† These authors contributed equally.
Vascular dementia is the second most common type of dementia, yet no effective treatment for it exists. Akt and Erk1/2 signaling pathways are involved in neuronal survival. It has been reported that bisperoxovanadium (pyridin-2-squaramide), a novel squaramide compound, protects against cerebral ischemia injury via activation of Akt and Erk1/2. Here, the potential neuroprotective effect of bisperoxovanadium is shown for the first time in a model of vascular dementia induced in 6-month-old male Sprague-Dawley rats by two-vessel occlusion injury applied to 6-month-old. Following this lesion, bisperoxovanadium (pyridin-2-squaramide) (1 mg/kg/day) was intragastrically administered for four successive weeks. The Morris water maze test estimated cognitive function. The morphological examination was performed by hematoxylin-eosin staining. Akt and Erk1/2 protein abundance were assessed by Western blot. Results showed that bisperoxovanadium (pyridin-2-squaramide) attenuated not only cognitive dysfunction but also alleviated histopathological changes in rats with vascular dementia. Moreover, bisperoxovanadium (pyridin-2-squaramide) ultimately reduced neuronal apoptosis represented by the Bax/Bcl-2 ratio in the CA1 (cornu ammonis 1) region of the hippocampus. Importantly, the levels of p-Akt (ser473) and p-Erk1/2 (Thr202/Tyr204) were increased after treatment with bisperoxovanadium (pyridin-2-squaramide). It is concluded that the novel squaramide compound bisperoxovanadium (pyridin-2-squaramide) might be effective in the treatment of vascular dementia by activation of Akt and Erk1/2.