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1.
Stem Cell Reports ; 3(1): 73-84, 2014 Jul 08.
Article in English | MEDLINE | ID: mdl-25068123

ABSTRACT

New neurons generated by the neural stem cells (NSCs) in the adult hippocampus play an important role in emotional regulation and respond to the action of antidepressants. Depression is a common and serious side effect of interferon-α (IFN-α), which limits its use as an antiviral and antitumor drug. However, the mechanism(s) underlying IFN-induced depression are largely unknown. Using a comprehensive battery of behavioral tests, we found that mice subjected to IFN-α treatment exhibited a depression-like phenotype. IFN-α directly suppressed NSC proliferation, resulting in the reduced generation of new neurons. Brain-specific mouse knockout of the IFN-α receptor prevented IFN-α-induced depressive behavioral phenotypes and the inhibition of neurogenesis, suggesting that IFN-α suppresses hippocampal neurogenesis and induces depression via its receptor in the brain. These findings provide insight for understanding the neuropathology underlying IFN-α-induced depression and for developing new strategies for the prevention and treatment of IFN-α-induced depressive effects.


Subject(s)
Depression/chemically induced , Interferon-alpha/adverse effects , Neural Stem Cells/pathology , Animals , Cell Proliferation/drug effects , Cell Proliferation/physiology , Cells, Cultured , Depression/metabolism , Depression/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Neural Stem Cells/drug effects
2.
Brain Res ; 1352: 187-99, 2010 Sep 17.
Article in English | MEDLINE | ID: mdl-20599805

ABSTRACT

Electroencephalographic (EEG) seizures and behavioral convulsions begin to appear spontaneously a few weeks after chemoconvulsant-induced status epilepticus (SE) and thereafter become more intense. This indicates the progressive development of a long-lasting epileptic focus. In addition, chemoconvulsant-induced SE increases neuronal proliferation in the dentate subgranular zone (SGZ) and ectopic migration of newborn neurons into the dentate hilus of adult animals. These seizure-induced newborn neurons, especially ectopic granule cells in the dentate hilus, are believed to facilitate the development of epileptic foci in animal models of temporal lobe epilepsy. In the present study, we examined the effects of a novel antiepileptic drug, levetiracetam, on the appearance of spontaneous EEG seizures and on the generation of newborn neurons, especially of ectopic granule cells in the dentate hilus, following kainate-induced SE. Levetiracetam treatment for 25 days, initiated 24 hours after induction of kainate-induced SE, significantly decreased the mean duration of spontaneous EEG seizures 58 days later. Levetiracetam treatment also prevented an SE-induced increase in the number of ectopic granule cells observed 58 days after kainate administration by suppressing neuronal proliferation in the dentate SGZ and abnormal migration of newborn neurons from the dentate SGZ to the hilus. These results are in accord with a previous report that an antimitotic agent that reduced the number of newborn neurons significantly decreased the frequency of spontaneous convulsions 1 month after pilocarpine-induced SE. This evidence from the kainate model of temporal lobe epilepsy suggests that levetiracetam may exert antiepileptogenic effects through the suppression of seizure-induced neurogenesis.


Subject(s)
Nootropic Agents/pharmacology , Piracetam/analogs & derivatives , Status Epilepticus/prevention & control , Animals , Animals, Newborn , Bromodeoxyuridine , Dentate Gyrus/drug effects , Dentate Gyrus/physiopathology , Disease Models, Animal , Electroencephalography , Homeodomain Proteins/drug effects , Homeodomain Proteins/metabolism , Immunohistochemistry , Kainic Acid/adverse effects , Kainic Acid/pharmacology , Levetiracetam , Neurons/cytology , Neurons/drug effects , Piracetam/pharmacology , Rats , Seizures/physiopathology , Seizures/prevention & control , Status Epilepticus/chemically induced , Status Epilepticus/physiopathology , Tetanus Toxin/cerebrospinal fluid , Time Factors , Tumor Suppressor Proteins/drug effects , Tumor Suppressor Proteins/metabolism
3.
Neuropsychopharmacology ; 31(12): 2619-26, 2006 Dec.
Article in English | MEDLINE | ID: mdl-16823390

