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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.

Aging leads to a gradual decline in the fidelity of cerebral blood flow (CBF) responses to neuronal activation, resulting in an increased risk for stroke and dementia. However, it is currently unknown when age-related cerebrovascular dysfunction starts or which vascular components and functions are first affected. The aim of this study was to examine the function of microcirculation throughout aging in mice. Microcirculation was challenged by inhalation of 5% and 10% CO2 or by forepaw stimulation in 6-week, 8-month, and 12-month-old FVB/N mice. The resulting dilation of pial vessels and increase in CBF was measured by intravital fluorescence microscopy and laser Doppler fluxmetry, respectively. Neurovascular coupling and astrocytic endfoot Ca2+ were measured in acute brain slices from 18-month-old mice. We did not reveal any changes in CBF after CO2 reactivity up to an age of 12 months. However, direct visualization of pial vessels by in vivo microscopy showed a significant, age-dependent loss of CO2 reactivity starting at 8 months of age. At the same age neurovascular coupling was also significantly affected. These results suggest that aging does not affect cerebral vessel function simultaneously, but starts in pial microvessels months before global changes in CBF are detectable.

Tissue hypoxia occurs in various conditions such as myocardial or brain ischemia and infarction, sepsis, and trauma, and induces cellular damage and tissue remodeling with recapitulation of fetal-like reprogramming, which eventually results in organ failure. Analogies seem to exist between the damaged hypoxic and developing organs, indicating that a regulatory network which drives embryonic organ development may control aspects of heart (or tissue) repair. In this context, thyroid hormone (TH), which is a critical regulator of organ maturation, physiologic angiogenesis, and mitochondrial biogenesis during fetal development, may be of important physiological relevance upon stress (hypoxia)-induced fetal reprogramming. TH signaling has been implicated in hypoxic tissue remodeling after myocardial infarction and T3 prevents remodeling of the postinfarcted heart. Similarly, preliminary experimental evidence suggests that T3 can prevent early tissue hypoxia during sepsis with important physiological consequences. Thus, based on common pathways between different paradigms, we propose a possible role of TH in tissue hypoxia after sepsis with the potential to reduce secondary organ failure.

Ischemia-reperfusion injury remains the main constraint of normothermic perfusion. The present study investigated the potential of therapies targeting reperfusion injury such as triiodothyronine and interventions mimicking ischemic preconditioning (PC) to optimize normothermic crystalloid perfusion. Rat hearts were perfused for 6 h with constant flow, in a Langendorff mode and Krebs-Henseleit as perfusate with glucose being the only metabolic substrate, (NP,  = 9). PC treated hearts were subjected to 5 cycles of 40 min low flow perfusion followed by 20 min normal flow perfusion with either vehicle (PC,  = 11) or 60nM T3 (PC + T3,  = 10). Left ventricular end diastolic pressure (LVEDP), left ventricular developed pressure (LVDP), perfusion pressure (PP), and percentage of change of these parameters from baseline values were measured. The ratio of LV weight to body weight was calculated as index of tissue edema. Baseline parameters were similar between groups. At the end of perfusion, no difference in LVDP was observed, LVEDP was significantly lower in PC and PC + T3 vs. NP,  < 0.05. PP was significantly lower in both PC and PC + T3 vs. NP hearts.  < 0.05. Both PC and PC + T3 significantly reduced tissue edema. Intermittent low flow mimicking ischemic preconditioning (PC) appears to optimize crystalloid based normothermic rat heart perfusion by limiting tissue edema and diastolic and vascular dysfunction.

Background Nogo-A and its putative receptor NgR are considered to be among the inhibitors of axonal regeneration in the CNS. However, few studies so far have addressed the issue of local NgR complex multilateral localization within inflammation in an MS mouse model of autoimmune demyelination. Methods Chronic experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice. Analyses were performed on acute (days 18–22) and chronic (day 50) time points and compared to controls. The temporal and spatial expression of the Nogo receptor complex (NgR and coreceptors) was studied at the spinal cord using epifluorescent and confocal microscopy or real-time PCR. Data are expressed as cells/mm 2 , as mean % ± SEM, or as arbitrary units of integrated density. Results Animals developed a moderate to severe EAE without mortality, followed by a progressive, chronic clinical course. NgR complex spatial expression varied during the main time points of EAE. NgR with coreceptors LINGO-1 and TROY was increased in the spinal cord in the acute phase whereas LINGO-1 and p75 signal seemed to be dominant in the chronic phase, respectively. NgR was detected on gray matter NeuN + neurons of the spinal cord, within the white matter inflammatory foci (14.2 ± 4.3 % NgR + inflammatory cells), and found to be colocalized with GAP-43 + axonal growth cones while no β-TubIII + , SMI-32 + , or APP + axons were found as NgR + . Among the NgR + inflammatory cells, 75.6 ± 9.0 % were microglial/macrophages (lectin + ), 49.6 ± 14.2 % expressed CD68 (phagocytic ED1 + cells), and no cells were Mac-3 + . Of these macrophages/monocytes, only Arginase-1 + /NgR + but not iNOS + /NgR + were present in lesions both in acute and chronic phases. Conclusions Our data describe in detail the expression of the Nogo receptor complex within the autoimmune inflammatory foci and suggest a possible immune action for NgR apart from the established inhibitory one on axonal growth. Its expression by inflammatory macrophages/monocytes could signify a possible role of these cells on axonal guidance and clearance of the lesioned area during inflammatory demyelination.

