Cytoprotective Efficacy and Mechanisms of the Liposoluble Iron Chelator 2,2Ј-Dipyridyl in the Rat Photothrombotic Ischemic Stroke Model

ABSTRACT We examined the efficacy of the liposoluble iron chelator 2,2Ј-dipyridyl (DP) in reducing histological damage in rats submitted to cerebral ischemia and the mechanisms involved in the potential cytoprotection. For this purpose, DP (20 mg/kg, i.p.) was administered 15 min before and 1 h after induction of cortical photothrombotic vascular occlusion in rat. Histological studies were performed to assess infarct volume (at days 1 and 3 postischemia) and astromicroglial activation (at day 3 postischemia). Damage to endothelial and neuronal cells was evaluated at day 1 postischemia by quantitative measurements of Evans Blue extravasation and N-acetylaspartate levels, respectively. Cerebral blood flow was recorded in the ischemic core by laser-Doppler flowmetry within the 15 min to 2 h period after photothrombosis. At 4-h postischemia, radical oxygen species (ROS) production was evaluated by measuring brain glutathione concentrations. The cortical expression of the proteins heme oxygenase-1 (HO-1) and hypoxia-inducible factor-1␣ (HIF-1␣) was analyzed by Western blotting at day 1 postischemia. Infarct volume and ischemic damage to endothelial and neuronal cells were significantly reduced by DP treatment. This cytoprotection was associated with a reduction in ROS production, perfusion deficits, and astrocytic activation. DP treatment also resulted in significant changes in HO-1 (ϩ100%) and HIF-1␣ (Ϫ50%) protein expression at the level of the ischemic core. These results report the efficacy of the liposoluble iron chelator DP in reducing histological damage induced by permanent focal ischemia

Hyperthymic affective temperament and hypertension are independent determinants of serum brain-derived neurotrophic factor level

BACKGROUND: Brain-derived neurotrophic factor (BDNF) has neuroprotective, proangiogenic and myogenic effects and, therefore, possibly acts as a psychosomatic mediator. Here, we measured serum BDNF (seBDNF) level in hypertensive patients (HT) and healthy controls (CONT) and its relation to affective temperaments, depression and anxiety scales, and arterial stiffness parameters. METHODS: In this cross-sectional study, affective temperaments, anxiety, and depression were studied with questionnaires (TEMPS-A, HAM-A, and BDI, respectively). SeBDNF level and routine laboratory parameters were measured as well. Arterial stiffness was evaluated with a tonometric method. RESULTS: Allover, 151 HT, and 32 CONT subjects were involved in the study. SeBDNF level was significantly higher in HT compared to CONT (24880 +/- 8279 vs 21202.6 +/- 6045.5 pg/mL, p < 0.05). In the final model of regression analysis, hyperthymic temperament score (Beta = 405.8, p = 0.004) and the presence of hypertension (Beta = 6121.2, p = 0.001) were independent determinants of seBDNF. In interaction analysis, it was found that in HT, a unit increase in hyperthymic score was associated with a 533.3 (95 %CI 241.3-825.3) pg/mL higher seBDNF. This interaction was missing in CONT. CONCLUSIONS: Our results suggest a complex psychosomatic involvement of BDNF in the pathophysiology of hypertension, where hyperthymic affective temperament may have a protective role. BDNF is not likely to have an effect on large arteries

''Role of cerebral blood flow in physical exercise-induced brain plasticity''

Banoujaafar, H. | Prigent-Tessier, A. | Mossiat, C. | Marie, C.International audienc

Stress response to hypoxia in gerbil brain: HO-1 and Mn SOD expression and glial activation.

International audienceHypoxic preconditioning has been shown to induce neuroprotection against a subsequent damaging insult. In order to study the underlying molecular and cellular mechanisms of hypoxic preconditioning, we investigated, in gerbil hippocampus, the effects in vivo of transient exposure to hypoxia (4% O(2) for 6 min followed by either 48 h or 7 days of reoxygenation) (i) on the induction of 72 kDa heat shock protein (HSP72), heme oxygenase-1 (HO-1) and manganese superoxide dismutase (Mn SOD) as assessed by Western immunoblotting and (ii) on the astroglial and microglial activation as detected by both immunohistochemistry and Western immunoblotting for GFAP, and histochemistry for isolectin B4, respectively. Our data show that, although hypoxia and subsequent reoxygenation led to neither neuronal damage nor HSP72 induction in gerbil hippocampus, it induced a progressive and sustained expression of HO-1 and Mn SOD. As expected from the absence of neuronal death, hypoxia was not associated with microglial activation but led to a significant astrocytic activation. These findings demonstrate that transient hypoxia enhances the antioxidative enzymatic defenses of the brain, which are susceptible to increased tolerance against a subsequent damaging insult

''Expression of endothelial brain-derived neurotrophic factor is dependent on endothelial function''

Quirie, A. | Prigent-Tessier, A. | Mossiat, C. | Nappey, M. | Marie, C. | Demougeot, C.International audienc

''Expression of endothelial brain-derived neurotrophic factor is dependent on endothelial function''

Quirie, A. | Prigent-Tessier, A. | Mossiat, C. | Nappey, M. | Marie, C. | Demougeot, C.International audienc

Chemical preconditioning with 3-nitropropionic acid: lack of induction of neuronal tolerance in gerbil hippocampus subjected to transient forebrain ischemia.

International audienceChemical preconditioning using the mitochondrial toxin, 3-nitropropionic acid (3-NP) has been reported to induce neuroprotection against subsequent global ischemia. To investigate the underlying mechanisms, Mongolian gerbils were pretreated with either vehicle or 3-NP at the dose of 3 or 10 mg/kg, intraperitoneal, 3 days prior to a 5-min bilateral carotid artery occlusion followed by either 48 h or 7 days of blood recirculation. Neuronal damage was assessed by a cresyl violet/fuchsin acid staining. Induction of heat shock protein 72 (HSP72) and manganese superoxide dismutase (MnSOD) expression was evaluated by Western blotting. Astroglial and microglial activation was detected by immunohistochemistry (glial fibrillary acid protein) and by histochemistry (isolectin B4 staining), respectively. Present data show that the hippocampal neuronal damage induced by ischemia were of similar extent between the vehicle- and 3-NP-treated gerbils, whatever the dose tested, indicating that 3-NP did not induce tolerance to transient forebrain ischemia under our experimental conditions. The lack of difference in the post-ischemic level of HSP72 and MnSOD protein expression and in the intensity of astroglial and microglial activation represents further indirect indications of the absence of 3-NP preconditioning effect. In conclusion, although chemical preconditioning with 3-NP is a well-established phenomenon at least in vitro and in models of focal ischemia, the relevance of 3-NP as a preconditioning molecule towards global brain ischemia remains an open question

''Expression of endothelial brain-derived neurotrophic factor is dependent on endothelial function''

Quirie, A. | Prigent-Tessier, A. | Mossiat, C. | Nappey, M. | Marie, C. | Demougeot, C.International audienc

Differential MNSOD and HO-1 expression in cerebral endothelial cells in response to sublethal oxidative stress

NRC publication: Ye