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Valid experimental models and behavioral tests are indispensable for the development of therapies for stroke. The translational failure with neuroprotective drugs has forced us to look for alternative approaches. Restorative therapies aiming to facilitate the recovery process by pharmacotherapy or cell-based therapy have emerged as promising options. Here we describe the most common stroke models used in cell-based therapy studies with particular emphasis on their inherent complications, which may affect behavioral outcome. Loss of body weight, stress, hyperthermia, immunodepression, and infections particularly after severe transient middle cerebral artery occlusion (filament model) are recognized as possible confounders to impair performance in certain behavioral tasks and bias the treatment effects. Inherent limitations of stroke models should be carefully considered when planning experiments to ensure translation of behavioral data to the clinic.

Alzheimer's disease (AD) and cerebral ischaemia share similar features in terms of altered amyloid precursor protein (APP) processing and β-amyloid (Aβ) accumulation. We have previously shown that Aβ and calcium deposition, and β-secretase activity, are robustly increased in the ipsilateral thalamus after transient middle cerebral artery occlusion (MCAO) in rats. Here, we investigated whether the non-selective calcium channel blocker bepridil, which also inhibits β-secretase cleavage of APP, affects thalamic accumulation of Aβ and calcium and in turn influences functional recovery in rats subjected to MCAO. A 27-day bepridil treatment (50 mg/kg, p.o.) initiated 2 days after MCAO significantly decreased the levels of soluble Aβ40, Aβ42 and calcium in the ipsilateral thalamus, as compared with vehicle-treated MCAO rats. Expression of seladin-1/DHCR24 protein, which is a potential protective factor against neuronal damage, was decreased at both mRNA and protein levels in the ipsilateral thalamus of MCAO rats. Conversely, bepridil treatment restored seladin-1/DHCR24 expression in the ipsilateral thalamus. Bepridil treatment did not significantly affect heme oxygenase-1- or NAD(P)H quinone oxidoreductase-1-mediated oxidative stress or inflammatory responses in the ipsilateral thalamus of MCAO rats. Finally, bepridil treatment mitigated MCAO-induced alterations in APP processing in the ipsilateral thalamus and improved contralateral forelimb use in MCAO rats. These findings suggest that bepridil is a plausible therapeutic candidate in AD or stroke owing to its multifunctional role in key cellular events that are relevant for the pathogenesis of these diseases.

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