ABSTRACT

The therapeutic use of interferon-alpha (IFN-alpha), a proinflammatory cytokine, is known to cause various neuropsychiatric adverse effects. In particular, depression occurs in 30-45% of patients, frequently interrupting treatment. IFN-alpha-treated animals also show depression-like behaviors. However, mechanisms underlying the depression caused by IFN-alpha remain to be defined. Recently, a decrease in adult hippocampal neurogenesis was revealed as a possible neuropathological mechanism of depression. Therefore, we investigated the effect of subchronic IFN-alpha treatment on neurogenesis in the adult rat dentate gyrus (DG). Immediately after the administration of IFN-alpha for 1 week, a decrease in the number of 5-bromo-deoxyuridine-labeled proliferating cells was observed in the DG; however, no effect was detected on the expression of mature neuronal phenotype in the newly formed cells 3 weeks later. Also, an increase in the level of interleukin-1beta (IL-1beta), a major proinflammatory cytokine, was observed in the hippocampus following the administration of IFN-alpha. Furthermore, coadministration of an IL-1 receptor antagonist completely blocked the IFN-alpha-induced suppression of the cell-proliferative activity in the DG. Our results indicate that IFN-alpha suppresses neurogenesis in the DG, and that IL-1beta plays an essential role in the suppression. The decreased cell proliferation caused by IFN-alpha-induced IL-1beta may be responsible, at least in part, for IFN-alpha-induced depression.


Subject(s)
Cell Proliferation/drug effects , Dentate Gyrus/drug effects , Interferon-alpha/adverse effects , Interleukin-1beta/agonists , Neurons/drug effects , Animals , Bromodeoxyuridine , Cell Division/drug effects , Cell Division/immunology , Dentate Gyrus/immunology , Dentate Gyrus/physiopathology , Depressive Disorder/chemically induced , Depressive Disorder/immunology , Depressive Disorder/physiopathology , Disease Models, Animal , Down-Regulation/drug effects , Down-Regulation/physiology , Immunologic Factors/adverse effects , Interleukin 1 Receptor Antagonist Protein/pharmacology , Interleukin-1beta/immunology , Interleukin-1beta/metabolism , Male , Neurons/immunology , Rats , Rats, Wistar , Receptors, Interleukin-1/antagonists & inhibitors , Receptors, Interleukin-1/immunology
4.
J ECT ; 22(2): 148-9, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16801833

ABSTRACT

We report a case of an uneventful course after electroconvulsive therapy (ECT) of a patient who had undergone coil embolization for an intracranial aneurysm 37 days earlier. There have been no reports until now of ECT after coil embolization. According to histopathologic examinations, it takes approximately 2 weeks after coil embolization for the aneurysm to become fixed. The ECT can be a therapeutic option even in patients with a previous history of coil embolization, as long as it is performed under proper anesthetic management.


Subject(s)
Electroconvulsive Therapy , Embolization, Therapeutic , Intracranial Aneurysm/therapy , Psychotic Disorders/therapy , Adult , Embolization, Therapeutic/adverse effects , Female , Humans , Psychotic Disorders/etiology
5.
Neurosci Lett ; 399(1-2): 171-4, 2006 May 15.
Article in English | MEDLINE | ID: mdl-16513267

ABSTRACT

In aged rats, although learning and memory impairment is prominent, both the number of granular cells and the degree of neuronal progenitor proliferation in the hippocampus are known to be preserved. We examined the association between the survival of newly generated neurons in the hippocampus and the learning ability in aged rats. By using BrdU, a cell proliferation marker to determine neurogenesis and contextual fear conditioning to determine learning ability, we found that in aged rats, along with memory impairment, the survival of both the proliferated cells at baseline and those enhanced by contextual fear conditioning decreased remarkably. These results suggest that the integration of newly generated neurons into hippocampal circuitry is decreased with aging, this phenomenon may, in part, explain the decline in learning and memory in aged rats.


Subject(s)
Aging , Cell Proliferation , Cell Survival , Hippocampus/cytology , Memory , Spatial Behavior , Animals , Bromodeoxyuridine/metabolism , Conditioning, Psychological , Fear , Hippocampus/metabolism , Immunohistochemistry , Male , Rats
6.
Neuropsychopharmacology ; 31(1): 212-20, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16123748

