Folate deficiency increases postischemic brain injury.
OBJECTIVE
Folate deficiency and resultant hyperhomocysteinemia impair vascular function and increase stroke risk. We tested the hypothesis that folate deficiency and high homocysteine levels promote DNA damage and increase brain injury after cerebral ischemia/reperfusion.


METHODS
129/Sv mice, uracil-DNA glycosylase-deficient (Ung-/-) mice, and Ung+/+ littermate mice were exposed to a folate-deficient diet for 3 months and then subjected to 30-minute middle cerebral artery (MCA) occlusion and reperfusion. Plasma homocysteine levels and physiological parameters were measured in selected animals. Outcome measures were neurological sensorimotor deficits, infarct size measured by computer-assisted volumetry, and oxidative DNA damage measured by a colorimetric assay.


RESULTS
Exposure to a folate-deficient diet for 3 months conferred approximately 6- to 10-fold higher plasma homocysteine levels than those associated with a normal diet. Cerebral lesion volumes and neurological deficits after MCA occlusion and 72-hour reperfusion were significantly 2.1-fold increased in folate-deficient 129/SV wild-type mice compared with those associated with a normal diet, which could not be explained by obvious differences in physiological parameters. Abasic sites, hallmarks of oxidative DNA damage, were significantly increased in DNA from the ischemic brain of folate-deficient animals at early time points after MCA occlusion. Folate deficiency further increased brain lesion size in animals lacking uracil-DNA glycosylase compared with wild-type littermate mice.


CONCLUSIONS
Folate deficiency and resultant hyperhomocysteinemia are not only associated with increased stroke risk but increase oxidative DNA damage and ischemic lesion size after MCA occlusion/reperfusion.
Endres
Matthias
M
Department of Neurology, Charité Hospital, Humboldt University, Berlin, Germany. matthias.endres@charite.de
Ahmadi
Michael
M
Kruman
Inna
I
Biniszkiewicz
Detlev
D
Meisel
Andreas
A
Gertz
Karen
K
D000818:Animals; D001921:Brain / Q000473:pathology; D001930:Brain Injuries / Q000473:pathology*; D002545:Brain Ischemia / Q000473:pathology*; D003124:Colorimetry; D004249:DNA Damage; D005492:Folic Acid / Q000378:metabolism; D005494:Folic Acid Deficiency / Q000209:etiology / Q000473:pathology*; D006710:Homocysteine / Q000097:blood / Q000737:chemistry / Q000378:metabolism; D020138:Hyperhomocysteinemia / Q000473:pathology; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010100:Oxygen / Q000378:metabolism; D015424:Reperfusion; D015427:Reperfusion Injury; D012306:Risk; D020521:Stroke / Q000175:diagnosis; D013997:Time Factors; D051981:Uracil-DNA Glycosidase / Q000235:genetics
D006710:Homocysteine; D005492:Folic Acid; D051981:Uracil-DNA Glycosidase; D010100:Oxygen