Etidronate-zinc Complex Ameliorated Cognitive and Synaptic Plasticity Impairments in 2-Vessel Occlusion Model Rats by Reducing Neuroinflammation

As one of the bisphosphonate derivatives, etidronate has proved to be beneficial to spatial learning and memory deficits caused by two-vessel occlusion (2-VO). In this study, the novel drug etidronate-zinc complex (Eti-Zn) was used to detect its role in synaptic plasticity and learning and memory functions in a rat model of 2-VO. Chronic cerebral hypoperfusion was induced by permanent occlusion of the common carotid artery bilaterally in adult Sprague-Dawley rats. Eti-Zn (20 mg/kg/day, tail vein injection) was administered for 7 days after a two-week operation. After treatment, a series of tests were carried out. Here, we found that Eti-Zn could reduce spatial learning and memory impairments in 2-VO model rats via the Morris water maze test. We also found that animals treated with Eti-Zn showed preference for the new-object in the novel object recognition test. In addition, the long-term potentiation and depotentiation from the Schaffer collaterals to the CA1 region in the hippocampus were enhanced by Eti-Zn treatment in 2-VO model rats. Furthermore, Eti-Zn significantly up-regulated NMDA receptor (NR) 2A, NR2B, postsynaptic density protein 95 and synaptophysin levels and prevented the destruction of dendritic spines. Moreover, Eti-Zn treatment reduced both the over-activation of microglia and the expressions of neuroinflammatory cytokines (TNF-α, IL-1β and IL-6) in the hippocampus. The increased NF-κB signaling pathway in the hippocampus of 2-VO rats was reversed after Eti-Zn treatment. In summary, these findings suggest that Eti-Zn could ameliorate the synaptic plasticity and cognitive impairments by reducing neuroinflammation in 2-VO model rats.