Abstract P765: Therapeutic Approaches to Reduce Post-Stroke Cognitive Impairment

Abstract

Introduction: Cognitive impairments and memory loss are common after stroke, with an emerging awareness of a high risk of conversion to post-stroke dementia. It is increasingly clear that in addition to neuronal injury following cerebral ischemia, impaired functional networks contribute to long-term functional deficits. Synaptic plasticity (LTP) is the leading cellular model of learning and memory. Thus, we utilize electrophysiological recordings of hippocampal LTP as an indicator of network health following ischemia in combination with neurobehavioral assessments of memory function. Hypothesis: Focal ischemic stroke increases soluble amyloid beta (Aβ) in the hippocampus, causing impaired plasticity and memory function. Methods: Extracellular field recordings of CA1 neurons were performed in acute hippocampal slices prepared 30 days after recovery from transient MCAO (45 min) in adult (6-8 week) mice. A behavioral fear conditioning paradigm (CFC) was used to evaluate memory. ELISA assay was used to quantify soluble Aβ42 from the hippocampus. Slices were treated with Aβ42 oligomers with and without our newly developed peptide inhibitor of TRPM2, termed tatM2NX. Results: Recordings from brain slices 30 days after MCAO showed near complete loss of LTP; 161±9%, n=6 in sham compared to 115±4%, n=7 30 days after MCAO in the hippocampus. MCAO decreased freezing behavior, indicating lack of memory (65±7% in sham mice (n=6) and 37±7% in MCAO mice, n=7). We observed a 48% increase in Aβ42 in the hippocampus 30 days after MCAo. We observed that addition of Aβ42 oligomers (500 nM) impaired LTP. This impaired LTP was prevented with co-application of the TRPM2 channel inhibitor tatM2NX. Consistent with a role of TRPM2 channels in post-stroke cognitive impairment, MCAO mice treated with tatM2NX (20 mg/kg iv injection 24 hr before testing) on day 29 post MCA demonstrated increasing freezing to 72±5% (n=9). Conclusion: Our data implicates increased levels of soluble Aβ42 in the hippocampus following stroke, resulting in activation of TRPM2 channels and impaired synaptic plasticity. Therefore, reducing soluble Aβ42 and/or inhibition of TRPM2 channels at chronic time points following ischemia may represent a novel strategy to improve functional recovery following stroke.