Inhaled Nitric Oxide Promotes Angiogenesis in the Rodent Developing Brain.

Inhaled nitric oxide (iNO) is a therapy used in neonates with pulmonary hypertension. Some evidence of its neuroprotective properties has been reported in both mature and immature brains subjected to injury. NO is a key mediator of the VEGF pathway, and angiogenesis may be involved in the reduced vulnerability to injury of white matter and the cortex conferred by iNO.

Collateral Supply in Preclinical Cerebral Stroke Models.

Enhancing the collateral blood supply during the acute phase of cerebral ischemia may limit both the extension of the core infarct, by rescuing the penumbra area, and the degree of disability. Many imaging techniques have been applied to rodents in preclinical studies, to evaluate the magnitude of collateral blood flow and the time course of responses during the early phase of ischemic stroke. The collateral supply follows several different routes at the base of the brain (the circle of Willis) and its surface (leptomeningeal or pial arteries), corresponding to the proximal and distal collateral pathways, respectively.

Poly(ADP-Ribose) Polymerase Inhibitor PJ34 Reduces Brain Damage after Stroke in the Neonatal Mouse Brain.

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).

Endothelial S1P Signaling Counteracts Infarct Expansion in Ischemic Stroke.

Rationale: Cerebrovascular function is critical for brain health, and endogenous vascular protective pathways may provide therapeutic targets for neurological disorders. S1P (Sphingosine 1-phosphate) signaling coordinates vascular functions in other organs, and S1P (S1P receptor-1) modulators including fingolimod show promise for the treatment of ischemic and hemorrhagic stroke. However, S1P also coordinates lymphocyte trafficking, and lymphocytes are currently viewed as the principal therapeutic target for S1P modulation in stroke.

Cerebral Vasodilator Property of Poly(ADP-Ribose) Polymerase Inhibitor (PJ34) in the Neonatal and Adult Mouse Is Mediated by the Nitric Oxide Pathway.

The poly(ADP-ribose) polymerase (PARP) inhibitor PJ34 has been reported to improve endothelial dysfunction in the peripheral system. We addressed the role of PJ34 on the vascular tone and vasoreactivity during development in the mouse brain. Blood flows were measured in the basilar trunk using ultrasonography.

A simple novel approach for detecting blood-brain barrier permeability using GPCR internalization.

Aims: Impairment of blood-brain barrier (BBB) is involved in numerous neurological diseases from developmental to aging stages. Reliable imaging of increased BBB permeability is therefore crucial for basic research and preclinical studies. Today, the analysis of extravasation of exogenous dyes is the principal method to study BBB leakage.

Early Sex Differences in the Immune-Inflammatory Responses to Neonatal Ischemic Stroke.

We recently reported that neonatal ischemia induces microglia/macrophage activation three days post-ischemia. We also found that female mice sustained smaller infarcts than males three months post-ischemia. The objective of our current study was to examine whether differential acute neuroinflammatory response and infiltrated immune cells occurs between male and females after three days post-ischemia.

Glatiramer acetate reduces infarct volume in diabetic mice with cerebral ischemia and prevents long-term memory loss.

Stroke is currently the second leading cause of death in industrialized countries and the second cause of dementia after Alzheimer's disease. Diabetes is an independent risk factor for stroke that exacerbates the severity of lesions, disability and cognitive decline. There is increasing evidence that sustained brain inflammation may account for this long-term prejudicial outcome in diabetic patients in particular.

Oxytocin receptor agonist reduces perinatal brain damage by targeting microglia.

Prematurity and fetal growth restriction (FGR) are frequent conditions associated with adverse neurocognitive outcomes. We have previously identified early deregulation of genes controlling neuroinflammation as a putative mechanism linking FGR and abnormal trajectory of the developing brain. While the oxytocin system was also found to be impaired following adverse perinatal events, its role in the modulation of neuroinflammation in the developing brain is still unknown.

Prostaglandin E1-Mediated Collateral Recruitment Is Delayed in a Neonatal Rat Stroke Model.

While arterial reflow after a stroke represents an important challenge for better outcomes, it is also very important that sudden recanalization does not produce local oxidative and nitrogen species, deleterious for the brain and more particularly the immature brain. Our objective was to determine whether a supply in prostaglandin (Pg) E1 (Alprostadil), via its action on arterial pressure, might progressively improve cerebral reperfusion in a neonatal stroke model. Arterial blood flow was measured using ultrasonography.

A Model of Perinatal Ischemic Stroke in the Rat: 20 Years Already and What Lessons?

Neonatal hypoxia-ischemia (HI) and ischemia are a common cause of neonatal brain injury resulting in cerebral palsy with subsequent learning disabilities and epilepsy. Recent data suggest a higher incidence of focal ischemia-reperfusion located in the middle cerebral artery (MCA) territory in near-term and newborn babies. Pre-clinical studies in the field of cerebral palsy research used, and still today, the classical HI model in the P7 rat originally described by Rice et al.

Sex differences in the effects of PARP inhibition on microglial phenotypes following neonatal stroke.

Neonatal acute ischemic stroke is a cause of neonatal brain injury that occurs more frequently in males, resulting in associated neurobehavioral disorders. The bases for these sex differences are poorly understood but might include the number, morphology and activation of microglia in the developing brain when subjected to stroke. Interestingly, poly (ADP-ribose) polymerase (PARP) inhibition preferentially protects males against neonatal ischemia.

