Polychlorinated biphenyls (PCBs) are accumulated in our body through food chain and cause a variety of adverse health effects including neurotoxicities such as cognitive deficits and motor dysfunction. In particular, neonates are considered as a high risk group for the neurotoxicity of PCBs exposure. The present study attempted to analyze the structure-activity relationship among PCB congeners and the mechanism of PCBs-induced neurotoxicity. We measured total protein kinase C (PKC) activities, PKC isoforms, reactive oxygen species (ROS), and induction of neurogranin (RC-3) and growth associated protein-43 (GAP-43) mRNA in cerebellar granule cells of neonatal rats with phorbol 12, 13-dibutyrate ([3H]PDBu) binding assay, western blot, ROS assay, and reverse transcription PCR (RT-PCR) analysis respectively following the different structural PCBs exposure. Only non-coplanar PCBs showed a significant increase of total PKC-alpha and betaII activity as measured with [3H]PDBu binding assay. ROS were more increased with non-coplanar PCBs than coplanar PCBs. The mRNA levels of RC-3 and GAP-43 were more induced with non-coplanar PCBs than coplanar PCBs, indicating that these factors may be useful biomarkers for differentiating non-coplanar PCBs from coplanar PCBs. Non-coplanar PCBs may be more potent neurotoxic congeners than coplanar PCBs. This study provides evidences that non-coplanar PCBs, which have been neglected in the risk assessment processes, should be added in the future to improve the quality and accuracy of risk assessment on the neuroendocrinal adverse effects of PCBs exposures.
Animals ; Blotting, Western ; Food Chain ; GAP-43 Protein ; Humans ; Infant, Newborn ; Nerve Growth Factor ; Neurogranin ; Neurons ; Neurotoxicity Syndromes ; Phorbols ; Polychlorinated Biphenyls ; Polymerase Chain Reaction ; Protein Isoforms ; Protein Kinase C ; Rats ; Reactive Oxygen Species ; Reverse Transcription ; Risk Assessment ; RNA, Messenger ; Structure-Activity Relationship ; Biomarkers

In the present study, we compared the expression patterns of neuritin mRNA in the dentate gyrus of hippocampal formation following single (1xECS) or repeated elctroconvulsive seizures (8xECS) treatments to the rat. The expression of neuritin mRNA was transiently increased, and returned to basal level within 12 hours after 1xECS. Whereas initial induction of neuritin mRNA was similarly seen, these increased mRNA level was maintained for 24 hours in 8xECS group. In contrast, induction profile of BDNF was similar following 1x and 8xECS. These results suggest that regulation of neuritin expression may be plastically changed by repeated ECS treatment.
Animals ; Brain-Derived Neurotrophic Factor ; Dentate Gyrus ; Hippocampus ; Neuronal Plasticity ; Plastics ; Rats ; RNA, Messenger ; Seizures

Manganese-enhanced magnetic resonance imaging (MEMRI) offers a novel neuroimaging method in visualizing the activity patterns of neural circuits. MEMRI is using the divalent manganese ion, which has been used as a cellular contrast agent. The present study was conducted to determine the contrast-enhancing effects of manganese ion administered into the spinal cord of rats. Manganese ion was administered into the spinal cord by lumbar puncture. Ex vivo magnetic resonance images were obtained at 6, 12, 24, and 48 hours after manganese ion injection. Although the highly contrasted images were not observed 6 or 12 hr after manganese injection, the distinctive manganese-enhanced images began to appear at 24 hours after manganese ion injection. These results suggest that the gray matter is the foci of intense paramagnetic signals and MEMRI may provide an effective technique to visualize the activity-dependent patterns in the spinal cord.
Animals ; Magnetic Resonance Imaging ; Magnetic Resonance Spectroscopy ; Magnetics ; Magnets ; Manganese ; Neuroimaging ; Rats ; Spinal Cord ; Spinal Puncture

