Mechanism of homocysteine‐induced dementia/spasm

Abstract

Although individuals with homozygous deficiency in cystathionine beta synthase (CBS), known as hyperhomocysteinemia, develop mental retardation and die in teens, the heterozygous live a normal life but develop vascular dementia (VA/spasm) and Alzheimer's disease (AD). The treatment with muscimol, a gamma amino butyric acid receptor‐A (GABA‐A) agonist, mitigates the AD syndrome. We tested the hypothesis that homocysteine (Hcy) antagonizes the GABA‐A receptor and behaves as an exitotoxic neurotransmitter and causes blood brain barrier (BBB) permeability and VA. The BBB permeability was measured by infusing evan's blue dye through tail vein. After three hours, excess dye was removed from blood circulation. The brain homogenates were prepared from GABA‐A (−/ −), CBS (−/+), CBS/GABA‐A double knockouts, and wild type (WT) mice in 50% trichloroacetic acid and the amount of evan's blue was measured on spectophotometer. To determine vascular dementia/spasm, carotid artery blood flow was measured by an ultrasonic flow meter. The level of Evans blue significantly increases in CBS/GABA‐A double knockouts > CBS(−/+) > GABA‐A (−/ −) > compared to WT. The carotid artery flows were 0.42 and 0.55 ml/min in GABA‐A (−/ −) and CBS/GABA‐A double knockouts, where as in WT it was 0.73 (ml/min). These results suggest that Hcy masks the GABA‐A receptor and decrease vascular flow causing (VA/spasm). In conclusion results are in coordination with increase in BBB permeability in cerebroventricle interstitium.