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1.
Nature ; 571(7766): 565-569, 2019 07.
Article in English | MEDLINE | ID: mdl-31316206

ABSTRACT

Parkinson's disease is a neurodegenerative disorder with motor symptoms linked to the loss of dopaminergic neurons in the substantia nigra compacta. Although the mechanisms that trigger the loss of dopaminergic neurons are unclear, mitochondrial dysfunction and inflammation are thought to have key roles1,2. An early-onset form of Parkinson's disease is associated with mutations in the PINK1 kinase and PRKN ubiquitin ligase genes3. PINK1 and Parkin (encoded by PRKN) are involved in the clearance of damaged mitochondria in cultured cells4, but recent evidence obtained using knockout and knockin mouse models have led to contradictory results regarding the contributions of PINK1 and Parkin to mitophagy in vivo5-8. It has previously been shown that PINK1 and Parkin have a key role in adaptive immunity by repressing presentation of mitochondrial antigens9, which suggests that autoimmune mechanisms participate in the aetiology of Parkinson's disease. Here we show that intestinal infection with Gram-negative bacteria in Pink1-/- mice engages mitochondrial antigen presentation and autoimmune mechanisms that elicit the establishment of cytotoxic mitochondria-specific CD8+ T cells in the periphery and in the brain. Notably, these mice show a sharp decrease in the density of dopaminergic axonal varicosities in the striatum and are affected by motor impairment that is reversed after treatment with L-DOPA. These data support the idea that PINK1 is a repressor of the immune system, and provide a pathophysiological model in which intestinal infection acts as a triggering event in Parkinson's disease, which highlights the relevance of the gut-brain axis in the disease10.


Subject(s)
Enterobacteriaceae Infections/microbiology , Enterobacteriaceae Infections/physiopathology , Intestines/microbiology , Parkinson Disease/genetics , Parkinson Disease/microbiology , Protein Kinases/deficiency , Protein Kinases/genetics , Animals , Antigen Presentation/immunology , Autoantigens/immunology , Axons/pathology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/pathology , Citrobacter rodentium/immunology , Citrobacter rodentium/pathogenicity , Disease Models, Animal , Dopaminergic Neurons/immunology , Dopaminergic Neurons/pathology , Enterobacteriaceae Infections/immunology , Enterobacteriaceae Infections/pathology , Female , Intestines/immunology , Intestines/pathology , Levodopa/therapeutic use , Male , Mice , Mitochondria/immunology , Mitochondria/pathology , Neostriatum/immunology , Neostriatum/microbiology , Neostriatum/pathology , Neostriatum/physiopathology , Parkinson Disease/drug therapy , Parkinson Disease/physiopathology , Protein Kinases/immunology , Ubiquitin-Protein Ligases/deficiency , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/immunology
2.
Transl Psychiatry ; 9(1): 135, 2019 04 12.
Article in English | MEDLINE | ID: mdl-30979867

ABSTRACT

Women exposed to a variety of viral and bacterial infections during pregnancy have an increased risk of giving birth to a child with autism, schizophrenia or other neurodevelopmental disorders. Preclinical maternal immune activation (MIA) models are powerful translational tools to investigate mechanisms underlying epidemiological links between infection during pregnancy and offspring neurodevelopmental disorders. Our previous studies documenting the emergence of aberrant behavior in rhesus monkey offspring born to MIA-treated dams extends the rodent MIA model into a species more closely related to humans. Here we present novel neuroimaging data from these animals to further explore the translational potential of the nonhuman primate MIA model. Nine male MIA-treated offspring and 4 controls from our original cohort underwent in vivo positron emission tomography (PET) scanning at approximately 3.5-years of age using [18F] fluoro-l-m-tyrosine (FMT) to measure presynaptic dopamine levels in the striatum, which are consistently elevated in individuals with schizophrenia. Analysis of [18F]FMT signal in the striatum of these nonhuman primates showed that MIA animals had significantly higher [18F]FMT index of influx compared to control animals. In spite of the modest sample size, this group difference reflects a large effect size (Cohen's d = 0.998). Nonhuman primates born to MIA-treated dams exhibited increased striatal dopamine in late adolescence-a hallmark molecular biomarker of schizophrenia. These results validate the MIA model in a species more closely related to humans and open up new avenues for understanding the neurodevelopmental biology of schizophrenia and other neurodevelopmental disorders associated with prenatal immune challenge.


