Modification of spatial recognition memory and object discrimination after chronic administration of haloperidol, amitriptyline, sodium valproate or olanzapine in normal and anhedonic rats.

In the present study we have investigated the effects of a chronic administration of olanzapine (Ola) on visual and spatial memory in normal and anhedonic rats. The effects of Ola have been compared to those of the typical antipsychotic Hal, the tricyclic antidepressant amitriptyline (Ami), and the mood stabilizer VPA. Anhedonia (assessed by reduction of sucrose preference) was induced by administration of a chronic mild stress (CMS) protocol, in which rats were exposed sequentially, over a period of 4 wk, to a variety of unpredictable mild stressors. The spatial memory was evaluated by testing the ability of the rats to discriminate a familiar vs. a novel environment, while the visual memory was assessed by testing the ability of the rats to discriminate familiar vs. novel objects. In CMS-free rats, VPA (5 or 30 mg/kg.d), Ola (0.02 or 0.1 mg/kg.d), Ami (2 mg/kg.d) and Hal (0.2 mg/kg.d) caused no detectable modifications of visual memory, whereas VPA (5 mg/kg.d), Ami (2 mg/kg.d) and Ola (0.02 mg/kg.d) did not modify spatial memory performance. In our experimental conditions, the administration of the CMS protocol caused an impairment of both visual and spatial memory. The chronic treatment of anhedonic rats with Ola (0.02 mg/kg.d) or Ami (2 mg/kg.d) prevented, at least in part, the stress-induced impairment of visuospatial performance. In conclusion, the results of the present preclinical study seem to indicate that the chronic administration of low doses of Ola or Ami has the potential to lead to substantial cognitive benefits in depressed patients

High-Mobility Group Box-1 Protein and β-Amyloid oligomers promote neuronal differentiation of adult hippocampal neural progenitors via Receptor for Advanced Glycation Endproducts/Nuclear Factor-kB axis: Relevance for Alzheimer’s disease.

Dysregulated hippocampal neurogenesis has been associated with neurodegenerative disorders, including Alzheimer's disease (AD), in which it may potentially represent an auto-reparatory mechanism that could counteract neuronal loss and cognitive impairment. We evaluated hippocampal neurogenesis in TgCRND8 mice and reported that, at 32 weeks of age, corresponding to an advanced AD-like neuropathology stage, increased numbers of proliferating cells, doublecortin-expressing progenitors/neuroblasts, and early postmitotic calretinin-expressing neurons were present compared with wild-type (WT) littermates. When hippocampal neural progenitor cells (NPCs) were isolated from TgCRND8 mice, we demonstrated that (1) their neurogenic potential was higher compared with WT NPCs; (2) medium conditioned by TgCRND8 NPC promoted neuronal differentiation of WT NPCs; and (3) the proneurogenic effect of TgCRND8-conditioned medium was counteracted by blockade of the receptor for advanced glycation end products (RAGE)/nuclear factor-\u3baB (NF-\u3baB) axis. Furthermore, we showed that \u3b2-amyloid 1-42 (A\u3b21-42) oligomers, but not monomers and fibrils, and the alarmin high-mobility group box-1 protein (HMGB-1) could promote neuronal differentiation of NPCs via activation of the RAGE/NF-\u3baB axis. Altogether, these data suggest that, in AD brain, an endogenous proneurogenic response could be potentially triggered and involve signals (A\u3b21-42 oligomers and HMGB-1) and pathways (RAGE/NF-\u3baB activation) that also contribute to neuroinflammation/neurotoxicity. A more detailed analysis confirmed no significant increase of new mature neurons in hippocampi of TgCRND8 compared with WT mice, suggesting reduced survival and/or integration of newborn neurons. Therapeutic strategies in AD should ideally combine the ability of sustaining hippocampal neurogenesis as well as of counteracting an hostile brain microenvironment so to promote survival of vulnerable cell populations, including adult generated neurons

Acquisition, Retention, and Recall of Memory After Injection of RS67333, a 5-HT4 Receptor Agonist, Into the Nucleus Basalis Magnocellularis of the Rat

