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Glyoxalase‐1 gene transfer prevents cerebral deficits in rats with type 1 diabetes (841.9)
Author(s) -
Alomar Fadhel,
Shao Chun,
Xia Jianxun,
Xiong Huangui,
Mayhan William,
Bidasee Keshore
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.841.9
Subject(s) - methylglyoxal , downregulation and upregulation , medicine , diabetes mellitus , type 1 diabetes , glycation , endocrinology , neuroscience , chemistry , psychology , gene , enzyme , biochemistry
Background: Individuals with type 1 diabetes (T1D) confront daily challenges including reduction in sustained attention, decreased decision‐making abilities and increased risks for accidents. Studies attribute these insufficiencies in part to reduced psychomotor efficiency, slowing in information processing speed, impaired visuo‐construction and cerebral vascular dysfunction. To date, the molecular cues responsible for these cerebral deficits in T1D remain poorly defined. Here we investigated whether the reactive carbonyl species methylglyoxal (MGO), whose production is upregulated in T1D, is an underlying cause. Methods and results: Brain levels of MGO were 6 times higher in T1D compared to non‐diabetic rats. Chronic administration of MGO to control rats impaired their nest building capabilities, an activity that requires decision‐making, visual and motor functions. MGO treatment also impaired endothelial‐mediated vasodilatation of cerebral microvessels, induced localized microvascular leakages, astrocytes activation and impaired synaptic transmission, akin to that seen in T1D. Increasing expression of the MGO‐degrading enzyme glyoxalase‐1 (Glo‐1) in rats after the onset of diabetes using an adeno‐associated viral construct, decreased brain MGO level and blunted cerebral impairments induced by T1D. Conclusion: From these data we conclude that upregulation of MGO is an underlying cause for cerebral deficits in T1D and MGO detoxification is sufficient to prevent these cerebral dysfunctions.