2013 Thomas Willis Award Lecture

Abstract

Abstract-The pathophysiology of stroke is complex. Adaptive and maladaptive signalling occurs between multiple cell types in the brain. There is crosstalk between central and systemic responses. And there are overlapping pathways during initial injury and subsequent repair. These numerous feed-forward and feed-back interactions have made it difficult to translate experimental discoveries into clinical applications. An emerging hypothesis in biomedical research now suggests that contrary to a traditional model, translation may not be efficiently obtained without a rigorous understanding of mechanisms. Hence, to optimize diagnostics and therapeutics for stroke patients, it is necessary to identify and define causal mechanisms. Mirroring the multi-compartment interactions in stroke pathophysiology, bench-to-bedside, and bedside-back-to-bench advances in stroke may be best achieved with inter-disciplinary collaborations between basic research, neuroimaging, and broadly based clinical science. Causation can then be two-fold, ie, dissecting mechanisms and targets, as well as developing future scientists who can blur the boundaries between basic, translational, and clinical research. In systems theory, a critical goal is to distinguish causation from correlation. In stroke research, causation may perhaps be found through a collaborative search for mechanisms.

Pharmacologically targeted NMDA receptor antagonism by NitroMemantine for cerebrovascular disease

“…Focal cerebral ischemia (stroke) and vascular dementia (due to multiple strokes in the microvasculature) represent leading causes of severe cognitive dysfunction and death worldwide 1 . While excessive stimulation of N -methyl- d -aspartate-type glutamate receptors (NMDARs) is acknowledged to be important in the etiology of cerebrovascular damage 2 3 , NMDAR antagonists were previously found to be either ineffective or clinically intolerable for cerebral ischemic insults in humans despite promising early results in animal models 4 5 6 .…”

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

“…Systematic differences between groups/experiments due to changing of animal care, housing conditions, diet, group sizes per cages, cage location in-house, instruments used, failure to complete protocols during the study (Lo, 2014;Dirnagl, 2016;Huang et al, 2020) Data and results bias Attrition bias Unequal occurrence and handling of deviations from protocol and loss to follow-up between treatment groups. For example, subjects dropping out of the study (e.g., unexpected death) or undefined exclusion of "outliers" (Dirnagl, 2016;Huang et al, 2020) Bias of results towards positive ones.…”

“…Biased allocation of animals at the beginning or during an experiment. Here belongs the improper randomization (Sena et al, 2010a;Lo, 2014) -Studies do not report allocation methods, randomization, and blinding assessment of outcome.…”

“…Others have also provided evidence that the rabbit small clot embolic stroke model (RSCEM) may correlate better with human brain timewindows, and probably should be used before decisions are made to authorize the clinical transfer of any novel treatment (Lapchak, 2010). In vitro cultures or brain slices from rodents as models of hypoxia are useful only as "add-on" methods to study isolated molecular pathways and genetic expression on cell substrates, considering all the limitations of such extra-corporal methods that lack the physiological cross-talk between the brain and the body (Honegger, 2001;Lo, 2014;Sunwoldt et al, 2017). Eventually, the selection of an appropriate model and type of study (screening, discovery, mechanistic, proof-of-concept or effectiveness of new treatment) (Gannon, 2014) may determine the result of translational research (Kola and Landis, 2004;Shanks et al, 2009;Howells et al, 2010;Dalgaard, 2015).…”

GLYX-13, a NMDA Receptor Glycine-Site Functional Partial Agonist, Attenuates Cerebral Ischemia Injury In Vivo and Vitro by Differential Modulations of NMDA Receptors Subunit Components at Different Post-Ischemia Stage in Mice

“…Currently, focal cerebral ischemia (stroke) is one of the most common reasons of death and disability in middle-aged and elderly people worldwide (Lo, 2014 ). Compared to other tissues and organs in the body, the brain is particularly vulnerable to ischemic injury.…”