François Chavant

Neuroprotective Effect of PACAP on Translational Control Alteration and Cognitive Decline in MPTP Parkinsonian Mice

Parkinson’s disease (PD) is characterized by a triade of motor symptoms due to the degeneration of nigrostriatal pathway. In addition to these motor impairments, cognitive disturbances have been reported to occur in PD patients in the early stage of the disease. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin widely used to produce experimental models of PD. In a previous work, we showed that MPTP altered the expression of proteins involved in mTOR antiapoptotic and PKR apoptotic pathways of translational control (TC) in neuroblastoma cells. In the present study, the results indicated that a subchronic MPTP intoxication in mice decreased the dopaminergic neuron number, produced an activation of PKR way and an inhibition of mTOR way of TC especially in striatum and frontal cortex associated with a great activation of PKR in hippocampus. Moreover, in parallel to biochemical analysis, the mnesic disturbances induced by MPTP were characterized in C57Bl/6 mice, by testing their performance in three versions of the Morris Water Maze task. Behavioral results showed that the MPTP lesion altered mice learning of a spatial working memory, of a cued version and of a spatial reference memory task in the water maze. Furthermore, we previously demonstrated that the neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) could counteract the MPTP toxicity on TC factors in neuroblastoma cells. Thus, the second objective of our study was to assess the PACAP effect on MPTP-induced TC impairment and cognitive deficit in mice. The pretreatment with PACAP27 by intravenous injections partially protected TH-positive neuron loss induced by MPTP, prevented the MPTP-induced protein synthesis control dysregulation and mnesic impairment of mice. Therefore, our results could indicate that PACAP may be a promising therapeutic agent in Parkinson’s disease.

Memory disorders associated with consumption of drugs: updating through a case/noncase study in the French PharmacoVigilance Database.

AIMS To investigate putative associations of reports of memory disorders and suspected drugs. METHODS We used the case/noncase method in the French PharmacoVigilance Database (FPVD). Cases were reports of memory loss in the FPVD between January 2000 and December 2009. Noncases were all other reports during the same period. To assess the association between memory impairment and drug intake, we calculated an odds ratio with its 95% confidence interval. RESULTS Among the 188,284 adverse drug reactions recorded, we identified 519 cases of memory loss. The sex ratio was 0.6 and the median age was 54 years (range 4-93). The maximal number of cases occurred between 40-49 and 50-59 years. Evolution was favourable in 63% of the cases. We found significant odds ratios for benzodiazepines (alprazolam, bromazepam, prazepam, clonazepam etc.), benzodiazepine-like hypnotics (zolpidem and zopiclone), antidepressants (fluoxetine, paroxetine and venlafaxine), analgesics (morphine, nefopam and tramadol), anticonvulsants (topiramate, pregabalin, levetiracetam etc.), antipsychotics (aripiprazole and lithium) and other drugs, such as trihexyphenidyl, ciclosporin and isotretinoin. CONCLUSIONS Our study confirmed an association between memory disorders and some drugs, such as benzodiazepines and anticonvulsants. However, other drugs, such as benzodiazepine-like hypnotics, newer anticonvulsants, serotonin reuptake inhibitor antidepressants, isotretinoin and ciclosporin were significantly associated with memory disorders, although this was not described or poorly described in the literature. Taking account of the limits of this study in the FPVD (under-reporting, notoriety bias etc.), the case/noncase method allows assessment and detection of associations between exposure to drugs and a specific adverse drug reaction, such as memory disorders, and could thus generate signals and orientate us to further prospective studies to confirm such associations.

Activation of the protein p7OS6K via ERK phosphorylation by cholinergic muscarinic receptors stimulation in human neuroblastoma cells and in mice brain.

Stimulation of cholinergic muscarinic receptors has been shown to provide substantial protection from DNA damage, oxidative stress and mitochondrial impairment, insults that may be encountered by neurons in development, aging, or neurodegenerative diseases. A study recently indicated that the activation of muscarinic receptors in astrocytoma cells modified the expression of the kinase p70S6K involved in the translational control. The translational control is in part regulated by a cascade of phosphorylation affecting proteins of the anti-apoptotic way controlled by mTOR (mammalian target of rapamycin) and the pro-apoptotic way controlled by PKR. The aim of our study was to investigate the effect of cholinergic muscarinic stimulation by an agonist oxotremorine on the anti-apoptotic way of translational control, in human neuroblastoma cells and in mice brain. Our results showed that muscarinic receptor activation significantly increased the expression of phosphorylated p70S6K, eIF4E and ERK without modification of mTOR activity in neuroblastoma cells and in cerebral cortex and hippocampus of mice, suggesting a stimulation of protein synthesis. Our findings support the notion that synaptic activity, through activation of neurotransmitter receptors, can provide substantial support of cellular survival mechanisms and suggest that loss of such synaptic input increases vulnerability to insult-induced programmed cell death.

Fetal renin-angiotensin-system blockade syndrome: renal lesions

BackgroundFetuses exposed to angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists during the second and/or third trimesters of gestation are at high risk of developing severe complications. They consist in fetal hypotension, and anuria/oligohydramnios leading to Potter sequence, frequently associated with hypocalvaria. Most fetuses die during the pre- or postnatal period, whereas others recover normal or subnormal renal function. However, the secondary occurrence of renal failure or hypertension has been reported in children after apparent complete recovery.MethodsIn this context, we analyzed renal lesions in 14 fetus/neonates who died soon after exposure to renin-angiotensin-system (RAS) blockers. Our objective was to determine the causes for the persistence or the secondary occurrence of renal complications reported in some of the survivors.ResultsAs previously described, renal tubular dysgenesis is usually observed. Additional lesions, such as thickening of the muscular wall of arterioles and interlobular arteries, glomerular cysts, and interstitial fibrosis, develop early during fetal life.ConclusionWe suggest that renal lesions that develop before birth may persist after withdrawal of the causative drugs and normalization of blood and renal perfusion pressure. Their persistence could explain the severe long-term outcome of some of these patients. Long-term study of children exposed to RAS blockers during fetal life is strongly recommended.

Time course of MPTP toxicity on translational control protein expression in mice brain

The present study investigated in mice brain, the time course of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity on the expression of translational control proteins. Mice received intraperitoneal injections of MPTP (30 mg/kg/day) for 5 days and were sacrificed 1, 2, 3, 4 and 7 days after the last injection. The results, obtained by western blot, indicated that MPTP produced an alteration of the expression of proteins involved in the mTOR anti-apoptotic way and the PKR pro-apoptotic pathway of translational control especially in striatum and frontal cortex of mice. These disturbances were associated with a great activation of PKR in hippocampus at D9, the time point corresponding to maximal translational control alterations. Furthermore, whereas no modification of translational control protein expression was observed in mice substantia nigra after western blot procedure, immunofluorescent labeling revealed, in this target region of the toxin MPTP, a decrease of the expression of phospho-mTOR and a great activation of the phosphorylated form of PKR, marker of pathogenesis.