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.2013 May 1:237:223-31.
doi: 10.1016/j.neuroscience.2013.01.068. Epub 2013 Feb 9.

NAD+ and nicotinamide: sex differences in cerebral ischemia

Affiliations

NAD+ and nicotinamide: sex differences in cerebral ischemia

C S Siegel et al. Neuroscience..

Abstract

Background: Previous literature suggests that cell death pathways activated after cerebral ischemia differ between the sexes. While caspase-dependent mechanisms predominate in the female brain, caspase-independent cell death induced by the activation of poly(ADP-ribose) polymerase (PARP) predominates in the male brain. PARP-1 gene deletion decreases infarction volume in the male brain, but paradoxically increases damage in PARP-1 knockout females.

Purpose: This study examined stroke-induced changes in NAD+, a key energy molecule involved in PARP-1 activation in both sexes.

Methods: Mice were subjected to middle cerebral artery occlusion and NAD+ levels were assessed. Caspase-3 activity and nuclear translocation were assessed 6h after ischemia. In additional cohorts, Nicotinamide (500 mg/kg i.p.) a precursor of NAD+ or vehicle was administered and infarction volume was measured 24h after ischemia.

Results: Males have higher baseline NAD+ levels than females. Significant stroke-induced NAD+ depletion occurred in males and ovariectomized females but not in intact females. PARP-1 deletion prevented the stroke-induced loss in NAD+ in males, but worsened NAD+ loss in PARP-1 deficient females. Preventing NAD+ loss with nicotinamide reduced infarct in wild-type males and PARP-1 knockout mice of both sexes, with no effect in WT females. Caspase-3 activity was significantly increased in PARP-1 knockout females compared to males and wild-type females, this was reversed with nicotinamide.

Conclusions: Sex differences exist in baseline and stroke-induced NAD+ levels. Nicotinamide protected males and PARP knockout mice, but had minimal effects in the wild-type female brain. This may be secondary to differences in energy metabolism between the sexes.

Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

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Figures

Figure 1
Figure 1. Sex Differences in NAD+ Levels
NAD+ levels were analyzed 60 minutes after ischemic onset in male, female, and ovx female WT (A) and PARP-1−/− (B) mice (n=8/group: p<0.05). Stroke-induced NAD+ depletion was seen in WT males, and WT Ovx females. PARP-1−/− males maintained their NAD+ levels, while PARP-1−/− females experienced a loss of NAD+ after stroke. NAD+ levels were analyzed 30 minutes after reperfusion in male, female, and Ovx female WT (C) and PARP-1−/− (D) mice (n=8/group: p<0.05). Stroke-induced NAD+ depletion was seen in WT males. PARP-1−/− males maintained their NAD+ levels in all sexes after stroke.
Figure 2
Figure 2. Sex Differences in Response to Nicotinamide Treatment
Nicotinamide was administered i.p. (500mg/kg) 20 minutes before MCAO to male, female, and Ovx female WT and PARP-1−/− mice (n=10/group: p<0.05). Infarction volume was measured 24 hours after ischemia. Nicotinamide was protective in WT males, PARP-1−/− males, and PARP-1−/− females.
Figure 3
Figure 3. Sex Differences in Caspase-3 Activity
(A) Wildtype male and female cytosolic fractions 6 hours after 90 minute MCAO were probed for caspase activity using αII-Spectrin cleavage (150kDa). MIF was utilized a cytosolic purity and loading control. Females exhibited increased caspase activity compared to males after stroke. (B) Wildtype nuclear fractions 6 hours after 90 minute MCAO were probed for caspase-3 with Histone as a nuclear purity and loading control. Females exhibited a stroke-induced increase in nuclear caspase-3 compared to males. (C) PARP-1−/− females had increased caspase activity and nuclear caspase-3 (D) as compared to the ischemic male brain.
Figure 4
Figure 4. Nicotinamide Alters Caspase Activity in Females
(A) Vehicle treated female WT and PARP-1−/− cytosolic fractions 6 hours after 90 minute MCAO were probed for caspase activity using αII-Spectrin cleavage (150kDa). MIF was utilized a cytosolic purity and loading control. PARP-1−/− females exhibited increased caspase activity compared to WT females after stroke. (B) Vehicle treated female nuclear fractions 6 hours after 90 minute MCAO were probed for caspase-3 with Histone as a purity and loading control. PARP-1−/− females exhibited a stroke-induced increase in nuclear caspase-3 compared to WT. (C) Nicotinamide treated WT and PARP-1−/− females illustrated equivalent caspase activity and nuclear caspase-3 (D).
Figure 5
Figure 5. Sex Differences in Caspase-3 Activity in PARP-1−/−
(A) Male WT and PARP-1−/− cytosolic fractions 6 hours after 90 minute MCAO were probed for caspase activity using αII-Spectrin cleavage (150kDa). MIF was utilized a cytosolic purity and loading control. No difference in caspase activity was found between male WT and PARP-1−/− animals. (B) Male WT and PARP-1−/− nuclear fractions 6 hours after 90 minute MCAO were probed for caspase-3 with Histone as a purity and loading control. Equivalent nuclear caspase-3 was observed in both groups. (C) Nicotinamide treated PARP-1−/− females exhibited a stroke-induced decrease in caspase activity, and nuclear caspase-3 (D) as compared to vehicle treated PARP-1−/− females.
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