Could conservative iron chelation lead to neuroprotection in amyotrophic lateral sclerosis?

Iron accumulation has been observed in mouse models and both sporadic and familial forms of Amyotrophic lateral sclerosis. Iron chelation could reduce iron accumulation and the related excess of oxidative stress in the motor pathways. However, classical iron chelation would induce systemic iron depletion. We assess the safety and efficacy of conservative iron chelation (i.e. chelation with low risk of iron depletion) in a murine preclinical model and pilot clinical trial. In Sod1G86R mice, deferiprone increased the mean life span as compared with placebo. The safety was good, without anemia after 12 months of deferiprone in the 23 ALS patients enrolled in the clinical trial. The decreases in the ALS Functional Rating Scale and the body mass index (BMI) were significantly smaller for the first 3 months of deferiprone treatment (30 mg/kg/day) than for the first treatment-free period. Iron levels in the cervical spinal cord, medulla oblongata and motor cortex (according to MRI), as well as cerebrospinal fluid levels of oxidative stress and neurofilament light chains were lower after deferiprone treatment. Our observation leads to the hypothesis that moderate iron chelation regimen that avoids changes in systemic iron levels may constitute a novel therapeutic modality of neuroprotection for ALS

Stroke-Induced Brain Parenchymal Injury Drives Blood–Brain Barrier Early Leakage Kinetics: A Combined in Vivo / in Vitro Study

International audienceThe disappointing clinical outcomes of neuroprotectants challenge the relevance of preclinical stroke models and data in defining early cerebrovascular events as potential therapeutic targets. The kinetics of blood–brain barrier (BBB) leakage after reperfusion and the link with parenchymal lesion remain debated. By using in vivo and in vitro approaches, we conducted a kinetic analysis of BBB dysfunction during early reperfusion. After 60 minutes of middle cerebral artery occlusion followed by reperfusion times up to 24 hours in mice, a non-invasive magnetic resonance imaging method, through an original sequence of diffusion-weighted imaging, determined brain water mobility in microvascular compartments (D*) apart from parenchymal compartments (apparent diffusion coefficient). An increase in D* found at 4 hours post reperfusion concurred with the onset of both Evans blue/Dextran extravasations and in vitro BBB opening under oxygen-glucose deprivation and reoxygenation (R). The BBB leakage coincided with an emerging cell death in brain tissue as well as in activated glial cells in vitro. The co-culture of BBB endothelial and glial cells evidenced a recovery of endothelium tightness when glial cells were absent or non-injured during R. Preserving the ischemic brain parenchymal cells within 4 hours of reperfusion may improve therapeutic strategies for cerebrovascular protection against stroke

Lack of direct involvement of a diazepam long-term treatment in the occurrence of irreversible cognitive impairment: a pre-clinical approach

AbstractSeveral observational studies have found a link between the long-term use of benzodiazepines and dementia, which remains controversial. Our study was designed to assess (i) whether the long-term use of benzodiazepines, at two different doses, has an irreversible effect on cognition, (ii) and whether there is an age-dependent effect. One hundred and five C57Bl/6 male mice were randomly assigned to the 15 mg/kg/day, the 30 mg/kg/day diazepam-supplemented pellets, or the control group. Each group comprised mice aged 6 or 12 months at the beginning of the experiments and treated for 16 weeks. Two sessions of behavioral assessment were conducted: after 8 weeks of treatment and after treatment completion following a 1-week wash-out period. The mid-treatment test battery included the elevated plus maze test, the Y maze spontaneous alternation test, and the open field test. The post-treatment battery was upgraded with three additional tests: the novel object recognition task, the Barnes maze test, and the touchscreen-based paired-associated learning task. At mid-treatment, working memory was impaired in the 15 mg/kg diazepam group compared to the control group (p = 0.005). No age effect was evidenced. The post-treatment assessment of cognitive functions (working memory, visual recognition memory, spatial reference learning and memory, and visuospatial memory) did not significantly differ between groups. Despite a cognitive impact during treatment, the lack of cognitive impairment after long-term treatment discontinuation suggests that benzodiazepines alone do not cause irreversible deleterious effects on cognitive functions and supports the interest of discontinuation in chronically treated patients

Dose-dependent metabolite changes after ethanol intoxication in rat prefrontal cortex using in vivo magnetic resonance spectroscopy

International audienceEthanol disrupts the balance between the excitatory (glutamatergic) and inhibitory (GABAergic) neurotransmission systems. We aimed to assess how acute ethanol intoxication in rats affects the levels of GABA, glutamate and other cerebral metabolites after injection of two different doses of ethanol. One in vivo magnetic resonance spectrum of the prefrontal cortex region was acquired before and six spectra were acquired after intraperitoneal injections of saline or ethanol (1 g/kg or 2 g/kg). Brain kinetics after exposure to ethanol were compared to blood ethanol kinetics. GABA levels significantly decreased after injection of 1 g/kg but not 2 g/kg doses of ethanol. Choline levels, which serve as a marker of alterations in membrane composition, significantly decreased after injection of 2 g/kg but not 1 g/kg doses of ethanol. Acute ethanol intoxication appears to result in specific dose-dependent changes in the GABA level and choline level

Demographic and clinical characteristics of PD patients and controls.

<p>Demographic and clinical characteristics of PD patients and controls.</p

Magnetic Resonance Imaging Features of the Nigrostriatal System: Biomarkers of Parkinson’s Disease Stages? - Fig 2

<p><b>(A): R2* values in the nigrostriatal system at different stages of PD; Fig (B): Striatal volumes at different stages of PD; (C): Shape analysis of caudate nucleus and putamen at different stages of PD relative to controls</b>. In blue no statistical difference p>0.05, from yellow to read decrease of p value from p<0.05 (p value of read surface< pvalue of yellow surface<0.05). Yellow and read surface correspond to surface contraction and thus atrophy; <b>(D): Iron overload in the MPTP mouse model of PD.</b> Mice were treated with MPTP (or not; n = 10 per group). Data are presented as the mean and SEM. Immunohistochemistry of tyrosine hydroxylase (TH) stained sections of the right substantia nigra (SN), illustrating the level of degeneration after MPTP intoxication. TH+ cell counts of both sides of the SN. *: Wilcoxon test: p<0.0001. Total iron levels in the SN, as measured by atomic absorption spectrometry. *: p = 0.035. R2* multiple-echo spin echo value (7 T MRI) in the SN (MRI performed <i>in vivo</i> prior to sacrifice and spectrometry measurements) (R2* = 1/T2*(ms-1) x 103) *: p = 0.001. Motor handicap scores (measured in a 10-minute actimetry test). Number of rearings *: p = 0.004. Maximum speed: *: p = 0.03.</p