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Backgrounds/Objective: The impact of metabolic disturbances induced by an unbalanced diet on cognitive decline in mid-life is now widely observed, although the mechanisms are not well identified. Here we report that glutamatergic vasoactive pathways are a key feature of high-fat-diet (HFD)-induced neurogliovascular uncoupling in mice. Methods: C57Bl6/J mice are fed either with normal diet (ND) or high-fat diet (HFD) during 6 or 12 months and characterized for metabolic status. Cerebral vascular tree from pial to intraparenchymal arteries, is investigated with Halpern’s arteriography and with differential interference contrast infrared imaging of brain slices. Results: A 70% alteration in the myogenic tone of the basilar artery is observed as early as 6 months (M6) after the HFD. Infrared imaging revealed a 77% reduction in the glutamate-induced vasodilation of intraparenchymal arterioles appearing after 12 months (M12) of the HFD. The respective contributions of enzymes involved in glutamatergic pathways were altered as a function of HFD and time. The decrease in astrocytic COX I observed at M6 was followed by a loss of neuronal COX II and a compensatory action of NOS at M12. Conclusions: This HFD-induced neurogliovascular uncoupling pathway offers therapeutic targets to consider for improving cerebral vasoactive functions while preventing peripheral metabolic disturbances.

Background: The origin of pre-existing cognitive impairment in stroke patients remains controversial, with a vascular or a degenerative hypothesis. Objective: To determine whether endothelial dysfunction is associated with pre-existing cognitive problems, lesion load and biological anomalies in stroke patients. Methods: Patients originated from the prospective STROKDEM study. The baseline cognitive state, assessed using the IQ-CODE, and risk factors for stroke were recorded at inclusion. Patients with an IQ-CODE score >64 were excluded. Endothelial function was determined 72 h after stroke symptom onset by non-invasive digital measurement of endothelium-dependent flow-mediated dilation and calculation of the reactive hyperemia index (RHI). RHI ≤ 1.67 indicated endothelial dysfunction. Different biomarkers of endothelial dysfunction were analysed in blood or plasma. All patients underwent MRI 72 h after stroke symptom onset. Results: A total of 86 patients were included (52 males; mean age 63.5 ± 11.5 years). Patients with abnormal RHI have hypertension or antihypertensive treatment more often. The baseline IQ-CODE was abnormal in 33 (38.4%) patients, indicating a pre-existing cognitive problem. Baseline IQ-CODE > 48 was observed in 15 patients (28.3%) with normal RHI and in 18 patients (54.6%) with abnormal RHI (p = 0.016). The RHI median was significantly lower in patients with abnormal IQ-CODE. Abnormal RHI was associated with a significantly higher median FAZEKAS score (2.5 vs. 2; p = 0.008), a significantly higher frequency of periventricular lesions (p = 0.015), more white matter lesions (p = 0.007) and a significantly higher cerebral atrophy score (p < 0.001) on MRI. Vascular biomarkers significantly associated with abnormal RHI were MCP-1 (p = 0.009), MIP_1a (p = 0.042), and homocysteinemia (p < 0.05). Conclusions: A vascular mechanism may be responsible for cognitive problems pre-existing stroke. The measurement of endothelial dysfunction after stroke could become an important element of follow-up, providing an indication of the functional and cognitive prognosis of stroke patients.

The impact of fenofibrate, a peroxisome proliferator-activated receptor-alpha (PPAR-α) agonist, on the risk of thrombolysis-induced hemorrhage during the acute phase of stroke in a rat model of stroke was studied. One-hour middle cerebral artery occlusion followed by thrombolysis with tissue plasminogen activator was made in rats receiving either fenofibrate or vehicle for 72 h after stroke. Evaluation of infarct, hemorrhage, middle cerebral artery vasoreactivity, and immunochemistry (CD11b for microglial activation, myeloperoxidase, and ICAM-1 for neutrophil infiltration) was performed. The PPAR-alpha agonist significantly reduced the risk of hemorrhage after thrombolysis in parallel with a decrease in the infarct volume and in the stroke-induced vascular endothelial dysfunction. These effects are concomitant with a reduction in microglial activation and neutrophil infiltration in infarct area. Our results strengthen the idea that using drugs such as fenofibrate, with pleiotropic properties due to PPAR-alpha agonism, may be of value to reduce thrombolysis-induced hemorrhage during acute stroke.

Background: Persistent pulmonary hypertension of the newborn (PPHN) causes significant morbidity and mortality in neonates. n-3 Poly-unsaturated fatty acids have vasodilatory properties in the perinatal lung. We studied the circulatory effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in fetal sheep and in fetal pulmonary arterial rings. Methods: At 128 days of gestation, catheters were placed surgically in fetal systemic and pulmonary circulation, and a Doppler probe around the left pulmonary artery (LPA). Pulmonary arterial pressure and LPA flow were measured while infusing EPA or DHA for 120 min to the fetus, to compute pulmonary vascular resistance (PVR). The dose effects of EPA or DHA were studied in vascular rings pre-constricted with serotonin. Rings treated with EPA were separated into three groups: E+ (intact endothelium), E− (endothelium stripped) and LNA E+ (pretreatment of E+ rings with l-nitro-arginine). Results: EPA, but not DHA, induced a significant and prolonged 25% drop in PVR (n = 8, p < 0.001). Incubation of vascular rings with EPA (100 µM) caused a maximum relaxation of 60% in the E+ (n = 6), whereas vessel tone did not change in the E− (n = 6, p < 0.001). The vascular effects of EPA were significantly decreased in LNA E+ (n = 6). Incubation with DHA resulted in only a mild relaxation at the highest concentration of DHA (300 µM) compared to E+. Conclusions: EPA induces a sustained pulmonary vasodilatation in fetal lambs. This effect is endothelium- and dose-dependent and involves nitric oxide (NO) production. We speculate that EPA supplementation may improve pulmonary circulation in clinical conditions with PPHN.

