Christoph Kleinschnitz

Neuroprotection for Stroke: Current Status and Future Perspectives

Neuroprotection aims to prevent salvageable neurons from dying. Despite showing efficacy in experimental stroke studies, the concept of neuroprotection has failed in clinical trials. Reasons for the translational difficulties include a lack of methodological agreement between preclinical and clinical studies and the heterogeneity of stroke in humans compared to homogeneous strokes in animal models. Even when the international recommendations for preclinical stroke research, the Stroke Academic Industry Roundtable (STAIR) criteria, were followed, we have still seen limited success in the clinic, examples being NXY-059 and haematopoietic growth factors which fulfilled nearly all the STAIR criteria. However, there are a number of neuroprotective treatments under investigation in clinical trials such as hypothermia and ebselen. Moreover, promising neuroprotective treatments based on a deeper understanding of the complex pathophysiology of ischemic stroke such as inhibitors of NADPH oxidases and PSD-95 are currently evaluated in preclinical studies. Further concepts to improve translation include the investigation of neuroprotectants in multicenter preclinical Phase III-type studies, improved animal models, and close alignment between clinical trial and preclinical methodologies. Future successful translation will require both new concepts for preclinical testing and innovative approaches based on mechanistic insights into the ischemic cascade.

Regional distribution of protein and activity of the nitric oxide receptor, soluble guanylyl cyclase, in rat brain suggests multiple mechanisms of regulation

Nitric oxide (NO) is an unconventional neuromodulator that signals by intercellular diffusion. Its effects are often mediated by activation of its cytosolic receptor, the hemoprotein soluble guanylyl cyclase (sGC). Regional distribution of heterodimeric (alpha/beta) sGC at both the activity and protein level and its regulation are still unclear. Here, sGC was analyzed in rat brain by Western blot and NO donor-stimulated cyclic GMP accumulation. sGCalpha(1) and sGCbeta(1) immunoreactive protein signals strongly correlated with each other. However, V(max) values depended on the type of NO donor used. Sodium nitroprusside, the most widely used compound and formally an NO(+) donor, was up to 20-fold less effective in stimulating sGC activity than the NO donor diethylamine NONOate. In contrast to the rather even distribution of sGC proteins and SNP-stimulated cGMP accumulation in various regions of rat brain, diethylamine NONOate-stimulated sGC activity varied up to 8-fold between the different brain regions tested. In conclusion, we show that expression of both sGCalpha(1) and sGCbeta(1) subunits is tightly coregulated in rat brain, while yet unknown additional mechanisms affect the V(max) of sGC.

Platelets in Acute Ischemic Stroke

Ischemic stroke and myocardial infarction are the major causes of death and disability worldwide. Rapid restoration of blood flow by pharmacological thrombolysis and/or mechanical thrombectomy is the mainstay of acute stroke treatment, but does not guarantee a favorable outcome. Reperfusion injury denotes the acute, paradoxically harmful aspect of blood flow return in the ischemic brain which involves platelet activation and, surprisingly, immune cell recruitment. In experimental stroke, glycoprotein (GP)Ibα facilitated tethering of platelets to the postischemic brain endothelium by binding to von Willebrand factor (VWF), while firm adhesion and platelet activation were mediated by GPVI signaling. Accordingly, blocking of platelet GPIbα or GPVI, as well as reducing circulating VWF, dramatically improved stroke outcome by protecting the microvasculature during reperfusion and in addition accelerated recanalization during thrombolysis. Despite interfering with platelet function, no bleeding complications occurred, in contrast to devastating intracranial hemorrhages observed after blocking platelet aggregation via αIIbβ3. It will be essential to further dissect pathological platelet functions and activation pathways involved in reperfusion injury from those indispensable as gatekeepers of hemostasis in the stroke-injured brain. The pathophysiology of acute stroke is even more complex since it involves concerted detrimental actions of platelets and T-cells, referred to as “thrombo-inflammation,” which await further elucidation.

A diseasome cluster-based drug repurposing of soluble guanylate cyclase activators from smooth muscle relaxation to direct neuroprotection

Network medicine utilizes common genetic origins, markers and co-morbidities to uncover mechanistic links between diseases. These links can be summarized in the diseasome, a comprehensive network of disease–disease relationships and clusters. The diseasome has been influential during the past decade, although most of its links are not followed up experimentally. Here, we investigate a high prevalence unmet medical need cluster of disease phenotypes linked to cyclic GMP. Hitherto, the central cGMP-forming enzyme, soluble guanylate cyclase (sGC), has been targeted pharmacologically exclusively for smooth muscle modulation in cardiology and pulmonology. Here, we examine the disease associations of sGC in a non-hypothesis based manner in order to identify possibly previously unrecognized clinical indications. Surprisingly, we find that sGC, is closest linked to neurological disorders, an application that has so far not been explored clinically. Indeed, when investigating the neurological indication of this cluster with the highest unmet medical need, ischemic stroke, pre-clinically we find that sGC activity is virtually absent post-stroke. Conversely, a heme-free form of sGC, apo-sGC, was now the predominant isoform suggesting it may be a mechanism-based target in stroke. Indeed, this repurposing hypothesis could be validated experimentally in vivo as specific activators of apo-sGC were directly neuroprotective, reduced infarct size and increased survival. Thus, common mechanism clusters of the diseasome allow direct drug repurposing across previously unrelated disease phenotypes redefining them in a mechanism-based manner. Specifically, our example of repurposing apo-sGC activators for ischemic stroke should be urgently validated clinically as a possible first-in-class neuroprotective therapy.Systems based pharmacology: drug repurposing by diseasomeSystems medicine utilizes common genetic origins and co-morbidities to uncover mechanistic links between diseases, which are summarized in the diseasome. Shared pathomechanisms may also allow for drug repurposing within these disease clusters. Here, Schmidt and co-workers show indeed that, based on this principle, a cardio-pulmonary drug can be surprisingly repurposed for a previously not recognised application as a direct neuroprotectant. They find that the cyclic GMP forming soluble guanylate cyclase becomes dysfunctional upon stroke but regains catalytic activity in the presence of specific activator compounds. This new mechanism-based therapy should be urgently validated clinically as a possible first-in-class treatment in stroke.

