  Acute neuroprotection in numerous human clinical trials has been an abject
failure. Major systemic-and procedural-based issues have subsequently been
identified in both clinical trials and preclinical animal model
experimentation. As well, issues related to the neuroprotective moiety itself
have contributed to clinical trial failures, including late delivery,
mono-targeting, low potency and poor tolerability. Conditioning (pre-or post-)
strategies can potentially address these issues and are therefore gaining
increasing attention as approaches to protect the brain from cerebral ischemia.
In principle, conditioning can address concerns of timing (preconditioning
could be pre-emptively applied in high-risk patients, and post-conditioning
after patients experience an unannounced brain infarction) and signaling
(multi-modal). However, acute neuroprotection and conditioning strategies face
a common translational issue: a myriad of possibilities exist, but with no
strategy to select optimal candidates. In this review, we argue that what is
required is a neuroprotective framework to identify the "best" agent(s), at the
earliest investigational stage possible. This may require switching mindsets
from identifying how neuroprotection can be achieved to determining how
neuroprotection can fail, for the vast majority of candidates. Understanding
the basis for failure can in turn guide supplementary treatment, thereby
forming an evidence-based rationale for selecting combinations of therapies. An
appropriately designed in vitro (neuron culture, brain slices) approach, based
on increasing the harshness of the ischemic-like insult, can be useful in
identifying the "best" conditioner or acute neuroprotective therapy, as well as
how the two modalities can be combined to overcome individual limitations. This
would serve as a base from which to launch further investigation into therapies
required to protect the neurovascular unit in in vivo animal models of cerebral
ischemia. Based on these respective approaches, our laboratories suggest that
there is merit in examining synaptic activity-and nutraceutical-based
preconditioning / acute neuroprotection.
