RESUMEN
OBJECTIVE Tissue plasminogen activator (tPA) is the only approved pharmaco-logical therapy for acute brain ischaemia;however,a major limitation of tPA is the haemorrhagic trans-formation that follows tPA treatment. Here, we determined whether nicotinamide mononucleotide (NMN), a key intermediate of nicotinamide adenine dinucleotide biosynthesis, affects tPA-induced haemorrhagic transformation. METHODS Middle cerebral artery occlusion (MCAO) was achieved in CD1 mice by introducing a filament to the left MCA for 5 h.When the filament was removed for reperfusion, tPA was infused via the tail vein.A single dose of NMN was injected i.p.(300 mg·kg-1).Mice were killed at 24 h post ischaemia, and their brains were evaluated for brain infarction, oedema, haemoglobin content, apoptosis, neuroinflammation, blood-brain barrier (BBB) permeability, the expression of tight junction proteins(TJPs)and the activity/expression of MMPs. RESULTS In the mice infused with tPA at 5 h post ischaemia, there were significant increases in mortality, brain infarction, brain oedema, brain haemoglobin level, neural apoptosis, Iba-1 staining (microglia activation) and myeloperoxidase staining (neutrophil infiltration). All these tPA-induced alterations were significantly prevented by NMN administration. Mechanistically, the delayed tPA treatment increased BBB permeability by down-regulating TJPs, including claudin-1, occludin and zonula occludens-1,and enhancing the activities and protein expression of MMP9 and MMP2. Similarly, NMN administration partly blocked these tPA-induced molecular changes. CONCLUSION Our results demonstrate that NMN ameliorates tPA-induced haemorrhagic transformation in brain ischaemia by maintaining the integrity of the BBB.
RESUMEN
BACKGROUND AND PURPOSE: To evaluate the frequency and outcome of haemorrhagic transformation (HT) after ischaemic stroke in patients treated with non-vitamin K antagonist oral anticoagulants (NOACs). METHODS: Patients with stroke on treatment with a NOAC were prospectively enrolled in this multicentre observational study between February 2012 and 2015. Brain imaging at admission and follow-up imaging until day 7 were reviewed for HT. Functional outcome was assessed by the modified Rankin scale (mRS) before the index event, at discharge, and at 3-months. RESULTS: 231 patients without recanalisation therapy (no-RT), and 32 patients with RT were eligible for analysis. Any HT was present at admission in 9/231 no-RT patients (3.9%, 95% CI 2.0 to 7.3) and in none of the patients with RT. In patients with follow-up imaging (no-RT, n=129, and RT, n=32), HT was present in 14.0% (no-RT; 95% CI, 8.9 to 21.1), and 40.6% (RT, 95% CI, 25.5 to 57.8), respectively. After adjustment for stroke severity, this difference between the no-RT and RT groups became non-significant. Symptomatic ICH was observed in 1 patient per group. HT was not associated with unfavourable outcome (mRS 3-6) at 3-months in multivariable analysis. Resumption of OAC after stroke was delayed in patients with HT compared to those without (15 d [IQR, 5–26] vs. 1 d [0–4], P<0.001). CONCLUSIONS: The frequency and severity of HT after stroke on NOAC appears similar to previous reports for vitamin K antagonists and no anticoagulation. Whether asymptomatic HT should delay resumption of preventive anticoagulation requires further investigation.