Tissue-type plasminogen activator (tPA) is a serine proteinase which plays important roles in functional and structural synaptic plasticity, neural migration, as well as excitotoxic injuries in several pathological situations including ischemic stroke, seizure and Alzheimer's disease (AD). It has been suggested that a divalent cation zinc also plays pathological roles in ischemia and seizure. Interestingly, it has been suggested that zinc and tPA may negatively regulate the activity or the level of each other by mechanism involving physical interaction between the two. In the present study, we investigated the effect of zinc in tPA activity and expression in rat primary astrocyte. Astrocytes were transiently exposed to 20~200micrometer Zn2+ for 2 h and then were recovered for 24 h. In the culture supernatants, zinc treatment concentration-dependently inhibited the activity of tPA which was determined by casein-plasminogen zymography. There was only marginal changes, if any, in the level of tPA mRNA and protein. On the other hand, the activity of an endogenous inhibitor of tPA, plasminogen activator inhibitor-1 (PAI-1) as well as its expression was increased by zinc treatment in a concentration-dependant manner. These results suggest that zinc-induced decrease in tPA activity was also, at least in part, regulated by indirect way by regulating the level of PAI-1. The decrease in tPA activity may be a part of body's plan to reduce excitotoxic neural injury in a condition of elevated zinc in the brain.
Alzheimer Disease ; Animals ; Astrocytes ; Brain ; Hand ; Ischemia ; Plasminogen ; Plasminogen Activator Inhibitor 1 ; Plasminogen Activators ; Plastics ; Rats ; RNA, Messenger ; Seizures ; Serine Proteases ; Stroke ; Tissue Plasminogen Activator ; Zinc

Stem cells provide an important means for regenerative medicine due to the capacity to generate multiple types of differentiated cells and at the same time to maintain self-renewal. To identify the therapeutic effect of the transplantation of neural stem cells, differentiation and migration capacity of the neural stem cells that were isolated from E14 rat embryo and maintained in culture were examined after transplantation to the striatum of the quinolinic acid (QA)-induced Huntington's disease rat model. in vitro co-culture of the neural stem cells with the mixture of primary neurons and astrocytes promoted the maturation and the synapse formation of neuronal progenies of neural stem cells. Following the implantation, the neural stem cells survived, differentiated, and migrated in the damaged striatum region, exhibiting immunoreactivities against nestin, Tuj-1, GFAP, GAD(67) and synapsin 1 to a varying degree. These data provide clear evidence supporting that the neural stem cells isolated from the rat embryo and maintained in the primary culture have a multiple capacity to differentiate into neurons or glial cells both in vitro and in vivo.
Animals ; Astrocytes ; Brain ; Coculture Techniques ; Embryonic Structures ; Huntington Disease ; Intermediate Filament Proteins ; Nerve Tissue Proteins ; Neural Stem Cells ; Neuroglia ; Neurons ; Quinolinic Acid ; Rats ; Regenerative Medicine ; Synapses ; Transplants

Alcoholism is caused by a complex interaction between genetic and environmental factors. Findings obtained from several studies indicate that some tissue damage occurring in alcohol abusers is due to the generation of reactive oxygen species during the ethanol metabolism The objective of this study was to examine the associations between the polymorphisms of glutathione S-transferase (GST) M1 and T1 genes and Korean male patients with alcoholism. We investigated the distribution of deletion of GSTM1 and GSTT1 in Korean male patients diagnosed with alcoholism (n=133) and Korean male control subject without alcoholism (n=91) with polymerase chain reaction (PCR) method. GSTM1 showed significant associations with alcoholism susceptibility (p=0.0002). But GSTT1 showed no significant associations (p=0.0948). In combined analysis, both gene deletion and GSTM1 deletion were associated with alcoholism (p<0.0001 and p<0.0150). These results suggest that GSTM1 gene deletion might play an important role in risk for alcoholism.
Alcoholism ; Ethanol ; Gene Deletion ; Glutathione Transferase ; Humans ; Male ; Polymerase Chain Reaction ; Polymorphism, Genetic ; Reactive Oxygen Species

Recently, restricted progenitor cells have been identified in the substantia nigra (SN) of the rat and mouse, raising a hope that resident stem/progenitor cells may be useful for the therapy of Parkinson's disease. However, it is controversial whether dopamine (DA) neurons can be spontaneously or injury-dependently generated from the endogenous stem cells in the adult brain. Here, we explored the neurogenesis in C57Bl/6 adult mice under the normal and neurotoxin-injured conditions. To monitor adult neurogenesis, we injected 5-bromodeoxyuridine (BrdU) 2 weeks after striatal injection of neurotoxin 6-hydroxydopamine (6-OHDA), and sacrificed the animals 6 weeks after 6-OHDA injection. Whereas the number of BrdU-labeled cells was slightly increased in ipsilateral side than contralateral side of the midbrain, none of BrdU- labeled cells, however, exhibited neuronal markers, NeuN or DCX. Instead, BrdU- labeled cells expressed glial markers such as GFAP (astrocyte), Olig2 (oligodendrocyte) and Iba-1 (microglia). Especially, larger portion of BrdU-labeled cells in the ipsilateral side exhibited microglial marker, indicating that increased cell production in response to the 6-OHDA injection is not related to the adult neurogenesis.
Adult ; Animals ; Brain ; Bromodeoxyuridine ; Dopamine ; Dopaminergic Neurons ; Humans ; Mesencephalon ; Mice ; Neurogenesis ; Neurons ; Organothiophosphorus Compounds ; Oxidopamine ; Parkinson Disease ; Rats ; Stem Cells ; Substantia Nigra

