PPARs (peroxisome-proliferator-activated receptors) are ligand-activated transcriptional factor receptors belonging to the so-called nuclear receptor family. The three isoforms of PPAR (α, β/δ and γ) are involved in regulation of lipid or glucose metabolism. Beyond metabolic effects, PPARα and PPARγ activation also induces anti-inflammatory and antioxidant effects in different organs. These pleiotropic effects explain why PPARα or PPARγ activation has been tested as a neuroprotective agent in cerebral ischaemia. Fibrates and other non-fibrate PPARα activators as well as thiazolidinediones and other non-thiazolidinedione PPARγ agonists have been demonstrated to induce both preventive and acute neuroprotection. This neuroprotective effect involves both cerebral and vascular mechanisms. PPAR activation induces a decrease in neuronal death by prevention of oxidative or inflammatory mechanisms implicated in cerebral injury. PPARα activation induces also a vascular protection as demonstrated by prevention of post-ischaemic endothelial dysfunction. These vascular effects result from a decrease in oxidative stress and prevention of adhesion proteins, such as vascular cell adhesion molecule 1 or intercellular cell-adhesion molecule 1. Moreover, PPAR activation might be able to induce neurorepair and endothelium regeneration. Beyond neuroprotection in cerebral ischaemia, PPARs are also pertinent pharmacological targets to induce neuroprotection in chronic neurodegenerative diseases.

The treatment of ischemic strokes is limited to the prevention of cerebrovascular risk factors and to the modulation of the coagulation cascade during the acute phase. A new therapeutic strategy could be to preventively protect the brain against noxious biological reactions induced by cerebral ischemia such as oxidative stress and inflammation to minimize their neurological consequences. Here, we show that a peroxisome proliferator-activated receptor (PPAR-α) activator, fenofibrate, protects against cerebral injury by anti-oxidant and anti-inflammatory mechanisms. A 14 d preventive treatment with fenofibrate reduces susceptibility to stroke in apolipoprotein E-deficient mice as well as decreases cerebral infarct volume in C57BL/6 wild-type mice. The neuroprotective effect of fenofibrate is completely absent in PPAR-α-deficient mice, suggesting that PPAR-α activation is involved as a mechanism of the protection against cerebral injury. Furthermore, this neuroprotective effect appears independently of any improvement in plasma lipids or glycemia and is associated with (1) an improvement in middle cerebral artery sensitivity to endothelium-dependent relaxation unrelated to an increase in nitric oxide synthase (NOS) type III expression, (2) a decrease in cerebral oxidative stress depending on the increase in numerous antioxidant enzyme activities, and (3) the prevention of ischemia-induced expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in cerebral vessels without any change in NOS II expression. These data demonstrate that PPAR-α could be a new pharmacological target to preventively reduce the deleterious neurological consequences of stroke in mice and suggest that PPAR-α activators could preventively decrease the severity of stroke in humans.

Background and purpose:  Polymorphonuclear neutrophils (PMNs) contribute to the vascular damage caused by transient cerebral ischaemia. Here we have evaluated the role of PMNs in intracerebral haemorrhage (ICH) induced in a model of thrombolysis with recombinant tissue plasminogen activator (t‐PA) during the acute phase of cerebral ischaemia.Experimental approach:  The middle cerebral artery (MCA) of male spontaneously hypertensive rats was occluded for 1 h followed by reperfusion and, 5 h later, infusion of thrombolytic products (generated in vitro by t‐PA on autologous clots). Effects of pretreatment (before the MCA occlusion) with vinblastine (4 days before; 0.5 mg·kg⁻¹), monoclonal anti‐neutrophil antibody (mAbRP3; 12 h, 0.3 mg·kg⁻¹) or saline on ICH, neutrophil infiltration, MCA vascular reactivity and brain infarct volume were assessed, 24 h after the beginning of reperfusion.Key results:  Depletion of circulating neutrophils significantly reduced t‐PA‐induced ICH (vinblastine, 4.6 ± 1.0; mAbRP3, 5.2 ± 1.0 vs. saline, 10.8 ± 2.7 haemorrhages; P < 0.05). This depletion was associated with a decrease in cerebral infiltration by neutrophils and a decrease of endothelium‐dependent, vascular dysfunction in isolated MCA, induced by the ischaemia/reperfusion and t‐PA treatment. Brain infarct volume was significantly decreased after vinblastine treatment (159 ± 13 mm³ vs. 243 ± 16 mm³ with saline; P < 0.01) but not after depletion with mAbRP3 (221 ± 22 mm³).Conclusions and implications:  Our results showed that pharmacological depletion of PMNs prevented t‐PA‐induced ICH, in parallel with a decrease in cerebral infiltration by PMNs and a decreased endothelial dysfunction in cerebral blood vessels.Mandarin translation of

In stroke, there is an imperative need to develop disease-modifying drugs able to (1) induce neuroprotection and vasculoprotection, (2) modulate recovery and brain plasticity, and (3) limit the short-term motor and cognitive consequences. We hypothesized that fenofibrate, a peroxisome proliferator-activated receptor- α (PPAR- α) agonist, could exert a beneficial effect on immediate and short-term poststroke consequences related to its pleiotropic mechanisms. Rats or mice were subjected to focal ischemia to determine the effects of acute treatment by fenofibrate on (i) motor and memory impairment, (2) both cerebral and vascular compartments, (3) inflammation, (4) neurogenesis, and (5) amyloid cascade. We show that fenofibrate administration results in both neuronal and vascular protection and prevents the short-term motor and cognitive poststroke consequences by interaction with several mechanisms. Modulation of PPAR- α generates beneficial effects in the immediate poststroke consequences by mechanisms involving the interactions between polynuclear neutrophils and the vessel wall, and microglial activation. Fenofibrate modulates mechanisms involved in neurorepair and amyloid cascade. Our results suggest that PPAR- α agonists could check the key points of a potential disease-modifying effect in stroke.

Background and Purpose— In a model of mechanical focal ischemia, we investigated the involvement of thrombolysis products (TLP) in recombinant tissue plasminogen activator (rtPA)-induced intracerebral complications and the effects on infarct volume and postischemic endothelial function. Methods— Hemorrhage incidence and severity were evaluated by histomorphometric analysis in male spontaneously hypertensive rats (SHR) subjected to 60-minute intraluminal middle cerebral artery (MCA) occlusion and receiving intravenously 5 hours later either saline, rtPA (3, 10, or 30 mg/kg), or rtPA (10 mg/kg) associated with TLP (rtPA+TLP). In addition, MCA reactivity was assessed in rtPA- or rtPA+TLP-treated SHR versus control Wistar-Kyoto rats or SHR. Results— No hemorrhage was observed visually in SHR receiving saline. In contrast, rtPA administration induced hemorrhagic complications in infarcted areas in a dose-independent manner. Administration of rtPA+TLP solution, containing a high concentration of plasmin, did not affect hemorrhage incidence but significantly increased hemorrhage severity (8.8±2.3 petechiae versus 3.0±1.0 petechiae in rtPA group; P <0.001). This increased severity was associated with a significant increase of both infarct volume (182±10 versus 144±15 mm ³ in rtPA group; P <0.01) and postischemic impairment of MCA endothelium-dependent relaxation (9±0.5% versus 13±1% in rtPA group; P <0.05). Conclusions— Treatment with rtPA led to intracerebral hemorrhages, in contrast to saline-treated animals, and the presence of TLP increased the severity of these hemorrhages, in parallel with increased infarct volume and worsened endothelial function.