Subject(s)
Behavior, Animal/drug effects , Corpus Striatum/physiology , Dopamine/physiology , Neostriatum/pathology , Animals , Corpus Striatum/diagnostic imaging , Disease Models, Animal , Female , Macaca mulatta , Male , Neostriatum/immunology , Poly I-C/pharmacology , Positron-Emission Tomography , Pregnancy , Prenatal Exposure Delayed Effects/immunology , Prenatal Exposure Delayed Effects/pathology , Schizophrenia/immunology , Stereotyped Behavior
3.
Bipolar Disord ; 17(5): 507-17, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25929806

ABSTRACT

OBJECTIVES: Several recent studies have suggested that the physiopathology of bipolar disorder (BD) is related to immune system alterations and inflammation. Lithium (Li) is a mood stabilizer that is considered the first-line treatment for this mood disorder. The goal of the present study was to investigate the effects of Li administration on behavior and cytokine levels [interleukin (IL)-1ß, IL-4, IL-6, IL-10, and tumor necrosis factor-alpha (TNF-α)] in the periphery and brains of rats subjected to an animal model of mania induced by amphetamine (d-AMPH). METHODS: Male Wistar rats were treated with d-AMPH or saline (Sal) for 14 days; on Day 8 of treatment, the rats were administered Li or Sal for the final seven days. Cytokine (IL-1ß, IL-4, IL-6, IL-10, and TNF-α) levels were evaluated in the cerebrospinal fluid (CSF), serum, frontal cortex, striatum, and hippocampus. RESULTS: The present study showed that d-AMPH induced hyperactivity in rats (p < 0.001), and Li treatment reversed this behavioral alteration (p < 0.001). In addition, d-AMPH increased the levels of IL-4, IL-6, IL-10, and TNF-α in the frontal cortex (p < 0.001), striatum (p < 0.001), and serum (p < 0.001), and treatment with Li reversed these cytokine alterations (p < 0.001). CONCLUSIONS: Li modulates peripheral and cerebral cytokine production in an animal model of mania induced by d-AMPH, suggesting that its action on the inflammatory system may contribute to its therapeutic efficacy.


Subject(s)
Antimanic Agents/pharmacology , Behavior, Animal/drug effects , Bipolar Disorder/immunology , Brain/drug effects , Cytokines/drug effects , Lithium Compounds/pharmacology , Motor Activity/drug effects , Animals , Antimanic Agents/therapeutic use , Bipolar Disorder/chemically induced , Bipolar Disorder/drug therapy , Brain/immunology , Central Nervous System Stimulants/toxicity , Cytokines/cerebrospinal fluid , Cytokines/immunology , Dextroamphetamine/toxicity , Disease Models, Animal , Frontal Lobe/drug effects , Frontal Lobe/immunology , Hippocampus/drug effects , Hippocampus/immunology , Hyperkinesis/chemically induced , Hyperkinesis/drug therapy , Hyperkinesis/immunology , Interleukin-10/cerebrospinal fluid , Interleukin-10/immunology , Interleukin-1beta/cerebrospinal fluid , Interleukin-1beta/drug effects , Interleukin-1beta/immunology , Interleukin-4/cerebrospinal fluid , Interleukin-4/immunology , Interleukin-6/cerebrospinal fluid , Interleukin-6/immunology , Lithium Compounds/therapeutic use , Male , Motor Activity/immunology , Neostriatum/drug effects , Neostriatum/immunology , Rats , Rats, Wistar , Tumor Necrosis Factor-alpha/cerebrospinal fluid , Tumor Necrosis Factor-alpha/drug effects , Tumor Necrosis Factor-alpha/immunology
4.
PLoS One ; 6(2): e16638, 2011 Feb 10.
Article in English | MEDLINE | ID: mdl-21347362

