title: NAD+ and nicotinamide: sex differences in cerebral ischemia.
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.
  
  
  OBJECTIVE
  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.
authors: Department of Neurology, The University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, United States.
authors: C S
authors: CS
authors: Siegel
authors: L D
authors: LD
authors: McCullough
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009243:NAD / Q000378:metabolism*; D009536:Niacinamide / Q000378:metabolism*; D010052:Ovariectomy; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D012727:Sex Characteristics; D013049:Spectrin / Q000378:metabolism; D013347:Subcellular Fractions / Q000201:enzymology
chemical_list: D009243:NAD; D013049:Spectrin; D009536:Niacinamide; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3
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