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Minocycline decreases blood-brain barrier permeability following aneurysmal subarachnoid hemorrhage: a randomized,
Ben A Strickland1, Giuseppe Barisano1, Aidin Abedi1
11Departments of Neurosurgery.
Objective:
Aneurysmal subarachnoid hemorrhage (aSAH)-induced vasospasm is linked to increased inflammatory cell trafficking across a permeable blood-brain barrier (BBB). Elevations in serum levels of matrix metalloprotease 9 (MMP9), a BBB structural protein, have been implicated in the pathogenesis of vasospasm onset. Minocycline is a potent inhibitor of MMP9. The authors sought to detect an effect of minocycline on BBB permeability following aSAH.
Methods:
Patients presenting within 24 hours of symptom onset with imaging confirmed aSAH (Fisher grade 3 or 4) were randomized to high-dose (10 mg/kg) minocycline or placebo. The primary outcome of interest was BBB permeability as quantitated by contrast signal intensity ratios in vascular regions of interest on postbleed day (PBD) 5 magnetic resonance permeability imaging. Secondary outcomes included serum MMP9 levels and radiographic and clinical evidence of vasospasm.
Results:
A total of 11 patients were randomized to minocycline (n = 6) or control (n = 5) groups. No adverse events or complications attributable to minocycline were reported. High-dose minocycline administration was associated with significantly lower permeability indices on imaging analysis (p < 0.01). There was no significant difference with respect to serum MMP9 levels between groups, although concentrations trended upward in both cohorts. Radiographic vasospasm was noted in 6 patients (minocycline = 3, control = 3), with only 1 patient developing symptoms of clinical vasospasm in the minocycline cohort. There was no difference between cohorts with respect to Lindegaard ratios, transcranial Doppler values, or onset of vasospasm.
Conclusions:
Minocycline at high doses is well tolerated in the ruptured cerebral aneurysm population. Minocycline curtails breakdown of the BBB following aSAH as evidenced by lower permeability indices, though minocycline did not significantly alter serum MMP9 levels. Larger randomized clinical trials are needed to assess minocycline as a neuroprotectant against aSAH-induced vasospasm. Clinical trial registration no.: NCT04876638 (clinicaltrials.gov).
Insights
High-dose minocycline effectively reduced blood-brain barrier permeability after aneurysmal subarachnoid hemorrhage (aSAH), showing promise as a neuroprotectant. Further trials are needed to confirm its efficacy against vasospasm.
Area of Science:
- Neuroscience
- Pharmacology
- Neurosurgery
Background:
- Aneurysmal subarachnoid hemorrhage (aSAH) often leads to vasospasm due to increased blood-brain barrier (BBB) permeability.
- Matrix metalloprotease 9 (MMP9) is implicated in BBB breakdown and vasospasm pathogenesis.
- Minocycline, an MMP9 inhibitor, is investigated for its potential to mitigate these effects.
Purpose of the Study:
- To evaluate the efficacy of high-dose minocycline in reducing BBB permeability following aSAH.
- To assess the impact of minocycline on serum MMP9 levels and the incidence of vasospasm.
Main Methods:
- A randomized trial involving patients with confirmed aSAH (Fisher grade 3 or 4) within 24 hours of symptom onset.
- Participants received either high-dose minocycline (10 mg/kg) or placebo.
- Blood-brain barrier permeability was measured using magnetic resonance permeability imaging on postbleed day 5.
Main Results:
- Minocycline treatment was associated with significantly lower BBB permeability indices (p < 0.01).
- No significant difference in serum MMP9 levels was observed between groups.
- While radiographic vasospasm was similar, only one patient in the minocycline group developed clinical vasospasm.
Conclusions:
- High-dose minocycline is well-tolerated in patients with ruptured cerebral aneurysms.
- Minocycline effectively reduces BBB breakdown post-aSAH, independent of MMP9 levels.
- Larger trials are warranted to establish minocycline's neuroprotective role against aSAH-induced vasospasm.
