6 research outputs found
Neuroprotection of midbrain dopamine neurons by nicotine is gated by cytoplasmic Ca 2+
International audienceEpidemiological and experimental evidence indicates that nicotine is protective for Parkinson disease vulnerable dopamine neurons, but the underlying mechanism of this effect remains only partly characterized. To address this question, we established rat midbrain cultures maintained in experimental conditions that favor the selective and spontaneous loss of dopamine neurons. We report here that nicotine afforded neuroprotection to dopamine neurons (EC(50)=0.32 μM) but only in a situation where cytosolic Ca(2+) (Ca(2+)(cyt)) was slightly and chronically elevated above control levels by concurrent depolarizing treatments. By a pharmacological approach, we demonstrated that the rise in Ca(2+)(cyt) was necessary to sensitize dopamine neurons to the action of nicotine through a mechanism involving α-bungarotoxin-sensitive (presumably α7) nicotinic acetylcholine receptors (nAChRs) and secondarily T-type voltage-gated calcium channels. Confirming the role played by α7 nAChRs in this effect, nicotine had no protective action in midbrain cultures prepared from genetically engineered mice lacking this receptor subtype. Signaling studies revealed that Ca(2+)(cyt) elevations evoked by nicotine and concomitant depolarizing treatments served to activate a survival pathway involving the calcium effector protein calmodulin and phosphatidylinositol 3-kinase. Collectively, our data support the idea that the protective action of nicotine for dopamine neurons is activity-dependent and gated by Ca(2+)(cyt)
Tumor Necrosis Factor-Like Weak Inducer of Apoptosis Induces Astrocyte Proliferation through the Activation of Transforming-Growth Factor-α/Epidermal Growth Factor Receptor Signaling Pathway
Aging of the dopaminergic system and motor behavior in mice intoxicated with the parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
International audienceJ. Neurochem. (2012) 122, 10321046. Abstract 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication of mice is a standard model of Parkinsons disease (PD). However, it does not reproduce functionally PD. Given the occurrence of PD during aging, symptoms might only be detected in MPTP-intoxicated mice after aging. To address this, mice injected with MPTP at 2.5 months were followed up to a maximum age of 21 months. There was no loss of dopamine cells with aging in control mice; moreover, the initial post-MPTP intoxication decrease in dopamine cell was no longer significant at 21 months. With aging, striatal dopamine level remained constant, but concentrations of the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were markedly reduced in both groups. There was also a late impairment of fine motor skills. After MPTP intoxication, hyperactivity was immediately detected and it became greater than in control mice from 14 months of age; fine motor skills were also more impaired; both these symptoms were correlated with striatal dopamine, DOPAC and HVA concentrations. In bothgroups, neither motor symptoms nor dopamine changes worsened with age. These findings do not support the notion that PD develops with age in mice after MPTP intoxication and that the motor deficits seen are because of an aging process
Flavaglines as Potent Anticancer and Cytoprotective Agents
Flavaglines represent a family of plant natural products
that display
potent anticancer, cardioprotective, and neuroprotective activities.
Novel flavagline derivatives were synthesized and examined for their
cytotoxicity on a panel of human cancer cell lines, their cardioprotection
against doxorubicin-induced apoptosis in cardiomyocytes, and their
neuroprotection in culture models of Parkinson’s disease and
cisplatin-induced neurotoxicity. The structural requirements of flavaglines
for cardio- and neuroprotection were for the first time unraveled
and appeared to be slightly different from those for cytotoxicity
on cancer cells. We provide also the first evidence that flavaglines
may alleviate cisplatin-induced neurotoxicity, suggesting a prophylactic
potential of these compounds to prevent this frequently encountered
adverse effect of cancer chemotherapies