Attenuation of hyperhomocysteinemia induced vascular dementia by sodium orthovanadate perhaps via PTP1B: Pertinent downstream outcomes

摘要

Vascular dementia (VaD) is the second most common form of dementia after Alzheimer's disease, but drug regulatory authorities have not approved any effective medication for this indication. Researchers are keenly aware of the need to uncover precise and druggable targets for VaD. However, finding such a target is an experimentally impractical and challenging task, owing to the highly complex interplay between cognitive and functional abilities of the brain with a diversity of vascular diseases that usually results from various underlying risk factors. Network pharmacology, may, therefore be an alternative and rational choice because a network of disease targets let researchers select the best target from a disease module. According to this approach, inhibition of protein tyrosine phosphatase 1B (PTP1B) may trigger downstream effects of VaD relevance, but specific inhibitors of this enzyme are currently not in medical use. To assess whether PTP1B mediated actions are possible and are relevant to VaD or not, the impact of sodium orthovanadate on homocysteine-induced endothelial dysfunction, oxidative stress, cholinergic dysfunction learning and memory impairments investigated. The visual, spatial, emotional and fear-motivated learning, and memory impairment assessed by object recognition, water maze, step-through and elevated plus maze task, respectively. These impairments significantly attenuated by sodium orthovanadate, therefore, downstream effects seems to be relevant, and the role of PTP1B is suspected. However, sodium orthovanadate is a non-specific inhibitor of PTP1B; therefore, further in-vivo validation warranted, and it is possible in future because specific PTP1B inhibitors are in development phase.