Ncpneuro_highlights_november.indd

The patient had failed to recover command- specifically damaging oligodendrocytes, for response or communication functions, despite 4 weeks and were subsequently tested on a a 2-year course of inpatient rehabilitation and Y-maze task. Treatment of mice with quetiapine 4 years in a nursing home. Functional MRI beginning 1 week before introduction of cupri- revealed a preserved large-scale bihemispheric zone significantly prevented behavioral changes cerebral language network. Inpatient rehabilita- compared with the control group (P <0.05).
tion was reinitiated, and the patient underwent These findings suggest a mechanism for the implantation of DBS electrodes 4 months later. antipsychotic action of quetiapine that targets An 18-week titration phase began 50 days after oligodendrocytes. Furthermore, the data help surgery, with the duration of alternating time on to establish a role for oligodendrocytes in the and off stimulation increasing from 3 days to etiopathology of schizophrenia, although it is 14 days. Behavioral improvements, including not clear whether oligodendrocytes can also be longer periods of eye opening, increased com- implicated in other neuropsychiatric disorders mand response, improved functional object use involving myelination development problems. and intelligent verbalization, were noted shortly The authors suggest that promyelinating treat- after the initiation of the titration phase. Finally, ment could be a viable therapeutic approach the patient entered a crossover phase during which DBS was alternately on and off for 30-day Original article Xiao L et al. (2007) Quetiapine facilitates
periods. Improvements in cognitively mediated oligodendrocyte development and prevents mice from behaviors, functional limb control and oral feeding myelin breakdown and behavioral changes. Mol Psychiatry [doi:10.1038/sj.mp.4002064] were associated with DBS-on periods.
The authors suggest that DBS might promote functional recovery many years after an initial injury in MCS patients with only inter mittent Intramuscular anti-β-amyloid
immunotherapy for AD
Original article Schiff ND et al. (2007) Behavioural
improvements with thalamic stimulation after severe
Experimental and clinical studies have suggested traumatic brain injury. Nature 448: 600–603
that clearance of amyloid-β (Aβ) plaques can slow cognitive decline in Alzheimer’s disease (AD). Immunotherapy targeting Aβ has shown Quetiapine targets
promise in reducing plaques, but has adverse oligodendrocytes and could be
effects including microhemorrhage and brain a treatment for schizophrenia
inflammation. Wang et al. recently tested the ability of a single-chain antibody against Aβ Recent structural and neuroimaging studies (scFv) to promote plaque clearance in a mouse have reported white matter abnormalities in the model of AD. This scFv lacks the normal anti- brains of patients with schizophrenia, suggesting body’s constant (Fc) region, which has been that oligodendrocytes might be involved in the suggested to mediate the detrimental side etiopathology of this condition. To investigate effects of other anti-Aβ immunotherapies. this hypothesis, Xiao et al. studied the response The investigators first demonstrated that of oligodendrocytes to antipsychotic drugs.
recombinant scFv could inhibit the formation Neural progenitor cells (NPCs) isolated from of Aβ fibrils and promote the disaggregation rat fetuses were treated with a range of anti- of preformed fibrils in vitro. To test the tech- psychotic drugs, but only quetiapine (in con- nique in vivo, the scFv gene was delivered by junction with other growth factors) increased recombined adeno-associated virus vectors proliferation of NPCs in neurosphere cultures. into 9-month-old transgenic mice with numer- Quetiapine also stimulated NPCs to differentiate ous brain Aβ deposits. Compared with control into oligo dendrocytes, through extracellular signal- animals, levels of Aβ peptide in the brains of related kinases, and increased myelin basic pro- treated animals were significantly lower follow- tein expression in cortical aggregate cultures in ing intramuscular (P <0.05) as well as intra- a dose-dependent manner (P <0.0001). To test cranial (P <0.01) delivery of scFv. Three months the effect of quetiapine on cortical myelin break- after delivery, no antibodies against scFv down in vivo, 8-week-old mice were fed 0.2% were detected, no T-lymphocyte infiltration cuprizone, which causes myelin breakdown by was observed, and there was no increase in 2007 Nature Publishing Group
the number of microhemorrhage profiles in aid the development of therapies to alleviate scFv-treated mice compared with controls.
comorbidities associated with shift work.
