Neuroprotection after EMPHASIS: a scoping review of minocycline in acute ischaemic stroke — mechanisms, clinical evidence, and research agenda

Minocycline, a tetracycline antibiotic with anti-neuroinflammatory, matrix metalloproteinase-9-inhibiting, and blood–brain-barrier-protective properties, has been studied as a neuroprotective candidate in acute ischaemic stroke (AIS) for two decades, with inconsistent results from small randomised trials. The field reached an inflection point in 2026: the EMPHASIS trial (Lancet 2026;407:679–88; n=1,724) was the first large, double-blind RCT to show that oral minocycline initiated within 72 h of AIS onset improves 90-day excellent functional outcome (mRS 0–1: 52.6% vs 47.4%; adjusted RR 1.11, 95% CI 1.03–1.20), whereas the phase 2 MIST-A trial (Lancet Reg Health West Pac 2026;71:101898; n=189) found no benefit of adjunctive minocycline on infarct growth or functional outcome in patients with anterior-circulation large-vessel occlusion who achieved successful recanalisation after mechanical thrombectomy. The clinical evidence is heterogeneous in design, dose regimens, therapeutic windows, outcome definitions, and reperfusion context, making a quantitative meta-analytic summary premature. This scoping review, conducted per the JBI methodology and reported per PRISMA-ScR, will (i) map the volume, distribution, and design of clinical evidence on minocycline in AIS; (ii) characterise intervention parameters and outcome definitions across studies; (iii) describe reported efficacy and safety before vs after EMPHASIS and by reperfusion context; (iv) catalogue completed and ongoing registered trials; and (v) identify evidence gaps to inform future trial design. No meta-analysis and no risk-of-bias appraisal will be performed (optional under PRISMA-ScR); both decisions are reported transparently.