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Why can we still not translate preclinical research to clinical treatments for acute strokes? Despite > 1000 successful preclinical studies, drugs, and concepts for acute stroke, only two have reached clinical translation. This is the translational block. Yet, we continue to routinely model strokes using almost the same concepts we have used for over 30 years. Methodological improvements and criteria from the last decade have shed some light but have not solved the problem. In this conceptual analysis, we review the current status and reappraise it by thinking “out-of-the-box” and over the edges. As such, we query why other scientific fields have also faced the same translational failures, to find common denominators. In parallel, we query how migraine, multiple sclerosis, and hypothermia in hypoxic encephalopathy have achieved significant translation successes. Should we view ischemic stroke as a “chronic, relapsing, vascular” disease, then secondary prevention strategies are also a successful translation. Finally, based on the lessons learned, we propose how stroke should be modeled, and how preclinical and clinical scientists, editors, grant reviewers, and industry should reconsider their routine way of conducting research. Translational success for stroke treatments may eventually require a bold change with solutions that are outside of the box.

Abstract Background and aims Ischemic stroke causes significant long-term residual deficits that are poorly modelled and understood. Here, we build on our previous concept of “chronic mouse stroke model” to study 6-months´ clinical and tissue changes in young and old mice. Methods Adult male C57BL/6N young (n=31, 3 months old) and old (n= 30, 14 months old) mice were subjected to 1 hour transient middle cerebral artery occlusion with filament (fMCAo), were optimally supported with the “mouse Stroke Unit” protocol to increase survival for long-term studies, and were followed behaviorally (the open-field, tail suspension, cylinder, Corner and the horizontal ladder-rung test) and clinically (temperature, body weight, detailed neurological status) up to 6 months. At 6 months, brains and spinal cords were cryosectioned and studied for local and remote atrophy and cellular changes. Results Old mice had significantly higher acute mortality versus young, primarily due to edema-related herniation. Survivors exhibited prolonged (>1 month) and age-dependent weight loss (p<0.05). Both age groups developed severe focal neurological deficits with partial spontaneous recovery but persistent sensorimotor impairments up to 6 months. Ιpsilesional hemispheric atrophy (approximately 30% in both groups) was accompanied by ventricular enlargement and remote atrophy of sensory cortex, corpus callosum and thalamus, associated with ultra-chronic, region- and age-dependent astrocytic and microglial activation in brain. Spinal cord architecture showed preserved neuronal populations with affected contralateral corticospinal tracts and corresponding chronic residual microglial activation. Conclusions Mice can translationally model core long-term ischemic stroke parameters, revealing multiple chronic targets for drug discovery and treatment in stroke. Conflict of interest CP, IM and AL were supported by Unipharma S.A. with Research Grants. NK: nothing to disclose, APav: nothing to disclose, NZ: nothing to disclose, MG: nothing to disclose, ES-P: nothing to disclose, CPet: nothing to disclose, NP:nothing to disclose, AKot: nothing to disclose, AC: nothing to disclose, AKok: nothing to disclose

Abstract Background and aims Data on the role of thyroid hormone (TH) signaling in stroke have been contradictory between studies. Here, we aim to study the acute effects after TH-agonist/-antagonist treatment in experimental stroke. Methods C57BL/6 mice (n=90) underwent transient focal middle cerebral artery occlusion (fMCAO) for 1 hour, followed clinically up to day 3. Animals were randomized blindly to groups receiving either T3 (at doses of 25 μg/kg or 200 μg/kg), Desethyl-amiodarone (DEA) or Desbutyl-dronedarone (DBD) (at doses 25mg/kg) at reperfusion and on day 1; Sobetirome at 1mg/kg at reperfusion and daily up to day 3; controls received the corresponding vehicle. Histopathological brain studies on cryosections included infarct and hemispheric edema volumetry, as well as astrocytosis and neuronal death using a novel developed FluoroJadeB method for histological detection of penumbra from core and healthy tissue. Results Acute high-dose of T3 did not improve brain edema, infarct volume or neuronal survival compared to controls (p>0.1). Low-dose T3 worsened penumbral neuronal survival (p=0.0086). TH-receptors’ antagonism with DEA induced a clinical worsening with corresponding increased infarct size and neuronal death at day 3 (p<0.05); DBD conferred no effects (p>0.1). TRβ agonism with Sobetirome did not show any clinical effect or penumbral neuronal benefit (p>0.1). Conclusions Acute post-ischemic TH-receptor activation with low- and high- T3 doses or sobetirome confers mixed effects that need further clarification. However, TH-receptors antagonism with DEA (the active metabolite of amiodaron) is detrimental for stroke and should probably be avoided, at least during the first 3 days post-ischemia. Conflict of interest APav and NZ were supported by Tsetis Foundation, CP, IM and AL were supported by Uni-pharma S.A. with Research Grants. AK: nothing to disclose, IT: nothing to disclose, VA: nothing to disclose, EK: nothing to disclose, APap: nothing to disclose, MG: nothing to disclose, APap: nothing to disclose