Abstracts

Rationale: Stroke is one of the most common CNS causes of morbidity and mortality. The incidence of developing epilepsy after stroke is approximately 2-20%, with data varying substantially, depending on the study. In addition, stroke also frequently causes cognitive impairment, observed in up to 70% of acute stroke patients. While these early cognitive problems often partially resolve in weeks or months after onset, cognitive deficits remain present in many patients. In this study, we hypothesized that focal stroke leads to neuronal hyperexcitability at sites distant from the primary lesion, leading to impaired cognition. We further tested if the anticonvulsant drug eslicarbazepine acetate (ESL) could be useful to curb hyperexcitability and improve cognition in a photothrombotic stroke mouse model.

Methods: We induced a very restricted infarct (0.1 mm³) in the somatosensory cortex using a photothrombotic stroke mouse model. Overall, 140 mice in 5 experimental groups were treated with ESL or vehicle over the course of 5 weeks (n=28 mice/group).

Results: Behavioral assessment during this period revealed a stroke-induced significant reduction of long-term, but not short-term habituation to an open field arena, when compared to sham-stroke control mice. Moreover, we found a significant impairment of object memory (novel object recognition test), but not spatial working memory (spontaneous alteration in Y-maze). Importantly, the behavioral impairments were completely abolished by ESL treatment.

To obtain first insights into potential neuronal mechanisms, we have used systematic mapping of the activity-dependent immediate early gene c-fos to excitability in areas remote from the location of the focal stroke. In somatosensory cortex contralateral to the infarct site, the number of c-Fos-positive neurons was significantly increased after stroke. The number of c-Fos positive neurons was also higher in medial prefrontal cortex and the hippocampal CA1 subfield following stroke, suggesting elevated neuronal activity in those regions. Importantly, the numbers of c-Fos-positive neurons was completely normalized by ESL treatment.

Conclusions: In conclusion, in our stroke model, we found long-lasting cognitive impairment and hyperexcitability in brain regions remote to the infarct location. We further show that ESL was able to prevent those cognitive conspicuities as well as the increased neuronal activity in cognition-related brain regions. This study provides support for the notion that focal stroke leads to changes in the functional properties of connected regions, a phenomenon termed diaschisis proposed by Monakow in 1914. It further suggests that anticonvulsant drugs may be used to alleviate diaschisis and improve cognition.

Funding: Study supported by BIAL - Portela & Cª, S.A.