Iron deposition in the substantia nigra has been implicated in Parkinson’s disease. Chelation with deferiprone reduced brain iron content but led to worse scores on scales of the movement disorder at 36 weeks.

Background Even with optimal dopaminergic treatments, many patients with Parkinson's disease (PD) are frequently incapacitated by apathy prior to the development of dementia. We sought to establish whether rivastigmine's ability to inhibit acetyl- and butyrylcholinesterases could relieve the symptoms of apathy in dementia-free, non-depressed patients with advanced PD. Methods We performed a multicentre, parallel, double-blind, placebo-controlled, randomised clinical trial (Protocol ID: 2008-002578-36; clinicaltrials.gov reference: NCT00767091) in patients with PD with moderate to severe apathy (despite optimised dopaminergic treatment) and without dementia. Patients from five French university hospitals were randomly assigned 1:1 to rivastigmine (transdermal patch of 9.5 mg/day) or placebo for 6 months. The primary efficacy criterion was the change over time in the Lille Apathy Rating Scale (LARS) score. Finding 101 consecutive patients were screened, 31 were eligible and 16 and 14 participants were randomised into the rivastigmine and placebo groups, respectively. Compared with placebo, rivastigmine improved the LARS score (from −11.5 (−15/−7) at baseline to −20 (−25/−12) after treatment; F(1, 25)=5.2; p=0.031; adjusted size effect: −0.9). Rivastigmine also improved the caregiver burden and instrumental activities of daily living but failed to improve quality of life. No severe adverse events occurred in the rivastigmine group. Interpretation Rivastigmine may represent a new therapeutic option for moderate to severe apathy in advanced PD patients with optimised dopaminergic treatment and without depression dementia. These findings require confirmation in a larger clinical trial. Our results also confirmed that the presence of apathy can herald a pre-dementia state in PD. Registration Clinicaltrials.gov reference: NCT00767091.

Continuous compensation for cerebral dopamine deficiency represents an ideal treatment for Parkinson’s disease. Dopamine does not cross the digestive and blood–brain barriers and is rapidly oxidized. The new concept is the intracerebroventricular administration of anaerobic dopamine (A-dopamine) using an abdominal pump connected to a subcutaneous catheter implanted in the third ventricle, near the striatum. An open-label phase 1 study showed no serious adverse reactions induced by A-dopamine in 12 patients. A randomized, controlled, open-label, crossover phase 2 study of 1 month of A-dopamine versus 1 month of optimized oral antiparkinsonian therapy was conducted in 9 patients. The primary endpoint, a blinded assessment of the percentage over target (that is, time with dyskinesia or bradykinesia), recorded by home actimetry using a wristwatch, was significantly reduced on A-dopamine compared with that on oral treatment alone ( P  = 0.027), with a median within-patient difference of −10.4 (Hedge g  = −0.62 (95% confidence interval: −1.43, −0.08)). Home diaries were also significantly improved. These initial data on the feasibility, safety and effects of this new device-assisted therapy suggest validation by a large randomized double-blind trial. ClinicalTrials.gov registration: NCT04332276 . A phase 1/2 clinical trial of a new device-assisted therapy in Parkinson’s disease revealed that intracerebroventricular administration of anaerobic dopamine was safe and significantly reduced l -dopa-related complications.

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.

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 Granulocyte colony-stimulating factor (G-CSF) is a pharmacologic agent inducing neutrophil mobilization and a new candidate for neuroprotection and neuroregeneration in stroke. Its effects when used in combination with tissue plasminogen activator (tPA) were explored during the acute phase of ischemic stroke. Methods We used a middle cerebral artery occlusion (MCAO) model of cerebral ischemia, associated with treatment with tPA, in male spontaneously hypertensive rats (SHR). Granulocyte colony-stimulating factor (G-CSF; 60 μg/kg) was injected just before tPA. Neutrophil response in peripheral blood and in the infarct area was quantified in parallel to the infarct volume. Protease matrix metallopeptidase 9 (MMP-9) release from circulating neutrophils was analyzed by immunochemistry and zymography. Vascular reactivity and hemorrhagic volume in the infarct area was also assessed. Results Twenty four hours after ischemia and tPA, G-CSF administration induced a significant increase of neutrophils in peripheral blood ( P <0.05). At 72 hours post-ischemia, G-CSF was significantly associated with an increased risk of hemorrhage in the infarct area (2.5 times more likely; P <0.05) and significant cerebral endothelium-dependent dysfunction. Ex vivo, an increased MMP-9 release from neutrophils after tPA administration correlated to the increased hemorrhagic risk ( P <0.05). In parallel, G-CSF administration was associated with a decreased neutrophil infiltration in the infarct area (-50%; P <0.05), with a concomitant significant neuroprotective effect (infarct volume: -40%; P <0.05). Conclusions We demonstrate that G-CSF potentiates the risk of hemorrhage in experimental stroke when used in combination with tPA by inducing neutrophilia. This effect is concomitant to an increased MMP-9 release from peripheral neutrophils induced by the tPA treatment. These results highlight the potential hemorrhagic risk of associating G-CSF to thrombolysis during the acute phase of stroke.