The serotonin 5-HT4 subtype receptor is predominantly localized into anatomical structures linked to memory and cognition. A few experimental studies report that the acute systemic administration of selective 5-HT4 agonists has ameliorative effects on memory performance, and that these effects are reversed by contemporary administration of 5-HT4 receptor antagonists. To verify whether this procognitive action occurs via the activation of the cholinergic nucleus basalis magnocellularis (NBM)-cortical pathways, we examined the effects of RS67333, a selective partial agonist of the 5-HT4 receptor, on rat performance in a place recognition task upon local administration of the drug into the NBM area. The intra-NBM administration of RS67333 enhances the acquisition (200–500 ng/0.5 μL) and the consolidation (40–200 ng/0.5 μL) of the place recognition memory. These effects are reversed by pretreatment with the selective 5-HT4 receptor antagonist RS39604 (300 ng/0.5μL). Conversely, the recall of memory is not affected by the 5-HT4 agonist. Our results indicate that 5-HT4 receptors located within the NBM may play a role in spatial memory and that the procognitive effect of RS67333 is due, at least in part, to the potentiation of the activity of cholinergic NBM-cortical pathways

The management of intracranial aneurysms during pregnancy: a systematic review

Hemodynamic changes during pregnancy may favor the formation and rupture of intracranial aneurysms. Despite this risk, guidelines for managing intracranial aneurysms during pregnancy have not been clearly defined. The objective of this review is to describe the treatment options for pregnant women with intracranial aneurysms, and to report the maternal and fetal outcomes associated with different treatment strategies. A search of the literature was conducted using the PubMed database for the period January 1991 through June 2015. Aneurysm characteristics and management, pregnancy management, and maternal and fetal outcomes were evaluated. The most recent search was performed in June 2015. In total, 50 aneurysms (44 patients) were evaluated. Rupture was confirmed upon imaging in 36 aneurysms (72%), and most aneurysms ruptured during the third trimester (77.8%). Coil embolization was associated with a lower complication rate than clipping in patients with ruptured aneurysms (9.5% vs 23.1%). For patients with unruptured aneurysms, surgical management was associated with 31.9% fewer complications compared to no treatment. Most patients underwent Cesarean delivery (84%), and a combined neurosurgical-obstetrical procedure was used for 8 patients with ruptured aneurysms near term. Adverse outcomes were reported in 11.9% of children. Treatment of intracranial aneurysms during pregnancy is safe and effective. Furthermore, we suggest that coil embolization be considered a first line treatment over clipping for surgical management of the pregnant population. Going forward, we encourage the establishment of formal guidelines for managing intracranial aneurysms during pregnancy

Preclinical study on cognitive and antidepressant effects of chronic low-dose olanzapine

Background Although in bipolar patients the main therapeutic indication of olanzapine (OLA) is the management of acute mania, several observations suggest that this agent may exert antidepressant as well as antimanic effects. However, in our knowledge, there are no preclinical studies supporting this hypothesis. Thus, the main goal of the present work was to evaluate the putative antidepressant effect of OLA (0.02–0.1 or 0.5 mg/kg/day), in comparison to amitriptyline (AMI) (5 mg/kg/day), haloperidol (HAL) (0.2 mg/kg/day) and sodium valproate (VPA) (5.0 or 30 mg/kg/day), in rats exposed to a protocol of chronic mild stress (CMS). The second aim of this project was to assess the efficacy of OLA, AMI, HAL and VPA in reverting the cognitive impairment produced by the anhedonic state. Both control and anhedonic rats will be subjected to two short-memory paradigms, the place recognition test and the object discrimination test, in order to evaluate the effects of the examined drugs on visuospatial memory

Long-term psychiatric outcomes in pediatric brain tumor survivors

The increased efficacy of cancer treatments has led to a greater survival rate of patients with pediatric brain cancers. Therefore, it is imperative to explore the long-term consequences of therapies employed to treat pediatric brain tumors. The goal of this study was to provide a review of literature regarding the downstream psychological and psychiatric consequences experienced by adult survivors of pediatric brain cancer as a result of treatment, tumor type, or tumor location.A PubMed MeSH search and additional online database searches were conducted to include pertinent studies that discussed psychological deficits in childhood brain cancer survivors. The studies included were subjected to data extraction to quantify relevant information for further analysis.A total of 17 papers with 5320 pediatric brain tumor patients were incorporated in our review. Mean age at diagnosis (8.13 ± 0.77 years), mean follow-up time (9.98 ± 3.05 years), and male-to-female ratios (1.08:1) were compiled from studies reporting this information. Incidences of depression (19 %), anxiety (20 %), suicidal ideation (10.9 %), schizophrenia and its related psychoses (9.8 %), and behavioral problem (28.7 %) were higher among pediatric brain cancer survivors than in the normal population. Craniospinal radiotherapy and/or surgery corresponded to an increased likelihood of developing adverse deficits. Astrocytomas or other glial tumors were linked to poorer outcomes.Physicians treating pediatric brain tumor patients should be aware of the possible consequences associated with treatment. Psychiatric monitoring is warranted in survivors of pediatric brain tumors, but further investigation is needed to elucidate late outcomes regarding tumor type and location

