Repeated resveratrol administration confers lasting protection against neuronal damage but induces dose-related alterations of behavioral impairments after global ischemia

Resveratrol, a naturally occurring polyphenol, has been shown to protect the heart and brain against ischemic injury. The current study investigated the effects of administration with either a 1 or 10-mg/kg dose of resveratrol on CA1 neuronal injury and behavioral/cognitive impairments after 10-min global ischemia in rats. The open-field, eight-arm radial maze and object recognition tests served to evaluate effects of resveratrol treatment on ischemia-induced locomotor activity, and spatial and recognition memory impairments, respectively. CA1 and CA3 neuronal injury was assessed upon completion of behavioral testing, 85 days postischemia. A separate series of groups served to assess neuronal injury at 7 days postischemia. Global ischemia (10 min) led to approximately 50% CA1 cell injury, which was prevented at both short (7 days) and long (85 days) postischemic intervals by resveratrol treatment. Importantly, despite comparable neuronal protection, the two resveratrol doses showed distinct behavioral effects. Thus, the 10-mg/kg resveratrol dose led to an enhanced locomotor activity in the open-field 4-days postischemia and an impaired spatial memory in the delayed nonmatching to sample and delayed matching to sample radial-maze tasks initiated on day 13 postischemia. These findings suggest independent actions of resveratrol on distinct physiological systems mediating cellular survival and functional recovery and dose-related actions of the polyphenol on behavioral and memory processes.     

NOTCH, a new signaling pathway implicated in holoprosencephaly

Genetics of Holoprosencephaly (HPE), a congenital malformation of the developing human forebrain, is due to multiple genetic defects. Most genes that have been implicated in HPE belong to the sonic hedgehog signaling pathway. Here we describe a new candidate gene isolated from array comparative genomic hybridization redundant 6qter deletions, DELTA Like 1 (DLL1), which is a ligand of NOTCH. We show that DLL1 is co-expressed in the developing chick forebrain with Fgf8. By treating chick embryos with a pharmacological inhibitor, we demonstrate that DLL1 interacts with FGF signaling pathway. Moreover, a mutation analysis of DLL1 in HPE patients revealed a three-nucleotide deletion. These various findings implicate DLL1 in early patterning of the forebrain and identify NOTCH as a new signaling pathway involved in HPE.     

Ubiquitin C-terminal hydrolase-l1 activity induces polyubiquitin accumulation in podocytes and increases proteinuria in rat membranous nephropathy

Ubiquitin C-terminal hydrolase L1 (UCH-L1), a key protease of the ubiquitin-proteasome system (UPS), is associated with neurodegenerative diseases and cancer. Recently, de novo expression of UCH-L1 was described in podocytes in patients with membranous nephropathy (MN), in which UCH-L1 expression correlated with increased ubiquitin content. The objective of the present study was to investigate the role of UCH-L1 in ubiquitin homeostasis and proteasomal degradation in a rat model of MN. After disease induction, UCH-L1 expression increased in podocytes and coincided with decreased glomerular monoubiquitin content. After an initial increase in proteasomal activity, the UPS was impaired. In addition to an increase of ubiquitin in podocytes, aggregates were observed 1 year after disease induction, as in MN in human beings. Inhibition of UCH-L1 hydrolase function in MN reduced UPS impairment and ameliorated proteinuria. In contrast, inhibition of proteasomal activity enhanced UPS impairment, resulting in increased proteinuria. Stable UCH-L1 overexpression in cultured podocytes resulted in accumulation of monoubiquitin and polyubiquitin proteins. In contrast, stable knock-down of UCH-L1 reduced monoubiquitin and polyubiquitin proteins and significantly increased proteasomal activity, indicating that the observed effects in rat MN also occurred in cultured podocytes. These data demonstrate that UCH-L1 activity results in polyubiquitin accumulation, proteasome inhibition, and disease aggravation in experimental models of MN.     