ABSTRACT

BACKGROUND: Maternal immune activation (MIA) during prenatal life is a risk factor for neurodevelopmental disorders including schizophrenia and autism. Such conditions are associated with alterations in fronto-subcortical circuits, but their molecular basis is far from clear. METHODOLOGY/PRINCIPAL FINDINGS: Using two-dimensional differential in-gel electrophoresis (2D-DIGE) and mass spectrometry, with targeted western blot analyses for confirmation, we investigated the impact of MIA on the prefrontal and striatal proteome from an established MIA mouse model generated in C57B6 mice, by administering the viral analogue PolyI:C or saline vehicle (control) intravenously on gestation day (GD) 9. In striatum, 11 proteins were up-regulated and 4 proteins were down-regulated in the PolyI:C mice, while 10 proteins were up-regulated and 7 proteins down-regulated in prefrontal cortex (PFC). These were proteins involved in the mitogen-activated protein kinase (MAPK) signaling pathway, oxidation and auto-immune targets, including dual specificity mitogen-activated protein kinase kinase 1 (MEK), eukaryotic initiation factor (eIF) 4A-II, creatine kinase (CK)-B, L-lactate dehydrogenase (LDH)-B, WD repeat-containing protein and NADH dehydrogenase in the striatum; and guanine nucleotide-binding protein (G-protein), 14-3-3 protein, alpha-enolase, olfactory maker protein and heat shock proteins (HSP) 60, and 90-beta in the PFC. CONCLUSIONS/SIGNIFICANCE: This data fits with emerging evidence for disruption of critical converging intracellular pathways involving MAPK pathways in neurodevelopmental conditions and it shows considerable overlap with protein pathways identified by genetic modeling and clinical post-mortem studies. This has implications for understanding causality and may offer potential biomarkers and novel treatment targets for neurodevelopmental conditions.


Subject(s)
Mothers , Neostriatum/metabolism , Prefrontal Cortex/metabolism , Prenatal Exposure Delayed Effects/immunology , Prenatal Exposure Delayed Effects/metabolism , Transcriptome/immunology , Animals , Blotting, Western , Female , Inflammation/immunology , Mice , Mice, Inbred C57BL , Multivariate Analysis , Neostriatum/drug effects , Neostriatum/immunology , Poly I-C/pharmacology , Prefrontal Cortex/drug effects , Prefrontal Cortex/immunology , Pregnancy , Prenatal Exposure Delayed Effects/chemically induced , Proteomics , Reproducibility of Results , Transcriptome/drug effects , Two-Dimensional Difference Gel Electrophoresis
5.
Anat Sci Int ; 86(2): 86-97, 2011 Jun.
Article in English | MEDLINE | ID: mdl-20809266

ABSTRACT

Inflammatory response after middle cerebral artery occlusion (MCAO) has been a focus of research recently, but the effect of inflammatory cells on ischemic neurons remains unclear. In order to study the effect of the inflammatory reaction on brain ischemic injury, we observed the morphology, number and distribution of CD3-, CD8-, ED1- and ED2-positive cells systematically in the caudate-putamen of rats in a MCAO model. The present results show that all four types of inflammatory cells first infiltrated the ischemic penumbra and then migrated into the center of the ischemic area, but the morphological changes and infiltration processes differed significantly; the infiltration of CD3- and CD8-positive cells into the ischemic area started at 3 days postischemia, and their number peaked at 1 week; however, although ED1- and ED2-positive cells were also observed at 3 days after ischemia, they reached their maximum number at 2 and 4 weeks, respectively. Moreover, ED1-and ED2-positive cells showed evident hyperplasia and hypertrophy in morphology. Our results also showed that the response of CD3-, CD8-, ED1- and ED2-positive cells in the ischemic area and the pathological changes in ischemic brain tissue could be inhibited by cyclosporine A. The results suggest that the infiltration and reaction of inflammatory cells are involved in the pathological process of ischemic brain injury.


