"Abstract
Ketone bodies (KB) have been shown to
prevent neurodegeneration in models of Parkinson’s and Alzheimer’s diseases,
but the mechanisms underlying these effects remain unclear. One possibility is
that KB may exert antioxidant activity. In the current study, we explored the
effects of KB on rat neocortical neurons exposed to hydrogen peroxide (H2O2) or diamide – a thiol oxidant
and activator of mitochondrial permeability transition (mPT). We found that:
(i) KB completely blocked large inward currents induced by either H2O2 or diamide; (ii) KB
significantly decreased the number of propidium iodide-labeled cells in
neocortical slices after exposure to H2O2 or diamide; (iii) KB significantly decreased
reactive oxygen species (ROS) levels in dissociated neurons and in isolated
neocortical mitochondria; (iv) the electrophysiological effects of KB in
neurons exposed to H2O2 or diamide were mimicked by bongkrekic acid and cyclosporin A, known
inhibitors of mPT, as well as by catalase and DL – dithiothreitol, known
antioxidants; (v) diamide alone did not significantly alter basal ROS levels in
neurons, supporting previous studies indicating that diamide-induced neuronal
injury may be mediated by mPT opening; and (vi) KB significantly increased the
threshold for calcium-induced mPT in isolated mitochondria. Taken together, our
data suggest that KB may prevent mPT and oxidative injury in neocortical
neurons, most likely by decreasing mitochondrial ROS production."
prevent neurodegeneration in models of Parkinson’s and Alzheimer’s diseases,
but the mechanisms underlying these effects remain unclear. One possibility is
that KB may exert antioxidant activity. In the current study, we explored the
effects of KB on rat neocortical neurons exposed to hydrogen peroxide (H2O2) or diamide – a thiol oxidant
and activator of mitochondrial permeability transition (mPT). We found that:
(i) KB completely blocked large inward currents induced by either H2O2 or diamide; (ii) KB
significantly decreased the number of propidium iodide-labeled cells in
neocortical slices after exposure to H2O2 or diamide; (iii) KB significantly decreased
reactive oxygen species (ROS) levels in dissociated neurons and in isolated
neocortical mitochondria; (iv) the electrophysiological effects of KB in
neurons exposed to H2O2 or diamide were mimicked by bongkrekic acid and cyclosporin A, known
inhibitors of mPT, as well as by catalase and DL – dithiothreitol, known
antioxidants; (v) diamide alone did not significantly alter basal ROS levels in
neurons, supporting previous studies indicating that diamide-induced neuronal
injury may be mediated by mPT opening; and (vi) KB significantly increased the
threshold for calcium-induced mPT in isolated mitochondria. Taken together, our
data suggest that KB may prevent mPT and oxidative injury in neocortical
neurons, most likely by decreasing mitochondrial ROS production."
Kim, D. Y., Davis, L. M., Sullivan, P. G., Maalouf, M., Simeone, T. A., Brederode, J. v. and Rho, J. M. (2007), Ketone bodies are protective against oxidative stress in neocortical neurons. Journal of Neurochemistry, 101: 1316–1326. doi:10.1111/j.1471-4159.2007.04483.x