MS in Deutschland: Symptome und Behandlungsdefizite

Über die Situation der Menschen mit Multipler Sklerose war lange wenig bekannt. Verlässliche Daten zur Häufigkeit der Erkrankung und ihren Unterformen gab es nicht. Auch Versorgungsaspekte, wie verlaufsmodifizierende beziehungsweise medikamentöse und nicht medikamentöse symptomatische Therapien der Erkrankung waren nur für einzelne Einrichtungen und ihre Patienten bekannt. Das MS-Register wurde 2001 initiiert, um standardisierte Daten zu diesen Punkten, aber auch über den Einfluss der Erkrankung auf die Berufstätigkeit oder Arbeitsunfähigkeit der Betroffenen zu erhalten. Der nachfolgende Artikel gibt einen Einblick in die aktuelle Versorgungssituation MS-Kranker und gestattet erstmals einen historischen Vergleich.

Platelets and Stroke

Ischemic stroke is the third most common cause of disability worldwide. Since ischemic stroke results from an occlusion of a brain-supplying artery, rapid recanalization either by intravenous thrombolysis or by endovascular thrombectomy is the primary clinical objective. Following restoration of blood flow, reperfusion injury often occurs encompassing a large number of detrimental biochemical processes. Based on animal models of stroke, tethering of platelets on endothelial cells is mediated by the glycoprotein (GP) Ib–V–IX receptor complex on the surface of platelets. This complex facilitates the binding of von Willebrand factor (vWF) to the damaged sub-endothelium and thus the first critical step in platelet adhesion. Further glycoprotein receptors, i.e., glycoprotein (PG) VI, and GPIIb/IIIa are also involved in aggregation and adhesion of platelets. Aggregates of adherent, activated platelets express adhesive molecules, namely, P-selectin, which binds to P-selectin glycoprotein ligand-1 (PSGL-1), the main receptor for P-selectin on leukocytes. Adherence of leukocytes and the subsequent release of pro-inflammatory factors are particular mechanisms that show how platelets induce inflammatory processes. Platelets are also connected in further ways to cellular and humoral components of the immune system, such as T cells, macrophages, and the complement system. This has led us to develop the term “thrombo-inflammation.” Both thrombotic and inflammatory mechanisms are highly intertwined in the pathophysiology of ischemic stroke. Thrombus formation and inflammation are therefore promising targets for the development of novel therapeutic strategies. The growing insights into thrombo-inflammation after cerebral ischemia might provide a platform for further exploration of the critical interface between inflammation and thrombosis after ischemic stroke. These interesting findings in the field of cerebral thrombo-inflammation should encourage stroke researchers to seek further treatments that target the reduction of thrombo-inflammation in stroke and other cardiovascular diseases.

Gerinnungsfaktoren bei MS als Immunmodulatoren

Menschen mit Gerinnungsstörungen könnten neben den bekannten Blutungs- und Thrombosekomplikationen auch ein erhöhtes Risiko für die Entwicklung entzündlicher Erkrankungen haben. Zumindest legen dies aktuelle Studien nahe. Die Herausforderung der nächsten Jahre wird es sein, die medikamentöse Antikoagulation als mögliche Therapie für (neuro-)inflammatorische Erkrankungen zu verifizieren.

Lessons from the Past and Future Approaches for Immunologic Therapies in Multiple Sclerosis

Publisher Summary This chapter discusses the past and futures approaches for immunologic therapies in multiple sclerosis (MS). It also explores why the past therapeutic approaches failed and what these failures could mean to the concepts of pathogenesis and trial design. Future therapeutic approaches are also discussed and the most important examxadples are listed and named including pathogenetically oriented immune therapies, immunosuppressants and immunomodulators, novel immunomodulatory agents, and autologous stem cell transplantation. The examples from the past as well as the most important samples from future approaches for therapy are tabulated. Past approaches discussed are: modification of the cytokine pattern, chemotaxis, immunosuppressants, remyelination, and antigen-derived therapies such as altered peptide ligands. Despite the tremendous progress in MS therapy over the last years, the number of therapeutic strategies that failed to show benefit for MS patients, demonxadstrated a critical risk-benefit ratio, and raised controversies in terms of their assumed efficacy or practicability is considerable. The most important substances under development are summarized and highlight the possible sites of drug action. Major groupings of agents or strategies described are: (1) pathogenetically oriented immune therapies, (2) immunosuppressants and immunomodulators, and (3) autologous stem cell transplantation. Nevertheless, meaningful preclinical studies in animal models are indispensable to develop and verify rational therapeutic concepts in the future.