Translational Block in Stroke: A Constructive and Out-of-the-Box Reappraisal

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

Case report: Fatal Borna virus encephalitis manifesting with basal brain and brainstem symptoms

BackgroundSince the first report of fatal Borna virus-1 (BoDV-1) encephalitis in 2018, cases gradually increased. There is a lack of diagnostic algorithm, and there is no effective treatment so far.Case presentationWe report an acute BoDV-1 encephalitis in a 77-year-old female with flu-like onset, rapid progression to word-finding difficulties, personality changes, global disorientation, diffuse cognitive slowness, and gait ataxia and further deterioration with fever, meningism, severe hyponatremia, epileptic seizures, cognitive decline, and focal cortical and cerebellar symptoms/signs. The extensive diagnostic workup (cerebrovascular fluid, serum, and MRI) for (meningo-)encephalitis was negative for known causes. Our empirical common antiviral, antimicrobial, and immunosuppressive treatment efforts failed. The patient fell into coma 5 days after admission, lost all brainstem reflexes on day 18, remained fully dependent on invasive mechanical ventilation thereafter and died on day 42. Brain and spinal cord autopsy confirmed an extensive, diffuse, and severe non-purulent, lymphocytic sclerosing panencephalomyelitis due to BoDV-1, affecting neocortical, subcortical, cerebellar, neurohypophysis, and spinal cord areas. Along with our case, we critically reviewed all reported BoDV-1 encephalitis cases.ConclusionThe diagnosis of acute BoDV-1 encephalitis is challenging and delayed, while it progresses to fatal. In this study, we list all tried and failed treatments so far for future reference and propose a diagnostic algorithm for prompt suspicion and diagnosis

Neuroprotection from inflammation: Experimental allergic encephalomyelitis facilitates traumatic spinal cord injury recovery

Passive immunization with T cells activated against central nervous system (CNS) - associated myelin antigens has been found to provide neuroprotection following CNS trauma, leading to the concept of protective autoimmunity. However, limited research exists about whether actively induced CNS autoimmunity may offer any similar benefit. In this study, the kinetics and the effect of endogenously anti-myelin activated T cells following spinal cord injury (SCI), were investigated. Experimental allergic encephalomyelitis (EAE) was actively induced in Lewis rats following immunization with myelin basic protein (MBP). In vivo 5-Bromo-2-deoxyuridine (BrdU) incorporation from activated T cells was used as a marker of T cell- proliferation. BrdU was injected on 5th, 6th and 7th day post-induction (DPI) at all EAE-animals. On DPI 8, spinal cord compressive injury was induced by a transient extradural application of an aneurysm clip at the T8 spinal level. SCI resulted in spastic paralysis of hindlimbs, in all but sham-injured animals. Recovery from SCI was significantly better in EAE-animals. Activated mononuclear cells were selectively accumulated at the site of the injury. Axonal loss was less in the EAE group following SCI. Our findings indicate that actively induced autoimmunity against CNS myelin antigens may protect spinal cord pathways from mechanical injury

Transplantation of neural precursor stem cells and bone marrow stromal cells in a model of focal cerebral ischemia