Subject(s)
Infarction, Middle Cerebral Artery/immunology , Macrophages/physiology , Neostriatum/immunology , T-Lymphocytes/physiology , Animals , Cyclosporine , Infarction, Middle Cerebral Artery/pathology , Macrophages/pathology , Male , Neostriatum/pathology , Rats , Rats, Sprague-Dawley
6.
Brain Pathol ; 21(3): 330-48, 2011 May.
Article in English | MEDLINE | ID: mdl-20969653

ABSTRACT

Prenatal systemic inflammation has been implicated in neurological diseases, but optimal animal models have not been developed. We investigated whether a partial genetic deletion of glial cell line-derived neurotrophic factor (Gdnf(+/-)) increased vulnerability of dopamine (DA) neurons to prenatal lipopolysaccharide (LPS). LPS [0.01 mg/kg intraperitoneal (i.p.)] or saline was administered to wild-type (WT) or Gdnf(+/-) pregnant mice on gestational day 9.5. Male offspring were examined at 3 weeks, 3 and 12 months of age. There was a progressive degeneration of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN) with age in Gdnf(+/-) but not in WT mice, with no observed effects on locus coeruleus (LC) noradrenergic neurons or DA neurons of the ventral tegmental area. Inflammatory markers were elevated in SN of LPS treated offspring, with exacerbation in Gdnf(+/-) mice. Intracellular accumulation of α-synuclein (α-syn) immunoreactivity in DA neurons of SN was observed in all groups of Gdnf(+/-) and in WT mice with prenatal LPS, with altered distribution between pars reticulata (pr) and pars compacta (pc). The findings suggest that prenatal LPS leads to accelerated neuropathology in the SN with age, and that a partial loss of GDNF exacerbates these effects, providing a novel model for age-related neuropathology of the nigrostriatal DA system.


Subject(s)
Glial Cell Line-Derived Neurotrophic Factor/metabolism , Neurodegenerative Diseases/pathology , Prenatal Exposure Delayed Effects/immunology , Substantia Nigra/immunology , Tyrosine 3-Monooxygenase/metabolism , Age Factors , Animals , Disease Models, Animal , Dopamine/metabolism , Female , Glial Cell Line-Derived Neurotrophic Factor/genetics , Glial Cell Line-Derived Neurotrophic Factor/immunology , Heterozygote , Lipopolysaccharides/immunology , Male , Mice , Mice, Knockout , Neostriatum/immunology , Neostriatum/metabolism , Neostriatum/pathology , Neurodegenerative Diseases/immunology , Neurodegenerative Diseases/metabolism , Neurons/immunology , Neurons/metabolism , Neurons/pathology , Pregnancy , Substantia Nigra/metabolism , Tumor Necrosis Factor-alpha/metabolism
7.
Behav Brain Res ; 186(1): 84-90, 2008 Jan 10.
Article in English | MEDLINE | ID: mdl-17850895

ABSTRACT

Tourette syndrome (TS) is a heterogenous neuropsychiatric disorder. In most cases, tics are self-limited or can be treated by behavioral or pharmacological therapy. However, for some individuals, tics can cause lifelong impairment and life-threatening symptoms, which are intractable to traditional treatment. Neural stem cell (NSC) is a potential tool to treat certain neurological diseases. In this study, we proposed to use neural stem cell transplantation as a novel therapy to treat TS and discussed its efficacy. Wistar rats were microinfused with TS sera into the striatum followed by the transplantation of NSCs or vehicle at the infusion site. The sera of the TS patients were identified to have enriched antineural antibodies. Prior to grafting, rat embryonic NSCs were co-cultured with 5-bromodeoxyuridine (Brdu) for 24 h. Stereotypic behaviors were counted at 1, 7, 14 and 21 days after transplantation of NSCs. Morphological analyses revealed that NSCs survived and differentiated into neurons and astrocytes in the striatum 3 weeks after grafting. To sum it up, rat embryonic neural stem cell grafts survived and differentiated in the striatum of TS rat may help relieve stereotypic behaviors of the host. Our results suggest that transplantation of NSCs intrastriatum may have therapeutic potential for TS.


