TY - JOUR
T1 - Effect of acute mitochondrial dysfunction on hyperexcitable network activity in rat hippocampus in vitro
AU - Andreasen, Mogens
AU - Nedergaard, Steen
PY - 2021/1
Y1 - 2021/1
N2 - Metabolic stress imposed by epileptic seizures can result in mitochondrial dysfunction, believed to act as positive feedback on epileptogenesis and seizure susceptibility. As the mechanism behind this positive feedback is unclear, the aim of the present study was to investigate the causal link between acute mitochondrial dysfunction and increased seizure susceptibility in hyperexcitable hippocampal networks. Following the induction of spontaneous interictal-like discharges, acute selective pharmacological blockade of either of the mitochondrial respiratory complexes (MRC) I-IV induced seizure-like events (SLE) in 78–100% of experiments. A similar result was obtained by uncoupling the oxidative phosphorylation (OXPHOS) but not by selective blockade of MRCV (ATP synthase) which did not induce SLE. The reactive oxygen species (ROS) scavenger 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (tempol, 2 mM) significantly reduced the proconvulsant effect of blocking MRCI but did not reduce the proconvulsant effect of OXPHOS uncoupling. These findings indicate that acute mitochondrial dysfunction can lead to a convulsive state within a short timeframe, and that increased ROS production makes substantial contribution to such induction in addition to other mitochondrial related factors, which appears to be independent of changes in ROS and ATP production.
AB - Metabolic stress imposed by epileptic seizures can result in mitochondrial dysfunction, believed to act as positive feedback on epileptogenesis and seizure susceptibility. As the mechanism behind this positive feedback is unclear, the aim of the present study was to investigate the causal link between acute mitochondrial dysfunction and increased seizure susceptibility in hyperexcitable hippocampal networks. Following the induction of spontaneous interictal-like discharges, acute selective pharmacological blockade of either of the mitochondrial respiratory complexes (MRC) I-IV induced seizure-like events (SLE) in 78–100% of experiments. A similar result was obtained by uncoupling the oxidative phosphorylation (OXPHOS) but not by selective blockade of MRCV (ATP synthase) which did not induce SLE. The reactive oxygen species (ROS) scavenger 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (tempol, 2 mM) significantly reduced the proconvulsant effect of blocking MRCI but did not reduce the proconvulsant effect of OXPHOS uncoupling. These findings indicate that acute mitochondrial dysfunction can lead to a convulsive state within a short timeframe, and that increased ROS production makes substantial contribution to such induction in addition to other mitochondrial related factors, which appears to be independent of changes in ROS and ATP production.
KW - Epileptic seizure
KW - Hippocampus
KW - Mitochondria
KW - Oxidative phosphorylation
KW - Oxidative stress
KW - Reactive oxygen species
UR - http://www.scopus.com/inward/record.url?scp=85095828334&partnerID=8YFLogxK
U2 - 10.1016/j.brainres.2020.147193
DO - 10.1016/j.brainres.2020.147193
M3 - Journal article
C2 - 33157100
SN - 0006-8993
VL - 1751
JO - Brain Research
JF - Brain Research
M1 - 147193
ER -