Neuroprotection against ischemia by metabolic inhibition revisited: A comparison of hypothermia, a pharmacologic cocktail and magnesium plus mexiletine

Kenneth I. Maynard, Alfredo Quinones-Hinojosa, Junaid Y. Malek

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13 Citations (Scopus)

Abstract

Previous studies have suggested that metabolic inhibition is neuroprotective, but little evidence has been provided to support this proposal. Using the in vitro rabbit retina preparation as an established model of the central nervous system (CNS), we measured the rate of glucose utilization and lactate production, and the light-evoked compound action potentials (CAPs) as indices of neuronal energy metabolism and electrophysiologic function, respectively. We examined the effect of three (3) treatments options: hypothermia (i.e., 33°C acid 30°C), a six-member pharmacologic 'cocktail' (tetrodotoxin (0.1 μM), 2-amino-4-phosphonobutyric acid (20 μM), 2-amino-5-phosphonovaleric acid (1 mM), amiloride (1 mM), magnesium (10 mM) and lithium (10 mM)) and the combination of magnesium (Mg2+ 1 mM) and mexiletine (Mex, 300 μM) on in vitro rabbit retinas, to see if there is a correlation between neuronal energy metabolism during ischemia (simulated by the reduction of oxygen from 95% to 15% and glucose from 6 mM to 1 mM), and the subsequent recovery of function. Hypothermia and the 'cocktail' significantly inhibited both the rate of glucose utilization and lactate production, whereas Mg2+ and/or Mex showed only a nonsignificant tendency toward a reduction, compared to control retinas. Recovery of light-evoked CAPs was significantly improved in hypothermia- and cocktail-treated retinas, as well as with retinas exposed to the combination of Mg2+ plus Mex, but not with Mg2+ or Mex alone, relative to control retinas. A linear regression analysis of the % recovery of function versus the % reduction in the rate of glucose utilization during ischemia showed a significant correlation (r2 = 0.80, correlation coefficient = 0.9, p < 0.05) between these two parameters. This and other data discussed provide convincing evidence that there is a correlation between metabolic inhibition, achieved during ischemia, and neuroprotection.

Original languageEnglish (US)
Pages (from-to)240-254
Number of pages15
JournalAnnals of the New York Academy of Sciences
Volume890
StatePublished - 1999
Externally publishedYes

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Hypothermia
Mexiletine
Magnesium
Retina
Ischemia
Glucose
Recovery
Lactic Acid
Recovery of Function
2-Amino-5-phosphonovalerate
Energy Metabolism
Action Potentials
Amiloride
Tetrodotoxin
Neurology
Lithium
Linear regression
Regression analysis
Rabbits
Light

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

Cite this

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title = "Neuroprotection against ischemia by metabolic inhibition revisited: A comparison of hypothermia, a pharmacologic cocktail and magnesium plus mexiletine",
abstract = "Previous studies have suggested that metabolic inhibition is neuroprotective, but little evidence has been provided to support this proposal. Using the in vitro rabbit retina preparation as an established model of the central nervous system (CNS), we measured the rate of glucose utilization and lactate production, and the light-evoked compound action potentials (CAPs) as indices of neuronal energy metabolism and electrophysiologic function, respectively. We examined the effect of three (3) treatments options: hypothermia (i.e., 33°C acid 30°C), a six-member pharmacologic 'cocktail' (tetrodotoxin (0.1 μM), 2-amino-4-phosphonobutyric acid (20 μM), 2-amino-5-phosphonovaleric acid (1 mM), amiloride (1 mM), magnesium (10 mM) and lithium (10 mM)) and the combination of magnesium (Mg2+ 1 mM) and mexiletine (Mex, 300 μM) on in vitro rabbit retinas, to see if there is a correlation between neuronal energy metabolism during ischemia (simulated by the reduction of oxygen from 95{\%} to 15{\%} and glucose from 6 mM to 1 mM), and the subsequent recovery of function. Hypothermia and the 'cocktail' significantly inhibited both the rate of glucose utilization and lactate production, whereas Mg2+ and/or Mex showed only a nonsignificant tendency toward a reduction, compared to control retinas. Recovery of light-evoked CAPs was significantly improved in hypothermia- and cocktail-treated retinas, as well as with retinas exposed to the combination of Mg2+ plus Mex, but not with Mg2+ or Mex alone, relative to control retinas. A linear regression analysis of the {\%} recovery of function versus the {\%} reduction in the rate of glucose utilization during ischemia showed a significant correlation (r2 = 0.80, correlation coefficient = 0.9, p < 0.05) between these two parameters. This and other data discussed provide convincing evidence that there is a correlation between metabolic inhibition, achieved during ischemia, and neuroprotection.",
author = "Maynard, {Kenneth I.} and Alfredo Quinones-Hinojosa and Malek, {Junaid Y.}",
year = "1999",
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T2 - A comparison of hypothermia, a pharmacologic cocktail and magnesium plus mexiletine

AU - Maynard, Kenneth I.