Subject(s)
Antibodies/adverse effects , Caudate Nucleus/immunology , Embryonic Stem Cells/transplantation , Neostriatum/immunology , Neurons/immunology , Tics/prevention & control , Tourette Syndrome/immunology , Adult , Animals , Antibodies/administration & dosage , Antibodies/immunology , Case-Control Studies , Caudate Nucleus/surgery , Cell Differentiation , Child , Disease Models, Animal , Embryonic Stem Cells/cytology , Female , Graft Survival , Humans , Male , Matched-Pair Analysis , Microinjections , Neostriatum/cytology , Neostriatum/transplantation , Neurons/cytology , Neurons/transplantation , Rats , Rats, Wistar , Reference Values , Stem Cell Transplantation , Stereotyped Behavior/physiology , Tics/etiology , Tics/immunology , Tourette Syndrome/blood , Tourette Syndrome/therapy
8.
Neuroreport ; 18(12): 1275-9, 2007 Aug 06.
Article in English | MEDLINE | ID: mdl-17632282

ABSTRACT

The role of endothelin (ET)B receptors in chemokine production in the brain of rats was examined. Intracerebroventricular administration of 500 pmol/day of Ala(1,3,11,15)-ET-1, a selective ETB agonist, for 3 or 7 days increased monocyte chemoattractant protein (MCP)-1 and cytokine-induced neutrophil chemoattractant (CINC)-1 mRNA in the caudate-putamen and cerebrum, whereas it had no effects on regulated on activation normal T-cell expressed and secreted (RANTES), fractalkine and stromal cell-derived factor (SDF)-1alpha mRNA expression. Immunoreactive MCP-1 and CINC-1 in the caudate-putamen and the cerebrum were increased by the ETB agonist. Immunohistochemical observations on the Ala(1,3,11,15)-ET-1-infused rats showed that glial fibrillary acidic protein-positive astrocytes had immunoreactivity for MCP-1 and CINC-1. These findings indicate that the activation of brain ETB receptors causes the production of MCP-1 and CINC-1, and suggest a pathophysiological role for brain ETB receptors in nervous system damage.


Subject(s)
Brain/metabolism , Chemokine CCL2/metabolism , Chemokines, CXC/metabolism , Endothelin-1/metabolism , Receptor, Endothelin B/metabolism , Animals , Astrocytes/immunology , Astrocytes/metabolism , Brain/drug effects , Brain/immunology , Chemokine CCL2/genetics , Chemokine CCL2/immunology , Chemokine CXCL1 , Chemokines, CXC/genetics , Chemokines, CXC/immunology , Encephalitis/immunology , Encephalitis/metabolism , Encephalitis/physiopathology , Endothelin-1/analogs & derivatives , Endothelins/pharmacology , Glial Fibrillary Acidic Protein/metabolism , Gliosis/immunology , Gliosis/metabolism , Gliosis/physiopathology , Immunohistochemistry , Injections, Intraventricular , Male , Neostriatum/drug effects , Neostriatum/immunology , Neostriatum/metabolism , RNA, Messenger/drug effects , RNA, Messenger/metabolism , Rats , Rats, Wistar , Receptor, Endothelin B/agonists , Telencephalon/drug effects , Telencephalon/immunology , Telencephalon/metabolism , Up-Regulation/drug effects , Up-Regulation/immunology
9.
Neurobiol Dis ; 24(3): 492-505, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17023164

