Minocycline decreases blood-brain barrier permeability following aneurysmal subarachnoid hemorrhage: a randomized, double-blind, controlled trial

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  • 1 Departments of Neurosurgery,
  • | 2 Neuroradiology,
  • | 3 Biostatistics, and
  • | 4 Neurology, and
  • | 5 Neurorestoration Center, University of Southern California, Los Angeles, California
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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)

ABBREVIATIONS

ACA = anterior cerebral artery; aSAH = aneurysmal subarachnoid hemorrhage; BBB = blood-brain barrier; DCI = delayed cerebral ischemia; dMCA = deep branches of the middle cerebral artery; ELISA = enzyme-linked immunosorbent assay; FSL = FMRIB Software Library; MCA = middle cerebral artery; MMP9 = matrix metalloprotease 9; mRS = modified Rankin Scale; OD = optical density; PBD = postbleed day; PCA = posterior cerebral artery; ROI = region of interest; SI = signal intensity; sMCA = superior division of the MCA; SSS = superior sagittal sinus; TCD = transcranial Doppler; vROI = vascular region of interest/territory.

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