The results suggest that intramuscular delivery Original article Sookoian S et al. (2007) Serotonin and
of scFv is as effective and safe as intra cranial serotonin transporter gene variant in rotating shift workers. delivery for reducing the total Aβ burden in a Sleep 30: 1049–1053
mouse model of AD, and that neither mode of delivery elicits an inflammatory response. Neurotrophin receptor p75
Original article Wang Y-J et al. (2007) Intramuscular
delivery of a single chain antibody gene reduces brain Aβ
regulates the invasiveness
burden in a mouse model of Alzheimer’s disease. Neurobiol of malignant gliomas
Aging [doi:10.1016/j.neurobiolaging.2007.06.013] The highly invasive nature of malignant gliomas makes them very difficult to treat. To elucidate Polymorphism in 5-HT transporter
the underlying mechanism of glioma invasive- gene is associated with tolerance
ness, Johnston et al. used serial in vivo selec- of rotating shift work
tion to establish a mouse model of the disease. These authors subsequently identified the p75 Desynchronization of circadian rhythms from neurotrophin receptor (p75NTR) to be a major environ mental conditions can have important regulator of glioma invasion and migration. They health implications for rotating shift workers (those suggest that this receptor could be targeted to who work shifts that rotate or change according prevent recurrence of malignant gliomas.
to a set schedule). Those individuals have a high The authors isolated a population of invasive risk of developing cardio vascular and metabolic cells from a noninvasive human glioma cell line problems. Using a cohort of 683 Argentinian men following implantation in immuno compromised of European ancestry (437 day workers, 246 rotat- mice. After reinjection into a new group of ing shift workers), Sookoian et al. have explored the relationships between 5-hydroxytryptamine cells migrated far from the original tumor (5-HT; a neurotransmitter with an important role site and formed tumors with highly infiltrative in modulating circadian rhythms), 5-hydroxy- edges; by contrast, reinjected noninvasive indoleacetic acid (5-HIAA; a 5-HT metabolite), cells resulted in large tumors with well-defined functional polymorphism of the 5-HT transporter borders. Microarray analyses revealed that gene (SLC6A4), and work schedule.
p75NTR was upregulated in the invasive cells Platelet 5-HT and 5-HIAA content were both and not expressed in tumor cells, and reverse- greater in day workers than in shift workers. transcriptase polymerase chain reaction and Significantly decreased platelet 5-HIAA content, western blot analysis confirmed that ectopic but not platelet 5-HT content, was observed expression of p75NTR induced migration and in individuals homozygous for the SLC6A4 invasion in vitro. Furthermore, upregulation of promoter short variant, relative to other geno- p75NTR in glioblastoma cells from various cell types. The short (deletion) variant of the SLC6A4 lines dramatically increased their invasiveness promoter reduces SLC6A4 transcription rates in vivo. Disruption of the ability of p75NTR to relative to the long (44 bp insertion) variant. bind neurotrophin resulted in tumors similar Overall, SLC6A4 allele distribution differed to those derived from noninvasive cells, indi- between day workers and shift workers, with the short allele being more prevalent in shift workers. This difference was observed in individuals with observed that p75NTR results in striking actin at least 5 years’ exposure to their present work cytoskeletal rearrangements in invading cells. schedule, but not in those with shorter expo- sure, indicating that individuals harboring short strated that p75NTR is commonly expressed SLC6A4 variants (i.e. those with decreased in glioblastoma multiforme, and that p75NTR- serotonergic function) might better tolerate positive cells migrate at a greater rate than do shift work than those with long variants.
Original article Johnston ALM et al. (2007) The p75
neurotrophin receptor is a central regulator of glioma circadian rhythm desynchronization might invasion. PLoS Biol 5: e212
2007 Nature Publishing Group

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