AU - Quinones-Hinojosa, Alfredo

AU - Malek, Junaid Y.

PY - 1999

Y1 - 1999

N2 - Previous studies have suggested that metabolic inhibition is neuroprotective, but little evidence has been provided to support this proposal. Using the in vitro rabbit retina preparation as an established model of the central nervous system (CNS), we measured the rate of glucose utilization and lactate production, and the light-evoked compound action potentials (CAPs) as indices of neuronal energy metabolism and electrophysiologic function, respectively. We examined the effect of three (3) treatments options: hypothermia (i.e., 33°C acid 30°C), a six-member pharmacologic 'cocktail' (tetrodotoxin (0.1 μM), 2-amino-4-phosphonobutyric acid (20 μM), 2-amino-5-phosphonovaleric acid (1 mM), amiloride (1 mM), magnesium (10 mM) and lithium (10 mM)) and the combination of magnesium (Mg2+ 1 mM) and mexiletine (Mex, 300 μM) on in vitro rabbit retinas, to see if there is a correlation between neuronal energy metabolism during ischemia (simulated by the reduction of oxygen from 95% to 15% and glucose from 6 mM to 1 mM), and the subsequent recovery of function. Hypothermia and the 'cocktail' significantly inhibited both the rate of glucose utilization and lactate production, whereas Mg2+ and/or Mex showed only a nonsignificant tendency toward a reduction, compared to control retinas. Recovery of light-evoked CAPs was significantly improved in hypothermia- and cocktail-treated retinas, as well as with retinas exposed to the combination of Mg2+ plus Mex, but not with Mg2+ or Mex alone, relative to control retinas. A linear regression analysis of the % recovery of function versus the % reduction in the rate of glucose utilization during ischemia showed a significant correlation (r2 = 0.80, correlation coefficient = 0.9, p < 0.05) between these two parameters. This and other data discussed provide convincing evidence that there is a correlation between metabolic inhibition, achieved during ischemia, and neuroprotection.

AB - Previous studies have suggested that metabolic inhibition is neuroprotective, but little evidence has been provided to support this proposal. Using the in vitro rabbit retina preparation as an established model of the central nervous system (CNS), we measured the rate of glucose utilization and lactate production, and the light-evoked compound action potentials (CAPs) as indices of neuronal energy metabolism and electrophysiologic function, respectively. We examined the effect of three (3) treatments options: hypothermia (i.e., 33°C acid 30°C), a six-member pharmacologic 'cocktail' (tetrodotoxin (0.1 μM), 2-amino-4-phosphonobutyric acid (20 μM), 2-amino-5-phosphonovaleric acid (1 mM), amiloride (1 mM), magnesium (10 mM) and lithium (10 mM)) and the combination of magnesium (Mg2+ 1 mM) and mexiletine (Mex, 300 μM) on in vitro rabbit retinas, to see if there is a correlation between neuronal energy metabolism during ischemia (simulated by the reduction of oxygen from 95% to 15% and glucose from 6 mM to 1 mM), and the subsequent recovery of function. Hypothermia and the 'cocktail' significantly inhibited both the rate of glucose utilization and lactate production, whereas Mg2+ and/or Mex showed only a nonsignificant tendency toward a reduction, compared to control retinas. Recovery of light-evoked CAPs was significantly improved in hypothermia- and cocktail-treated retinas, as well as with retinas exposed to the combination of Mg2+ plus Mex, but not with Mg2+ or Mex alone, relative to control retinas. A linear regression analysis of the % recovery of function versus the % reduction in the rate of glucose utilization during ischemia showed a significant correlation (r2 = 0.80, correlation coefficient = 0.9, p < 0.05) between these two parameters. This and other data discussed provide convincing evidence that there is a correlation between metabolic inhibition, achieved during ischemia, and neuroprotection.

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