Stobadine-induced hastening of sensorimotor recovery after focal ischemia/reperfusion is associated with cerebrovascular protection.

In a model of 1 hour-intraluminal occlusion of rat middle cerebral artery (MCA), we investigated the spontaneous recovery of vascular functions and functional deficit together with ischemia volume evolution at 24 h, 3 days and 7 days of reperfusion. Infarct cerebral volumes and edema were quantified with histological methods. Endothelium-dependent and smooth muscle potassium inward rectifier current (Kir2.x)-dependent relaxing responses of MCA were tested using Halpern arteriograph and Kir2.x current density evaluated on MCA myocytes with whole-cell patch-clamp technique. Sensorimotor recovery was estimated according to performances obtained with adhesive removal test and prehensile traction test. A time-dependent improvement of smooth muscle K(+)-dependent vasorelaxation and Kir2.x current density is observed at 7 days of reperfusion while endothelium-dependent relaxation is still impaired. In parallel a significant reduction of functional deficit is observed at 7 days of reperfusion together with a time-matched reduction of striatal infarct and edema volumes. Administration of an antioxidant agent, stobadine, at time of reperfusion and 5 h later allowed: (i) a neuroprotective effect with a significant reduction of infarct size compared to vehicle-treated rats; (ii) a prevention of endothelial-dependent relaxation and Kir2.x current density reductions of MCA ipsilateral to occlusion; (iii) a hastening of the functional recovery. The beneficial effect of stobadine underlines a link between vascular protection, neuronal protection and sensorimotor recovery that could become a promising pharmacological target in the treatment of cerebral ischemia.

Neurogliovascular unit after cerebral ischemia: is the vascular wall a pharmacological target.

Ischemic stroke induces drastic alterations of the functions of the neurogliovascular unit with dramatic consequences on the well-being of the patients in terms of cognitive and motor handicap. Nowadays, only very few therapeutics are available as a treatment of ischemic stroke. Ischemia is a multifactorial pathology involving different cerebral cellular components such as neurons, astrocytes and vessels working as a functional unit. Recent experimental strategy investigation involving different agents with antioxidant properties (dt-BC, stobadine) or pleiotropic effects (lipopolysaccharide, LPS) has been developed to evaluate whether the vascular wall could be considered as a potential target in neuroprotection concept.

Early treatment with atorvastatin exerts parenchymal and vascular protective effects in experimental cerebral ischaemia.

BACKGROUND AND PURPOSE: From the clinical and experimental data available, statins appear to be interesting drug candidates for preventive neuroprotection in ischaemic stroke. However, their acute protective effect is, as yet, unconfirmed. EXPERIMENTAL APPROACH: Male C57Bl6/JRj mice were subjected to middle cerebral artery occlusion and treated acutely with atorvastatin (10-20 mg·kg(-1) day(-1) ; 24 or 72 h). Functional recovery (neuroscore, forelimb gripping strength and adhesive removal test) was assessed during follow-up and lesion volume measured at the end. Vasoreactivity of the middle cerebral artery (MCA), type IV collagen and FITC-dextran distribution were evaluated to assess macrovascular and microvascular protection. Activated microglia, leucocyte adhesion and infiltration were chosen as markers of inflammation. KEY RESULTS: Acute treatment with atorvastatin provided parenchymal and cerebral protection only at the higher dose of 20 mg·kg(-1) ·day(-1) . In this treatment group, functional recovery was ameliorated, and lesion volumes were reduced as early as 24 h after experimental stroke. This was associated with vascular protection as endothelial function of the MCA and the density and patency of the microvascular network were preserved. Acute atorvastatin administration also induced an anti-inflammatory effect in association with parenchymal and vascular mechanisms; it reduced microglial activation, and decreased leucocyte adhesion and infiltration. CONCLUSIONS AND IMPLICATIONS: Acute atorvastatin provides global cerebral protection, but only at the higher dose of 20 mg·kg(-1) ·day(-1) ; this was associated with a reduction in inflammation in both vascular and parenchymal compartments. Our results suggest that atorvastatin could also be beneficial when administered early after stroke.

PPAR: a new pharmacological target for neuroprotection in stroke and neurodegenerative diseases.

PPARs (peroxisome-proliferator-activated receptors) are ligand-activated transcriptional factor receptors belonging to the so-called nuclear receptor family. The three isoforms of PPAR (alpha, beta/delta and gamma) are involved in regulation of lipid or glucose metabolism. Beyond metabolic effects, PPARalpha and PPARgamma activation also induces anti-inflammatory and antioxidant effects in different organs. These pleiotropic effects explain why PPARalpha or PPARgamma activation has been tested as a neuroprotective agent in cerebral ischaemia. Fibrates and other non-fibrate PPARalpha activators as well as thiazolidinediones and other non-thiazolidinedione PPARgamma 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. PPARalpha 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.