Circadian effects on stroke outcome – did we not wake up in time for neuroprotection?

The occurrence of stroke in humans peaks in the morning. A recent study revealed that time of day mitigates the therapeutic impact of neuroprotective paradigms. These findings might not only explain the previous failure of translation of neuroprotective therapies but inspire new paradigms in stroke chronopathophysiology research. Taking chronotype into account may complement the many factors that influence efficacy of experimental therapies in stroke

Potential effects of commonly applied drugs on neural stem cell proliferation and viability : a hypothesis-generating systematic review and meta-analysis

Neural stem cell (NSC) transplantation is an emerging and promising approach to combat neurodegenerative diseases. While NSCs can differentiate into neural cell types, many therapeutic effects are mediated by paracrine, “drug-like” mechanisms. Neurodegenerative diseases are predominantly a burden of the elderly who commonly suffer from comorbidities and thus are subject to pharmacotherapies. There is substantial knowledge about drug-drug interactions but almost nothing is known about a potential impact of pharmacotherapy on NSCs. Such knowledge is decisive for designing tailored treatment programs for individual patients. Previous studies revealed preliminary evidence that the anti-depressants fluoxetine and imipramine may affect NSC viability and proliferation. Here, we derive a hypothesis on how commonly applied drugs, statins and antihypertensives, may affect NSC viability, proliferation, and differentiation. We conducted a systematic review and meta-analysis looking at potential effects of commonly prescribed antihypertensive and antihyperlipidemic medication on NSC function. PubMed and Web of Science databases were searched on according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Publications were assessed against a priori established selection criteria for relevancy. A meta-analysis was then performed on data extracted from publications eligible for full text review to estimate drug effects on NSC functions. Our systematic review identified 1,017 potential studies, 55 of which were eligible for full text review. Out of those, 21 were included in the qualitative synthesis. The meta-analysis was performed on 13 publications; the remainder were excluded as they met exclusion criteria or lacked sufficient data to perform a meta-analysis. The meta-analysis revealed that alpha-2 adrenoceptor agonists, an anti-hypertensive drug class [p < 0.05, 95% confidence intervals (CI) = –1.54; –0.35], and various statins [p < 0.05, 95% CI = –3.17; –0.0694] had an inhibiting effect on NSC proliferation. Moreover, we present preliminary evidence that L-type calcium channel blockers and statins, particularly lovastatin, may reduce NSC viability. Although the data available in the literature is limited, there are clear indications for an impact of commonly applied drugs, in particular statins, on NSC function. Considering the modes of action of the respective drugs, we reveal plausible mechanisms by which this impact may be mediated, creating a testable hypothesis, and providing insights into how future confirmative research on this topic may be conducted

Perioperative stroke : a perspective on challenges and opportunities for experimental treatment and diagnostic strategies

Perioperative stroke is an ischemic or hemorrhagic cerebral event during or up to 30 days after surgery. It is a feared condition due to a relatively high incidence, difficulties in timely detection, and unfavorable outcome compared to spontaneously occurring stroke. Recent preclinical data suggest that specific pathophysiological mechanisms such as aggravated neuroinflammation contribute to the detrimental impact of perioperative stroke. Conventional treatment options are limited in the perioperative setting due to difficult diagnosis and medications affecting coagulation in may cases. On the contrary, the chance to anticipate cerebrovascular events at the time of surgery may pave the way for prevention strategies. This review provides an overview on perioperative stroke incidence, related problems, and underlying pathophysiological mechanisms. Based on this analysis, we assess experimental stroke treatments including neuroprotective approaches, cell therapies, and conditioning medicine strategies regarding their potential use in perioperative stroke. Interestingly, the specific aspects of perioperative stroke might enable a more effective application of experimental treatment strategies such as classical neuroprotection whereas others including cell therapies may be of limited use. We also discuss experimental diagnostic options for perioperative stroke augmenting classical clinical and imaging stroke diagnosis. While some experimental stroke treatments may have specific advantages in perioperative stroke, the paucity of established guidelines or multicenter clinical research initiatives currently limits their thorough investigation

New mechanistic insights, novel treatment paradigms, and clinical progress in cerebrovascular diseases

The past decade has brought tremendous progress in diagnostic and therapeutic options for cerebrovascular diseases as exemplified by the advent of thrombectomy in ischemic stroke, benefitting a steeply increasing number of stroke patients and potentially paving the way for a renaissance of neuroprotectants. Progress in basic science has been equally impressive. Based on a deeper understanding of pathomechanisms underlying cerebrovascular diseases, new therapeutic targets have been identified and novel treatment strategies such as pre- and post-conditioning methods were developed. Moreover, translationally relevant aspects are increasingly recognized in basic science studies, which is believed to increase their predictive value and the relevance of obtained findings for clinical application.This review reports key results from some of the most remarkable and encouraging achievements in neurovascular research that have been reported at the 10th International Symposium on Neuroprotection and Neurorepair. Basic science topics discussed herein focus on aspects such as neuroinflammation, extracellular vesicles, and the role of sex and age on stroke recovery. Translational reports highlighted endovascular techniques and targeted delivery methods, neurorehabilitation, advanced functional testing approaches for experimental studies, pre-and post-conditioning approaches as well as novel imaging and treatment strategies. Beyond ischemic stroke, particular emphasis was given on activities in the fields of traumatic brain injury and cerebral hemorrhage in which promising preclinical and clinical results have been reported. Although the number of neutral outcomes in clinical trials is still remarkably high when targeting cerebrovascular diseases, we begin to evidence stepwise but continuous progress towards novel treatment options. Advances in preclinical and translational research as reported herein are believed to have formed a solid foundation for this progress