Tumor-like enlargement of the optic chiasm in an infant with Alexander disease

We report a patient with infantile Alexander disease (AXD) due to the recurrent p.Arg79Cys GFAP mutation. In addition to typical AXD abnormalities, magnetic resonance imaging demonstrated a tumor-like lesion of the optic chiasm suggestive of a glioma. A transient papilloedema appeared during the follow-up and the lesion partially regressed despite a worsening of white matter involvement. Rare radiological and pathological tumor-like lesions have already been reported in AXD patients. This patient confirms that enlargement of the optic chiasm is a rare feature of AXD, possibly linked to abnormal astrocytic proliferation.     

Neuropsychological and activity of daily living script performance in patients with positive or negative schizophrenia

Cognitive and psychiatric determinants of impairment of complex activities of daily living (ADLs) were investigated in 33 schizophrenic patients and 16 normal comparison subjects. The schizophrenic patients were cognitively impaired and were deficient in the ADL. However, the impairment of ADL could not be explained specifically by impairment of higher-order executive function or by negative symptoms: memory functions were more related to impairment of ADL and positive symptoms as much as the negative ones. Positive symptoms were significantly related to commissive errors in the ADL, whereas negative symptoms were nonsignificantly related to omissive errors. Negative symptoms were significantly more related to memory impairment than to impairment on measures of higher-order executive function (working memory). This investigation demonstrates that an ecologically oriented approach to test development and measurement of ADL is fruitful in understanding schizophrenia-especially if it is constrained by cognitive constructs compatible with the phenomenology of the disease.     

Dystrophin-dependent muscle degeneration requires a fully functional contractile machinery to occur in C. elegans

In mammals, the lack of dystrophin leads to a degeneration of skeletal muscles. It has been known for many years that this pathology can be blocked by denervation or immobilization of muscles. It is not yet clear, however, whether this suppressing effect is due to the absence of fiber contraction per se, or to other mechanisms which may be induced by such treatments. We took advantage of the genetic tools available in the animal model Caenorhabditis elegans to address this question. Using RNA interference and existing mutants, we genetically impaired the excitation-contraction cascade at specific points in a dystrophin-deficient C. elegans strain which normally undergoes extensive muscle degeneration. Our data show that reducing sarcomere contraction by slightly impairing the contraction machinery is sufficient to dramatically suppress muscle degeneration. Thus, it is the physical tension exerted on the muscle fibers which is the key deleterious event in the absence of dystrophin.     

Structural basis of NR2B-selective antagonist recognition by N-methyl-D-aspartate receptors

N-Methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors endowed with unique pharmacological and functional properties. In particular, their high permeability to calcium ions confers on NMDARs a central role in triggering long term changes in synaptic strength. Under excitotoxic pathological conditions, such as those occurring during brain trauma, stroke, or Parkinson's or Huntington's diseases, calcium influx through NMDAR channels can also lead to neuronal injury. This argues for the use of NMDAR antagonists as potential therapeutic agents. To date, the most promising NMDAR antagonists are ifenprodil and derivatives, compounds that act as noncompetitive inhibitors selective for NMDARs containing the NR2B subunit. Recent studies have identified the large N-terminal domain (NTD) of NR2B as the region controlling ifenprodil sensitivity of NMDARs. We present here a detailed characterization of the ifenprodil binding site using both experimental and computational approaches. 3D homology modeling reveals that ifenprodil fits well in a closed cleft conformation of the NRB NTD; however, ifenprodil can adopt either of two possible binding orientations of opposite direction. By studying the effects of cleft mutations, we show that only the orientation in which the phenyl moiety points deep toward the NTD hinge is functionally relevant. Moreover, based on our model, we identify novel NTD NR2B residues that are crucial for conferring ifenprodil sensitivity and provide functional evidence that these residues directly interact with the ifenprodil molecule. This work provides a general insight into the origin of the subunit-selectivity of NMDAR noncompetitive antagonists and offer clues for the discovery of novel NR2B-selective antagonists.