Sexually Dimorphic Outcomes after Neonatal Stroke and Hypoxia-Ischemia.

Cohort studies have demonstrated a higher vulnerability in males towards ischemic and/or hypoxic-ischemic injury in infants born near- or full-term. Male sex was also associated with limited brain repair following neonatal stroke and hypoxia-ischemia, leading to increased incidence of long-term cognitive deficits compared to females with similar brain injury. As a result, the design of pre-clinical experiments considering sex as an important variable was supported and investigated because neuroprotective strategies to reduce brain injury demonstrated sexual dimorphism.

Controlled arterial reflow after ischemia induces better outcomes in the juvenile rat brain.

Our objective was to determine whether controlled reflow on one side and/or the other side after bilateral carotid occlusion release could reduce cell death in focal ischemic P14 rats. Arterial blood flow was measured using ultrasonography. Cell death, inflammation and nitrotyrosine were measured using immunofluorescence.

Different response to antiepileptic drugs according to the type of epileptic events in a neonatal ischemia-reperfusion model.

Perinatal arterial stroke is the most frequent form of cerebral infarction in children. Neonatal seizures are the most frequent symptom during the neonatal period. The current management of perinatal stroke is based on supportive care.

Cyclooxygenase-2-Derived Prostaglandins Mediate Cerebral Microcirculation in a Juvenile Ischemic Rat Model.

Background And Purpose: We previously showed that the selective neuronal nitric oxide synthase inhibitor 7-nitroindazole (7-NI) increases cerebral microcirculation in a juvenile ischemic rat model. We address the roles of cyclooxygenase (COX)-elaborated prostaglandins in collateral recruitment and blood supply.

Methods: Fourteen-day-old rats were subjected to ischemia-reperfusion and treated with either PBS or 7-NI (25 mg/kg) at the reperfusion onset.

Transcriptomic regulations in oligodendroglial and microglial cells related to brain damage following fetal growth restriction.

Fetal growth restriction (FGR) is a major complication of human pregnancy, frequently resulting from placental vascular diseases and prenatal malnutrition, and is associated with adverse neurocognitive outcomes throughout life. However, the mechanisms linking poor fetal growth and neurocognitive impairment are unclear. Here, we aimed to correlate changes in gene expression induced by FGR in rats and abnormal cerebral white matter maturation, brain microstructure, and cortical connectivity in vivo.

Glial response to 17β-estradiol in neonatal rats with excitotoxic brain injury.

White-matter injury is the most common cause of the adverse neurodevelopmental outcomes observed in preterm infants. Only few options exist to prevent perinatal brain injury associated to preterm delivery. 17β-estradiol (E2) is the predominant estrogen in circulation and has been shown to be neuroprotective in vitro and in vivo.

Sildenafil, a cyclic GMP phosphodiesterase inhibitor, induces microglial modulation after focal ischemia in the neonatal mouse brain.

Background: Perinatal ischemic stroke is the most frequent form of cerebral infarction in neonates; however, evidence-based treatments are currently lacking. We have previously demonstrated a beneficial effect of sildenafil citrate, a PDE-5 inhibitor, on stroke lesion size in neonatal rat pups. The present study investigated the effects of sildenafil in a neonatal mouse stroke model on (1) hemodynamic changes and (2) regulation of astrocyte/microglia-mediated neuroinflammation.

Deleting IGF-1 receptor from forebrain neurons confers neuroprotection during stroke and upregulates endocrine somatotropin.

Insulin-like growth factors control numerous processes, namely somatic growth, metabolism and stress resistance, connecting this pathway to aging and age-related diseases. Insulin-like growth factor signaling also impacts on neurogenesis, neuronal survival and structural plasticity. Recent reports demonstrated that diminished insulin-like growth factor signaling confers increased stress resistance in brain and other tissues.

Early Recruitment of Cerebral Microcirculation by Neuronal Nitric Oxide Synthase Inhibition in a Juvenile Ischemic Rat Model.

Background: The development of collateral circulation is proposed as an inherent compensatory mechanism to restore impaired blood perfusion after ischemia, at least in the penumbra. We have studied the dynamic macro- and microcirculation after ischemia-reperfusion in the juvenile rat brain and evaluated the impact of neuronal nitric oxide synthase (nNOS) inhibition on the collateral flow.

Methods: Fourteen-day-old (P14) rats were subjected to ischemia-reperfusion and treated with either PBS or 7-nitroindazole (7-NI, an nNOS inhibitor, 25 mg/kg).

Nitric Oxide Pathway and Proliferation of Neural Progenitors in the Neonatal Rat.

Several lines of evidence demonstrate that inhaled nitric oxide (iNO) not only acts locally on the pulmonary vasculature but also has remote effects on the mature and developing brain under basal or pathological conditions by modulating cerebral blood flow and microvascularization, white matter maturation, inflammation, and subsequent brain repair. Previously, consistent studies demonstrated that increased levels of guanosine 3',5' cyclic monophosphate (cGMP), the main effector of biological effect induced by nitric oxide (NO), significantly augment proliferation and neuronal differentiation of adult neural progenitor cells (NPCs). In the present study, we ask the question whether iNO could promote the proliferation of NPCs in the uninjured developing brain.