Abstract
The poly(ADP-ribose) polymerase inhibitor PJ34 has recently been reported to increase cerebral blood flow, via the endothelial NO synthase, in the naive mouse brain throughout life. We addressed here the benefits of PJ34 after neonatal ischemia on hemodynamics and components of the neurovascular unit including the blood-brain barrier (BBB), microglia, and astrocytes. Nine-day-old mice were subjected to permanent MCA occlusion (pMCAo), and treated with either PBS or PJ34 (10 mg/kg). Mean blood-flow velocities (mBFV) were measured in both internal carotid arteries (ICA) and basilar trunk (BT) using Doppler-ultrasonography. BBB opening was assessed through somatostatin-receptor type-2 internalization and immunohistochemistry at 24 and 48 h. Lesion areas were measured 8 days after ischemia. In PBS-treated mice, pMCAo involved a drop in mBFV in the left ICA (p < 0.001 vs. basal), whereas mBFV remained stable in both right ICA and BT. PJ34 prevented this drop in the left ICA (NS vs. basal) and increased mBFV in the right ICA (p = 0.0038 vs. basal). No modification was observed in the BT. In contrast to PBS, BBB disruption extent and astrocyte demise were reduced in PJ34 mice only in the rostral brain at 48 h and 8 days post-pMCAo, respectively. Accordingly, 8 days after pMCAo, affected areas were reduced in the rostral brain (Bregma +0.86 and +0.14 mm), whereas total tissue loss was not reduced after PJ34 (4.0 ± 3.1%) vs. PBS (5.8 ± 3.4%). These results show that PJ34 reduced BBB permeability, astrocyte demise, and tissue loss (particularly in the rostral territories), suggesting that collateral supply mainly proceeds from the anterior ICA’s branches in the ischemic neonatal mouse brain.
Highlights
Neonatal arterial stroke is a cerebrovascular event that occurs near the time of birth, producing significant morbidity and severe long-term neurological and cognitive deficits such as cerebral palsy, impaired vision and language function, and epilepsy
In the cerebral vascular system, we recently reported that a single dose of the Poly(ADP-ribose) polymerase (PARP) inhibitor PJ34 (10 mg/kg) is able to increase cerebral blood-flow (CBF) by recruitment of the microvascular vasodilation reserve, and is likely to act on the endothelial function throughout life in the naive mouse [7]
No differences in Mean blood-flow velocities (mBFV) were recorded in the three arteries of the circle of Willis before ischemia and injections between PBS- and PJ34-treated mice
Summary
Neonatal arterial stroke is a cerebrovascular event that occurs near the time of birth, producing significant morbidity and severe long-term neurological and cognitive deficits such as cerebral palsy, impaired vision and language function, and epilepsy. Neonatal stroke is a disorder affecting both macro- and micro-vascular networks during ischemia and reperfusion, leading to blood-brain barrier (BBB) disruption, edema, and cell death. In the cerebral vascular system, we recently reported that a single dose of the PARP inhibitor PJ34 (10 mg/kg) is able to increase cerebral blood-flow (CBF) by recruitment of the microvascular vasodilation reserve (without sex effect), and is likely to act on the endothelial function throughout life (with a major effect in the neonatal and adult brain) in the naive mouse [7]. We address the cerebral vasodilator property of PJ34 (given as a single dose) after neonatal ischemia, and evaluate its incidence on blood-flow rerouting and NVU actors (early BBB leakage using G protein coupled receptor internalization [10]), microglia, and astrocyte phenotypes as indicators of tissue damage
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