 MAC depolarized ΔΨm, while [Ca2+]i remained unaltered. Sevoflurane 2 MAC attenuated the 4‐AP‐induced depolarization of ΔΨm. When mitoKATP was blocked, the sevoflurane‐induced depolarization of ΔΨm was attenuated, but not blocked. The depolarizing effect of sevoflurane on ΔΨm compared with FCCP was calculated to 13.2 ± 1.3% in Ca2+‐containing and 15.1 ± 1.2% in Ca2+‐depleted medium (n = 7).Conclusions: Sevoflurane depolarizes ΔΨm in rat synaptosomes, and the effect is not dependent on Ca2+‐influx to the cytosol. Opening of mitoKATP is partly responsible for the depolarizing effect of sevoflurane.

show abstract

Section: The Effects Of Volatile Anaesthetics On the Electron Transposupporting

confidence: 80%

Sevoflurane depolarizes pre‐synaptic mitochondria in the central nervous system

Moe¹,

Bains²,

Vinje³

et al. 2004

Acta Anaesthesiol Scand

View full text Add to dashboard Cite

show abstract

“…12 Overload of mtCa 2þ is a key event in developing IR injury. mt [Ca 2þ ] overload after ischaemia can contribute to ETC damage, 34,35 mitochondrial membrane depolarization, 36 uncoupling of oxidative phosphorylation, and impaired ATP synthesis. 37 These events impair the ability of mitochondria to resist Ca 2þ -induced opening of the mitochondrial permeability transition pore (MPTP).…”

Section: Discussionmentioning

confidence: 99%

WITHDRAWN: Inhibited mitochondrial respiration by amobarbital during cardiac ischemia improves redox state and reduces matrix Ca2+ overload and ROS release☆

Aldakkak

Stowe

Chen

et al. 2007

Cardiovascular Research

173

View full text Add to dashboard Cite

Aim Damage to the mitochondrial electron transport chain (ETC) occurs during ischaemia. Blockade of electron flow in the ETC just before ischaemia with the reversible complex I inhibitor amobarbital protects isolated mitochondria against ischaemic damage and preserves oxidative phosphorylation and cytochrome c content. We hypothesized that brief amobarbital perfusion just before ischaemia would improve cardiac recovery and decrease infarct size after ischaemia and reperfusion (IR) ] were significantly reduced, NADH-FAD redox state was preserved and cardiac function was markedly improved in the amobarbital group; infarct size was smaller in the amobarbital group compared to the untreated group. Conclusion Temporary blockade of mitochondrial complex I activity by amobarbital protects hearts by reducing production of O 2 2 † and mtCa 2þ loading during IR injury.

show abstract

“…To derive P s , we fitted E tot to measured CMR glc(ox) data for each state, whereas to derive P ns , we fitted E ns to measured CMR glc(ox) data for pentobarbital. Because barbiturates may also inhibit mitochondrial respiration (41) and if so, could lead to an overestimate of P ns , we fitted the data in Fig. 1B with and without the isoelectric pentobarbital data and found negligible differences in the slope, intercept, and goodness of fit [rat data: CMR glc(ox) = 0.92 neuronal activity (NA) + 0.13, R 2 = 0.97 with pentobarbital and CMR glc(ox) = 0.94 NA + 0.11, R 2 = 0.93 without pentobarbital].…”

Section: Glial Energy Demand and Excitatory Vs Inhibitory Neuronal Ementioning

confidence: 99%

Cortical energy demands of signaling and nonsignaling components in brain are conserved across mammalian species and activity levels

Hyder

Rothman

Bennett

2013

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

220

219

View full text Add to dashboard Cite

The continuous need for ion gradient restoration across the cell membrane, a prerequisite for synaptic transmission and conduction, is believed to be a major factor for brain's high oxidative demand. However, do energy requirements of signaling and nonsignaling components of cortical neurons and astrocytes vary with activity levels and across species? We derived oxidative ATP demand associated with signaling (P s ) and nonsignaling (P ns ) components in the cerebral cortex using species-specific physiologic and anatomic data. In rat, we calculated glucose oxidation rates from layer-specific neuronal activity measured across different states, spanning from isoelectricity to awake and sensory stimulation. We then compared these calculated glucose oxidation rates with measured glucose metabolic data for the same states as reported by 2-deoxy-glucose autoradiography. Fixed values for P s and P ns were able to predict the entire range of states in the rat. We then calculated glucose oxidation rates from human EEG data acquired under various conditions using fixed P s and P ns values derived for the rat. These calculated metabolic data in human cerebral cortex compared well with glucose metabolism measured by PET. Independent of species, linear relationship was established between neuronal activity and neuronal oxidative demand beyond isoelectricity. Cortical signaling requirements dominated energy demand in the awake state, whereas nonsignaling requirements were ∼20% of awake value. These predictions are supported by 13 C magnetic resonance spectroscopy results. We conclude that mitochondrial energy support for signaling and nonsignaling components in cerebral cortex are conserved across activity levels in mammalian species.T he brain is one of the most energy demanding tissues in the body (1). 13 C magnetic resonance spectroscopy (MRS) in the rat has shown that, in the resting awake state, ∼80% of cortical energy consumption is used to support signaling as reflected by the rate of glutamate neurotransmitter release and astroglial uptake (2, 3). Cerebral energy demand is also positively correlated with the rate of pyramidal neuron firing in rat cortex (4, 5). 13 C MRS findings in the human cortex have been generally consistent with the rat results (6). However, there remain questions as to how well the energy costs of specific subcellular processes needed to support synaptic transmission and conduction are conserved over different activity levels and/or across species.Recent bottom-up energy budgets for gray matter in the mammalian brain have attempted to understand the energetic costs of neuronal and glial electrical and neurotransmission events occurring in the neuropil (7,8) by calculating the ATP used per neuron for signaling (P s ) and nonsignaling (P ns ) events. In the awake cortex, the total ATP used per unit cortical volume per unit time (E tot ; in units of ATP/s per centimeter 3 ) was determined by multiplying the P s (in units of ATP/neuron per spike) and P ns (in units of ATP/neuron per second) parameter...

show abstract

Barbiturates Induce Mitochondrial Depolarization and Potentiate Excitotoxic Neuronal Death

Cited by 40 publications

References 41 publications

Sevoflurane depolarizes pre‐synaptic mitochondria in the central nervous system

Sevoflurane depolarizes pre‐synaptic mitochondria in the central nervous system

WITHDRAWN: Inhibited mitochondrial respiration by amobarbital during cardiac ischemia improves redox state and reduces matrix Ca2+ overload and ROS release☆

Cortical energy demands of signaling and nonsignaling components in brain are conserved across mammalian species and activity levels

Contact Info

Product

Resources

About