Heart transplantation remains the conventional treatment in end-stage heart failure, with static cold storage (SCS) being the standard technique used for donor preservation. Nevertheless, prolonged cold ischemic storage is associated with the increased risk of early graft dysfunction attributed to residual ischemia, reperfusion, and rewarming damage. In addition, the demand for the use of marginal grafts requires the development of new methods for organ preservation and repair. In this review, we focus on current knowledge and novel methods of donor preservation in heart transplantation. Hypothermic or normothermic machine perfusion may be a promising novel method of donor preservation based on the administration of cardioprotective agents. Machine perfusion seems to be comparable to cold cardioplegia regarding donor preservation and allows potential repair treatments to be employed and the assessment of graft function before implantation. It is also a promising platform for using marginal organs and increasing donor pool. New pharmacological cardiac repair treatments, as well as cardioprotective interventions have emerged and could allow for the optimization of this modality, making it more practical and cost-effective for the real world of transplantation. Recently, the use of triiodothyronine during normothermic perfusion has shown a favorable profile on cardiac function and microvascular dysfunction, likely by suppressing pro-apoptotic signaling and increasing the expression of cardioprotective molecules.

The effects of neural precursor cell (NPC) transplantation on the clinical course and the pathological features of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, were studied in mice. NPC recipients exhibited improved clinical outcome and less pronounced pathological features in their spinal cord. NPCs ameliorated EAE potentially by modulating the levels of chemokines expressed in the inflamed CNS, thus resulting in the impaired recruitment of immune cells. Neural precursor cell (NPC) transplantation has been proposed as a therapy for multiple sclerosis (MS) and other degenerative disorders of the central nervous system (CNS). NPCs are suggested to exert immune modulation when they are transplanted in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). Herein, we explore whether the effect of NPC transplantation on the clinical course and the pathological features of EAE is combined with the modulation of chemokines levels expressed in the inflamed CNS. NPCs were isolated from brains of neonatal C57/Bl6 mice and were subcutaneously administered in female mice with myelin oligodendrocyte glycoprotein (MOG)‐induced EAE. Clinical signs of the disease and transcript analysis of the CNS in the acute phase were performed. In addition, the presence of inflammatory components in the spinal cord was evaluated and ex vivo proliferation of lymphocytes was measured. NPC recipients exhibited ameliorated clinical outcome and less pronounced pathological features in their spinal cord. Downregulation of chemokine mRNA levels throughout the CNS was correlated with diminished Mac‐3‐, CD3‐, and CD4‐positive cells and reduced expression levels of antigen‐presenting molecules in the spinal cord. Moreover, NPC transplantation resulted in lymphocyte‐related, although not splenocyte‐related, peripheral immunosuppression. We conclude that NPCs ameliorated EAE potentially by modulating the levels of chemokines expressed in the inflamed CNS, thus resulting in the impaired recruitment of immune cells. These findings further contribute to the better understanding of NPCs' immunomodulatory properties in neuroinflammatory disorders, and may lead to faster translation into potential clinical use. Significance Endogenous neural precursor cells of the central nervous system are able to migrate and differentiate toward mature cells to repair an injury. There is increasing evidence that autologous transplantation of these cells in experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis, may have a beneficial effect on the disease process. Several mechanisms have been proposed—among them, the potentiation of endogenous precursor cell differentiation of the central nervous system and the modulation of demyelinating and neurodegenerative immune‐mediated processes. This article provides evidence of interference in immune signaling within the central nervous system as a potential mechanism underlying the immunomodulatory properties of transplanted neural precursor cells.

The present study investigated the effects of triiodothyronine (T3) administration in ex vivo model of rat heart normothermic perfusion. T3 is cardioprotective and has the potential to repair the injured myocardium. Isolated hearts were subjected to normothermic perfusion (NP) with Krebs-Henseleit for 4 h with vehicle (NP) or 60 nM T3 in the perfusate (NP + T3). Left ventricular end diastolic pressure (LVEDP), left ventricular developed pressure (LVDP), perfusion pressure (PP) and percentage of change of these parameters from the baseline values were measured. Activation of stress induced kinase signaling was assessed in tissue samples. Baseline parameters were similar between groups. LVEDP was increased from the baseline by 13% (70) for NP + T3 vs. 139% (160) for NP group, p = 0.048. LVDP was reduced by 18.2% (5) for NP + T3 vs. 25.3% (19) for NP group, p = 0.01. PP was increased by 41% (19) for NP + T3 vs.91% (56) for NP group, p = 0.024. T3 increased activation of pro-survival Akt by 1.85 fold ( p = 0.047) and AMPK by 2.25 fold ( p = 0.01) and reduced activation of pro-apoptotic p38 MAPK by 3fold ( p = 0.04) and p54 JNK by 4.0 fold ( p = 0.04). Administration of T3 in normothermic perfusion had favorable effects on cardiac function and perfusion pressure and switched death to pro-survival kinase signaling.

Neuroinflammation, the inflammatory response in the central nervous system (CNS), is a major determinant of neuronal function and survival during aging and disease progression. Microglia, as the resident tissue-macrophages of the brain, provide constant support to surrounding neurons in healthy brain. Upon any stress signal (such as trauma, ischemia, inflammation) they are one of the first cells to react. Local and/or peripheral signals determine microglia stress response, which can vary within a continuum of states from beneficial to detrimental for neuronal survival, and can be shaped by aging and previous insults. In this review, we discuss the roles of microglia upon an ischemic or traumatic injury, and give our perspective how aging may contribute to microglia behavior in the injured brain. We speculate that a deeper understanding of specific microglia identities will pave the way to develop more potent therapeutics to treat the diseases of aging brain.