ABSTRACT

There is compelling evidence for the involvement of hypothalamic-pituitary-adrenal (HPA) axis abnormalities in depression. Growing evidence has suggested that the combined dexamethasone (DEX)/corticotropin-releasing hormone (CRH) test is highly sensitive to detect HPA axis abnormalities. We organized a multicenter study to assess the DEX/CRH test as a state-dependent marker for major depressive episode in the Japanese population. We conducted the DEX/CRH test in 61 inpatients with major depressive episode (Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV)) and 57 healthy subjects. In all, 35 patients were repeatedly assessed with the DEX/CRH test on admission and before discharge. The possible relationships between clinical variables and the DEX/CRH test were also examined. Significantly enhanced pituitary-adrenocortical responses to the DEX/CRH test were observed in patients on admission compared with controls. Such abnormalities in patients were significantly reduced after treatment, particularly in those who underwent electroconvulsive therapy (ECT) in addition to pharmacotherapy. Age and female gender were associated with enhanced hormonal responses to the DEX/CRH test. Severity of depression correlated with DEX/CRH test results, although this was explained, at least in part, by a positive correlation between age and severity in our patients. Medication per se was unrelated to DEX/CRH test results. These results suggest that the DEX/CRH test is a sensitive state-dependent marker to monitor HPA axis abnormalities in major depressive episode during treatment. Restoration from HPA axis abnormalities occurred with clinical responses to treatment, particularly in depressed patients who underwent ECT.


Subject(s)
Corticotropin-Releasing Hormone , Depressive Disorder, Major/physiopathology , Dexamethasone , Hypothalamo-Hypophyseal System/physiopathology , Pituitary-Adrenal System/physiopathology , Adult , Age Factors , Female , Humans , Male , Middle Aged , Psychiatric Status Rating Scales , Sex Characteristics
7.
Brain Res ; 1054(1): 30-7, 2005 Aug 23.
Article in English | MEDLINE | ID: mdl-16054117

ABSTRACT

In the early process of long-term memory formation, cyclic AMP response element-binding protein (CREB), a transcription factor on which multiple signal transduction pathways converge, has been implicated. We examined whether the age difference in the performance of contextual fear conditioning (CFC) is associated with a change in activation of CREB in the hippocampus which is an important neural structure for long-term memory. The activation of CREB in the hippocampus in young (15 weeks old) and old (120 weeks old) male rats was determined immunohistochemically with an antibody that specifically recognizes the phosphorylated form of CREB (pCREB). Young rats exhibited better performance than old rats with respect to the freezing time in CFC. Phosphorylation of CREB as revealed by the ratio of the pCREB-immunoreactive cell number to the CREB-immunoreactive cell number was increased in the CA1 region, but not in other hippocampal regions following training for CFC. The close relationship between behavioral performance and CREB phosphorylation in the CA1 region suggests that hippocampal CREB is involved in age-related decline of learning and memory.


Subject(s)
Aging/physiology , Cyclic AMP Response Element-Binding Protein/metabolism , Hippocampus/metabolism , Memory/physiology , Analysis of Variance , Animals , Behavior, Animal , Cell Count/methods , Conditioning, Classical/physiology , Electroshock/methods , Fear , Immunohistochemistry/methods , Male , Phosphorylation , Rats , Time Factors
8.
Neurosci Res ; 51(1): 31-8, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15596238

ABSTRACT

Panax Ginseng is a commonly used galenical known to have an enhancing effect on learning. Neurogenesis in the hippocampus has been shown to be necessary for hippocampus/amygdala-dependent learning tasks. To investigate the role of Ginseng in neurogenesis and learning of rats, we administered both Ginseng and BrdU for five consecutive days. As a result, Ginseng increased the number of BrdU-positive cells in the dentate gyrus in a dose-dependent manner. Further, we administered one dose of BrdU after Ginseng treatment for five consecutive days, and the number of BrdU-positive cells did not increase significantly. However, when one dose of BrdU was given 1 day before the following five consecutive days of Ginseng treatment, the number of BrdU-positive cells markedly increased in the hippocampus. Therefore, it is likely that Ginseng enhances not proliferation but survival of newly generated neurons in the hippocampus. Second, we administered both Ginseng and BrdU to rats for five consecutive days. One day after the last Ginseng and BrdU co-administration, contextual fear conditioning (CFC) was conducted. Ginseng in a dose-dependent manner increased the % freezing time and the number of BrdU-positive cells in the dentate gyrus of rats that received CFC. Thus, an increase in CFC-related neurogenesis may be one mechanism of Ginseng's properties to enhance learning ability.


Subject(s)
Conditioning, Psychological/drug effects , Fear , Hippocampus/cytology , Neurons/drug effects , Panax/chemistry , Plant Extracts/pharmacology , Analysis of Variance , Animals , Behavior, Animal , Bromodeoxyuridine/metabolism , Cell Count/methods , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Administration Schedule , Exploratory Behavior/drug effects , Immunohistochemistry/methods , Male , Motor Activity/drug effects , Neurons/physiology , Phosphopyruvate Hydratase/metabolism , Plant Extracts/administration & dosage , Rats , Rats, Wistar
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