High-dosage granulocyte colony stimulating factor treatment alters monocyte trafficking to the brain after experimental stroke

Ischemic stroke elicits a prompt inflammatory response that is characterized by a well-timed recruitment of peripheral immune cells to the brain. Among these, monocytes play a particularly important, but multifaceted role and have been increasingly recognized to affect stroke outcome. Granulocyte colony stimulating factor (GCSF) is known for its immunosuppressive actions on mononuclear cells, but previous studies in the stroke field were mainly confined to its neuroprotective actions. Herein, we investigated whether GCSF affects post-stroke inflammation in a mouse model of focal brain ischemia by modulating monocyte responses. Treatment with GCSF was controlled by vehicle injection, sham surgery and naive animals. Despite a significant monocytosis, high-dosage GCSF reduced the number of brain-infiltrating monocytes/macrophages four days after stroke. Lower numbers of mononuclear phagocytes in the brain were associated with smaller cerebral edema and improved motor outcome after stroke. GCSF treatment over 72 h, but not 24 h diminished integrin expression on circulating Ly6C+ inflammatory monocytes. In vitro experiments further revealed that GCSF strongly promotes interleukin (IL)-10 secretion by activated mononuclear cells. Blockade of the IL-10 receptor partly reversed GCSF-induced downregulation of integrin surface expression. Overall, our results suggest that high-dosage GCSF mitigates monocyte infiltration after stroke, likely by attenuating integrin-mediated adhesion to the brain endothelium in an IL-10-dependent manner. Lower amounts of mononuclear cells in the brain translate to less severe brain edema and functional impairment and thus support a harmful role of Ly6C+ inflammatory monocytes in the acute stage of stroke

Arterial hypertension aggravates innate immune responses after experimental stroke

Arterial hypertension is not only the leading risk factor for stroke, but also attributes to impaired recovery and poor outcome. The latter could be explained by hypertensive vascular remodeling that aggravates perfusion deficits and blood–brain barrier disruption. However, besides vascular changes, one could hypothesize that activation of the immune system due to pre-existing hypertension may negatively influence post-stroke inflammation and thus stroke outcome. To test this hypothesis, male adult spontaneously hypertensive rats (SHRs) and normotensive Wistar Kyoto rats (WKYs) were subjected to photothrombotic stroke. One and 3 days after stroke, infarct volume and functional deficits were evaluated by magnetic resonance imaging and behavioral tests. Expression levels of adhesion molecules and chemokines along with the post-stroke inflammatory response were analyzed by flow cytometry, quantitative real-time PCR and immunohistochemistry in rat brains 4 days after stroke. Although comparable at day 1, lesion volumes were significantly larger in SHR at day 3. The infarct volume showed a strong correlation with the amount of CD45 highly positive leukocytes present in the ischemic hemispheres. Functional deficits were comparable between SHR and WKY. Brain endothelial expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and P-selectin (CD62P) was neither increased by hypertension nor by stroke. However, in SHR, brain infiltrating myeloid leukocytes showed significantly higher surface expression of ICAM-1 which may augment leukocyte transmigration by leukocyte–leukocyte interactions. The expression of chemokines that primarily attract monocytes and granulocytes was significantly increased by stroke and, furthermore, by hypertension. Accordingly, ischemic hemispheres of SHR contain considerably higher numbers of monocytes, macrophages and granulocytes. Exacerbated brain inflammation in SHR may finally be responsible for larger infarct volumes. These findings provide an immunological explanation for the epidemiological observation that existing hypertension negatively affects stroke outcome and mortality

New Mechanistic Insights, Novel Treatment Paradigms, and Clinical Progress in Cerebrovascular Diseases.

The past decade has brought tremendous progress in diagnostic and therapeutic options for cerebrovascular diseases as exemplified by the advent of thrombectomy in ischemic stroke, benefitting a steeply increasing number of stroke patients and potentially paving the way for a renaissance of neuroprotectants. Progress in basic science has been equally impressive. Based on a deeper understanding of pathomechanisms underlying cerebrovascular diseases, new therapeutic targets have been identified and novel treatment strategies such as pre- and post-conditioning methods were developed. Moreover, translationally relevant aspects are increasingly recognized in basic science studies, which is believed to increase their predictive value and the relevance of obtained findings for clinical application.This review reports key results from some of the most remarkable and encouraging achievements in neurovascular research that have been reported at the 10th International Symposium on Neuroprotection and Neurorepair. Basic science topics discussed herein focus on aspects such as neuroinflammation, extracellular vesicles, and the role of sex and age on stroke recovery. Translational reports highlighted endovascular techniques and targeted delivery methods, neurorehabilitation, advanced functional testing approaches for experimental studies, pre-and post-conditioning approaches as well as novel imaging and treatment strategies. Beyond ischemic stroke, particular emphasis was given on activities in the fields of traumatic brain injury and cerebral hemorrhage in which promising preclinical and clinical results have been reported. Although the number of neutral outcomes in clinical trials is still remarkably high when targeting cerebrovascular diseases, we begin to evidence stepwise but continuous progress towards novel treatment options. Advances in preclinical and translational research as reported herein are believed to have formed a solid foundation for this progress