Adult Bone Marrow Stromal Cells (BMSCs) and neonatal Neural Precursor Cells (NPCs) have been transplanted intravenously intraartenally or intraparenchymal but not intraventricularly (ICV) due to significant displacement phenomena of the lateral ventricles caused by post-ischemic edema. Adult male Wistar rats were subjected to 2-hours transient occlusion of the middle cerebral artery (t-MCAO). Animals were clinically monitored and their brains were studied for neuropathology at 3 (acute) and 60 (chronic phase) days post-infarction. Our results indicate that we successfully improved the t-MCAO model to induce severe highly reproducible (97.5% success rate) stroke without the risk of subarachnoid hemorrhage In addition we recalculated the stereotaxic coordinates based on the clinical scores of each animal to achieve highly reliable intraventricular invasion at 6-18 hours post-ischemia ICV infusion of cellular grafts revealed that both are widely dispersed throughout the ventricular system through the cerebrospinal fluid circulation but display different intraparenchymal migratory capability. BMSCs but not NPCs functioned as cellular trophic reactors and increased post-infarction survival improved clinical scores at 2 months reduced post-ischemic edema reduced neuronopathy and axonopathy reduced astrocytic activation and scar and induced the expression of VEGF and HGF (but not BDNF) from BMSCs and host ischemic tissue. Finally BMSCs develop masses that were attached to the ventricular walls and possibly constituted a graft-rejection reaction.Τα στρωματικά κύτταρα του μυελού των οστών (ΣΚΜΟ) και τα στελεχιαία προγονικά κύτταρα του ΚΝΣ (ΣΠΚ) έχουν μεταμοσχευθεί ενδοαγγειακά ή ενδοπαρεγχυματικά στο ισχαιμικό αγγειακό εγκεφαλικό επεισόδιο (ΙΑΕΕ) άλλα όχι ενδοκοιλιακά λόγω τεχνικών δυσκολιών πρόσβασης στο οιδηματώδες ισχαιμικό ημισφαίριο. Στην παρούσα διατριβή χρησιμοποιήθηκαν επίμυες Wistar και έγινε ΙΑΕΕ με παροδικό αποκλεισμό της μέσης εγκεφαλικής αρτηρίας (πα-ΜΕΑ) για 2 ώρες. Τα πειραματόζωα παρακολουθήθηκαν κλινικά και έγινε παθολογοανατομική μελέτη των εγκέφαλων στις 3 και 60 ήμερες μετά το ΙΑΕΕ. Επιτεύχθει -καταρχήν- βελτίωση του μοντέλου πα-ΜΕΑ, με μεγάλο και επαναλήψιμο ΙΑΕΕ χωρίς υπαραχνοειδή αιμορραγία και έγινε επαναπροσδιορισμός της στερεοταξίας των πλάγιων κοιλιών με βάση την κλινική εικόνα του κάθε πειραματόζωου για προβλέψιμη και αξιόπιστη ενδοκοιλιακή πρόσβαση στις 6-18 ώρες μετά την ισχαιμία. Η χορήγηση των 2 κυτταρικών μοσχευμάτων στις πλάγιες κοιλίες 6 ώρες μετά το ΙΑΕΕ έδειξε πως αμφότερα διασπείρονται με την ροή του ΕΝΥ στο κοιλιακό σύστημα αλλά με διαφορετική ενδοπαρεγχυματική μεταναστευτική ικανότητα. Τα ΣΚΜΟ (λειτουργώντας ως «τροφικοί αντιδραστήρες») αλλά όχι τα ΣΠΚ ελάττωσαν την μετεμφρακτική θνητότητα βελτίωσαν την κλινική εικόνα στους 2 μήνες μείωσαν το μετεμφρακτικό οίδημα ελάττωσαν την χρόνια νευρωνοπάθεια και αξονοπάθεια ελάττωσαν την αστροκυτταρική αντίδραση και οδήγησαν σε έκφραση των VEGF και HGF (αλλά όχι του BDNT) από τα ΣΚΜΟ και τον λήπτη εγκεφαλικό ιστό. Τέλος, τα ΣΚΜΟ αναπτύσσουν ινώδεις μάζες πιθανότατα ως αντίδραση απόρριψής τους

Microglia in action: how aging and injury can change the brain’s guardians

Neuroinflammation, the inflammatory response in the CNS, is a major determinant of neuronal function and survival during ageing 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 ageing and previous insults. In this review, we discuss the roles of microglia upon an ischemic or traumatic injury, and give our perspective how ageing 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 ageing brain

Effects of Thyroid Hormone on Tissue Hypoxia: Relevance to Sepsis Therapy

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

Effects of Thyroid Hormone on Tissue Hypoxia: Relevance to Sepsis Therapy

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

Long-term impairment of neurovascular coupling following experimental subarachnoid hemorrhage

CO2-reactivity and neurovascular coupling are sequentially lost within the first 24 h after subarachnoid hemorrhage (SAH). Whether and when these impairments recover is not known. Therefore, we investigated the reactivity of pial and intraparenchymal vessels by in vivo two-photon microscopy one month after experimental SAH. C57BL/6 mice were subjected to either sham surgery or SAH by filament perforation. One month later, cerebral blood flow following CO2-challenge and forepaw stimulation was assessed by laser Doppler fluxmetry. Diameters of pial and intraparenchymal arterioles were quantified by in vivo two-photon microscopy. One month after SAH, pial and parenchymal vessels dilated in response to CO2. Neurovascular coupling was almost completely absent after SAH: vessel diameter did not change upon forepaw stimulation compared to a 20% increase in sham-operated mice. The current results demonstrate that neurovascular function differentially recovers after SAH: while CO2-reactivity normalizes within one month after SAH, neurovascular coupling is still absent. These findings show an acute and persistent loss of neurovascular coupling after SAH that may serve as a link between early brain injury and delayed cerebral ischemia, two distinct pathophysiological phenomena after SAH that were so far believed not to be directly related