How to Pick a Neuroprotective Drug in Stroke Without Losing Your Mind?

Area of Science:

• Neuroscience
• Pharmacology
• Translational Medicine

Background:

• Clinical trials for neuroprotective therapies in cerebral ischemia have consistently failed, hindering progress in the field.
• Methodological flaws in both clinical and preclinical studies have been identified and are being addressed to improve rigor and transparency.
• Advances in re-canalization techniques offer potential for adjunctive neuroprotection to enhance patient outcomes.

Purpose of the Study:

• To propose a novel in vitro framework for prioritizing neuroprotective therapeutics for clinical translation.
• To address the challenge of selecting the most appropriate neuroprotective therapy given resource limitations and numerous potential strategies.
• To leverage improvements in clinical and preclinical methodologies to refine therapeutic selection.

Main Methods:

• Utilizing in vitro studies subjecting neurons to oxygen-glucose deprivation (OGD) across a lethal/supra-lethal continuum.
• Comparing drug efficacy alone and in combinations through 'head-to-head' evaluations.
• Employing multi-electrode arrays (MEAs) to assess functional neuroprotection and adverse effects.

Main Results:

• Increasing OGD durations necessitate drugs of greater potency and dose, particularly NMDA receptor (NMDAR) antagonists.
• Supra-lethal OGD conditions require potent anti-excitotoxic drug cocktails for neuroprotection.
• The proposed framework facilitates systematic comparison of existing and novel neuroprotective agents.

Conclusions:

• An in vitro OGD-based framework can effectively prioritize neuroprotective therapeutics by simulating varying degrees of ischemic severity.
• Anti-excitotoxic approaches appear crucial, but the framework accommodates diverse therapeutic strategies.
• This systematic approach aims to eliminate ineffectual treatments, advancing therapies with the highest therapeutic index for clinical translation.