Parkinson's disease is an age-related, slowly progressing neurodegenerative disorder characterized by abnormal deposition of aggregated alpha-synuclein in neuronal cell bodies (Lewy bodies) and neurites (Lewy neurites), as well as in glia. Based on semiquantitative assessment of Lewy pathologies in autopsy samples, a staging system was proposed indicating a highly predictable sequence of pathological progression. This staging system implicates a propagation of alpha-synuclein aggregation throughout the brain with an ascending pattern from lower brain stem to neocortex. The underlying mechanism for the pathological propagation is unknown. However, the recent discoveries on the secretion of neuronal alpha-synuclein and subsequent uptake of the protein by neighboring cells propose an interneuronal transmission of alpha-synuclein aggregates as a novel mechanism for the spread of Lewy pathology in PD. Elucidation of this mechanism is likely to identify novel therapeutic strategies that halt the progression of PD.
alpha-Synuclein ; Autopsy ; Brain ; Brain Stem ; Endocytosis ; Exocytosis ; Interneurons ; Lewy Bodies ; Neocortex ; Neurites ; Neurodegenerative Diseases ; Neuroglia ; Neurons

In the present study, neuroprotective property of celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, and its underlying mechanism were examined in the animal model of kainic acid (KA)-induced excitotoxicity. KA, administered intracerebroventricularly (i.c.v.), induced marked neuronal cell death with concurrent microglial activation and subsequent induction of inducible nitric oxide synthase (iNOS) in the hippocampus. Histopathological analysis demonstrated that celecoxib (100 mg/kg), pre-treated 1 hr before or post-treated 2 hr after KA i.c.v. injection, significantly attenuated KA-induced death of pyramidal neurons in CA3 region. Celecoxib obviously suppressed KA-induced microglial activation and subsequent iNOS expression. KA- induced phosphorylation of c-Jun N-terminal kinases (JNK) was attenuated with celecoxib treatments. The results of the present study demonstrate that suppression of JNK phosphorylation by celecoxib contributes to its neuroprotective action against KA-induced excitotoxicity suggesting that celecoxib may be a potentially valuable in the treatment of acute brain pathologies associated with excitotoxic neuronal damage such as epilepsy, stroke, and traumatic brain injury.
Brain ; Brain Injuries ; Cell Death ; Cyclooxygenase 2 ; Epilepsy ; Hippocampus ; JNK Mitogen-Activated Protein Kinases ; Kainic Acid ; Microglia ; Models, Animal ; Neurons ; Nitric Oxide Synthase Type II ; Phosphorylation ; Phosphotransferases ; Pyrazoles ; Stroke ; Sulfonamides ; Celecoxib

Repeated administration of amphetamine (AMPH) produces behavioral sensitization, a proposed model for the escalation of drug use characteristic of human addicts. beta-Phenylethylamine (PEA) is an endogenous trace amine found in mammalian brain and resembles AMPH both structurally and behaviorally. Previously, it has been reported that chronic PEA administration produces behavioral sensitization to the challenges of AMPH. However, these data were obtained with very high amount of PEA for a relatively long period of time. Further, the effect of PEA challenge on the expression of behavioral sensitization developed by AMPH pre-exposures has not been tested yet. Thus, we examined in the present experiment the expression of behavioral sensitization with AMPH challenge after a mild chronic PEA treatment. Rats were repeatedly administered with systemic injections of saline, beta-phenylethylamine (PEA) (10 or 50 mg/kg), or amphetamine (AMPH) (1.5 mg/kg). When challenged a week after the last pre-injection, rats pre-exposed to either PEA or AMPH showed behavioral sensitization to AMPH (1.0 mg/kg), while these effects were not observed to PEA (50 mg/kg) itself. These results demonstrate that repeated exposure to PEA produces behavioral sensitization to AMPH challenge, while PEA challenge has no effect on the expression of behavioral sensitization developed by AMPH pre-exposures, suggesting that PEA may play a role in the development of locomotor sensitization to AMPH, but not in the expression of it.
Amphetamine ; Animals ; Brain ; Humans ; Peas ; Phenethylamines ; Rats ; Schizophrenia