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Bioenergetic deficits are known to be significant contributors to neurodegenerative diseases. Nevertheless, identifying safe and effective means to address intracellular bioenergetic deficits remains a significant challenge. This work provides mechanistic insights into the energy metabolism-regulating function of colloidal Au nanocrystals, referred to as CNM-Au8, that are synthesized electrochemically in the absence of surface-capping organic ligands. When neurons are subjected to excitotoxic stressors or toxic peptides, treatment of neurons with CNM-Au8 results in dose-dependent neuronal survival and neurite network preservation across multiple neuronal subtypes. CNM-Au8 efficiently catalyzes the conversion of an energetic cofactor, nicotinamide adenine dinucleotide hydride (NADH), into its oxidized counterpart (NAD ), which promotes bioenergy production by regulating the intracellular level of adenosine triphosphate. Detailed kinetic measurements reveal that CNM-Au8-catalyzed NADH oxidation obeys Michaelis-Menten kinetics and exhibits pH-dependent kinetic profiles. Photoexcited charge carriers and photothermal effect, which result from optical excitations and decay of the plasmonic electron oscillations or the interband electronic transitions in CNM-Au8, are further harnessed as unique leverages to modulate reaction kinetics. As exemplified by this work, Au nanocrystals with deliberately tailored structures and surfactant-free clean surfaces hold great promise for developing next-generation therapeutic agents for neurodegenerative diseases

Validation de trois nouveaux modèles animaux de maladies neurologiques humaines et réflexions sur la modélisation

STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Glutamate carboxypeptidase II inhibition behaviorally and physiologically improves pyridoxine-induced neuropathy in rats.

Pyridoxine is used as a supplement for treating conditions such as vitamin deficiency as well as neurological disorders such as depression, epilepsy and autism. A significant neurologic complication of pyridoxine therapy is peripheral neuropathy thought to be a result of long-term and high dose usage. Although pyridoxine-induced neuropathy is transient and can remit after its withdrawal, the process of complete recovery can be slow. Glutamate carboxypeptidase II (GCP II) inhibition has been shown to improve symptoms of both chemotherapy- and diabetic-induced neuropathy. This study evaluated if GCP II inhibition could behaviorally and physiologically improve pyridoxine-induced neuropathy. In the current study, high doses of pyridoxine (400 mg/kg, twice a day for seven days) were used to induce neuropathy in rats. An orally bioavailable GCP II inhibitor, 2-(3-mercaptopropyl) pentanedioic acid (2-MPPA), was administered daily at a dose of 30 mg/kg starting from the onset of pyridoxine injections. Body weight, motor coordination, heat sensitivity, electromyographical (EMG) parameters and nerve morphological features were monitored. The results show beneficial effects of GCP II inhibition including normalization of hot plate reaction time, foot fault improvements and increased open field distance travelled. H wave frequency, amplitude and latency as well as sensory nerve conduction velocity (SNCV) were also significantly improved by 2-MPPA. Lastly, GCP II inhibition resulted in morphological protection in the spinal cord and sensory fibers in the lumbar region dorsal root ganglia (DRG). In conclusion, inhibition of GCP II may be beneficial against the peripheral sensory neuropathy caused by pyridoxine

Timeline of experiment.

<p>Timeline of experiment.</p

GCP II inhibition did not significantly affect weight loss induced by pyridoxine.

<p>Weights were measured every day of the study. A significant difference was observed between the controls and both the pyridoxine treated groups (p<0.05); no difference was observed between the pyridoxine/vehicle and pyridoxine/2-MPPA groups (p>0.05). N = 10/group. Data = mean ± SEM. * = p<0.05.</p

GCP II inhibition improves hot plate reaction times.

<p>Pyridoxine intoxication increased reaction time on the hot plate, which was improved by GCP II on days 18–25. By day 29, both of the pyridoxine treated groups had recovered to control levels. N = 10/group. Data = mean ± SEM. * = p<0.05.</p

Para -Substituted α-Phenyl- N - tert -butyl Nitrones: Spin-Trapping, Redox and Neuroprotective Properties

International audienceIn this work, a series of para-substituted α-phenyl-N-tert-butyl nitrones (PBN) were studied. Their radical-trapping properties were evaluated by electron paramagnetic resonance, with 4-CF 3-PBN being the fastest derivative to trap the hydroxymethyl radical (• CH 2 OH). The redox properties of the nitrones were further investigated by cyclic voltammetry, and 4-CF 3-PBN was the easiest to reduce and the hardest to oxidize. This is due to the presence of the electron-withdrawing CF 3 group. Very good correlations between the Hammett constants (σ p) of the substituents and both spin-trapping rates and redox potentials were observed. These correlations were further supported by computationally determined ionization potentials and atom charge densities. Finally, the neuroprotective effect of these derivatives was studied using two different in vitro models of cell death on primary cortical neurons injured by glutamate exposure or on glial cells exposed to t BuOOH. Trends between the protection afforded by the nitrones and their lipophilicity were observed. 4-CF 3-PBN was the most potent agent against t BuOOH-induced oxidative stress on glial cells, while 4-Me 2 N-PBN showed potency in both models

Design, synthesis and biological characterization of novel activators of the TrkB neurotrophin receptor

International audienc