Activation of NF-κB in Schwann Cells Is Dispensable for Myelination In Vivo

Peripheral myelination is a dynamic process orchestrated by axons and Schwann cells. Although the signaling mechanisms governing myelination are not fully understood, NF-κB activation in Schwann cells has been implicated as a key regulator in vitro . Using a mouse model, we show that nuclear factor κB activation in Schwann cells is not required for myelination in vivo

Prior regular exercise improves clinical outcome and reduces demyelination and axonal injury in experimental autoimmune encephalomyelitis

Although previous studies have shown that forced exercise modulates inflammation and is therapeutic acutely for experimental autoimmune encephalomyelitis (EAE), the long-term benefits have not been evaluated. In this study, we investigated the effects of preconditioning exercise on the clinical and pathological progression of EAE. Female C57BL/6 mice were randomly assigned to either an exercised (Ex) or unexercised (UEx) group and all of them were induced for EAE. Mice in the Ex group had an attenuated clinical score relative to UEx mice throughout the study. At 42 dpi, flow cytometry analysis showed a significant reduction in B cells, CD4(+) T cells, and CD8(+) T cells infiltrating into the spinal cord in the Ex group compared to UEx. Ex mice also had a significant reduction in myelin damage with a corresponding increase in proteolipid protein expression. Finally, Ex mice had a significant reduction in axonal damage. Collectively, our study demonstrates for the first time that a prolonged and forced preconditioning protocol of exercise improves clinical outcome and attenuates pathological hallmarks of EAE at chronic disease13616373sem informaçã

Inhibition of soluble tumour necrosis factor is therapeutic in experimental autoimmune encephalomyelitis and promotes axon preservation and remyelination

Tumour necrosis factor is linked to the pathophysiology of various neurodegenerative disorders including multiple sclerosis. Tumour necrosis factor exists in two biologically active forms, soluble and transmembrane. Here we show that selective inhibition of soluble tumour necrosis factor is therapeutic in experimental autoimmune encephalomyelitis. Treatment with XPro1595, a selective soluble tumour necrosis factor blocker, improves the clinical outcome, whereas non-selective inhibition of both forms of tumour necrosis factor with etanercept does not result in protection. The therapeutic effect of XPro1595 is associated with axon preservation and improved myelin compaction, paralleled by increased expression of axon-specific molecules (e.g. neurofilament-H) and reduced expression of non-phosphorylated neurofilament-H which is associated with axon damage. XPro1595-treated mice show significant remyelination accompanied by elevated expression of myelin-specific genes and increased numbers of oligodendrocyte precursors. Immunohistochemical characterization of tumour necrosis factor receptors in the spinal cord following experimental autoimmune encephalomyelitis shows tumour necrosis factor receptor 1 expression in neurons, oligodendrocytes and astrocytes, while tumour necrosis factor receptor 2 is localized in oligodendrocytes, oligodendrocyte precursors, astrocytes and macrophages/microglia. Importantly, a similar pattern of expression is found in post-mortem spinal cord of patients affected by progressive multiple sclerosis, suggesting that pharmacological modulation of tumour necrosis factor receptor signalling may represent an important target in affecting not only the course of mouse experimental autoimmune encephalomyelitis but human multiple sclerosis as well. Collectively, our data demonstrate that selective inhibition of soluble tumour necrosis factor improves recovery following experimental autoimmune encephalomyelitis, and that signalling mediated by transmembrane tumour necrosis factor is essential for axon and myelin preservation as well as remyelination, opening the possibility of a new avenue of treatment for multiple sclerosis