ABSTRACT

Complete Freund's adjuvant (CFA), a pro-inflammatory agent, was inoculated, subcutaneously, to Sprague-Dawley rats prior to the intrastriatal injection of 6-hydroxydopamine (6-OHDA). Animals were sacrificed 7 and 28 days following 6-OHDA injection; neuronal damage, glial activation and cytokine levels, within the nigrostriatal system, were then investigated. Nigrostriatal degeneration induced by 6-OHDA was accompanied by early microglial and astroglial activation, which preceded the onset of dopaminergic cell loss, in the SNc, without significant changes in cytokine levels. CFA pretreatment markedly reduced the SNc neuronal loss and associated microglial activation, as well as the rotational response to apomorphine. These changes were associated with moderate, transient increases in the nigrostriatal levels of glial-cell-derived neurotrophic factor (GDNF) and pro-inflammatory cytokines, including interleukin (IL)-1alpha, IL-1beta and IL-6. Our results show that prior delivery of a peripheral, pro-inflammatory stimulus induces neuroprotection, in a rodent model of Parkinson's disease, possibly through the modulation of cytokine production at the nigrostriatal level.


Subject(s)
Freund's Adjuvant/immunology , Nerve Degeneration/immunology , Neuroglia/immunology , Neuroprotective Agents/immunology , Parkinsonian Disorders/immunology , Adjuvants, Immunologic/therapeutic use , Analysis of Variance , Animals , Disease Models, Animal , Freund's Adjuvant/therapeutic use , Male , Motor Activity/physiology , Neostriatum/drug effects , Neostriatum/immunology , Neostriatum/pathology , Nerve Degeneration/chemically induced , Neuroglia/pathology , Neuroprotective Agents/therapeutic use , Oxidopamine , Parkinsonian Disorders/chemically induced , Parkinsonian Disorders/pathology , Parkinsonian Disorders/prevention & control , Random Allocation , Rats , Rats, Sprague-Dawley , Substantia Nigra/immunology , Substantia Nigra/pathology
10.
Int J Neurosci ; 115(10): 1375-82, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16162445

ABSTRACT

Rabies has been an enigmatic disease of the nervous system because microscopic findings in the brain tissue are not paralleled by the severity of the clinical illness. The calcium binding protein calbindin (CB) is a neuronal marker of great interest in neuroanatomy and neuropathology. CB-ir neurons in the striatum and cerebral cortex are gabaergic cells. In the present work CB-immunoreactivity was evaluated in brains of normal and rabies-infected mice. Rabies infection caused loss of CB-immunostaining in the cortical supragranular layers as well as in the striatum. Loss of CB in the brains of mice infected with rabies virus can produce impairment in Ca++ homeostasis and in the gabaergic neurotransmission.


Subject(s)
Cerebral Cortex/metabolism , Neostriatum/metabolism , Rabies/metabolism , S100 Calcium Binding Protein G/metabolism , Animals , Animals, Newborn , Calbindins , Cerebral Cortex/immunology , Cerebral Cortex/ultrastructure , Female , Immunoglobulin G/immunology , Immunohistochemistry , Mice , Mice, Inbred ICR , Neostriatum/immunology , Neostriatum/ultrastructure , Rabies/immunology , Rabies/pathology
11.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 21(1): 83-5, 89, 2005 Jan.
Article in Chinese | MEDLINE | ID: mdl-15629092

ABSTRACT

AIM: To investigate the occurrence of rejection in brain tissue transplantation. METHODS: Ventral mesencephalon(VM) single cell suspensions from newborn rats were allografted into the striata of Parkinson's disease model recipient rats. Surviving animals were sacrificed at 2, 4 and 6 wk after transplantation, and the brain tissues were stained with HE or immunocytochemically to inspect the expression of tyrosine hydroxylase (TH) and major histocompatibility complex class II antigens (MHC II). RESULTS: High MHC II expression was observed within and around the allografts compared with control at 2 wk after grafting. MHC II expression then decreased at 4 wk and at 6 wk only few immunopositive cells remained. The number of TH positive neurons was low at 2 wk, but increased at 4 and 6 wk after transplantation. CONCLUSION: The brain is not an "immunologically privileged site" and graft rejection exists in brain tissue transplantation. This rejection maybe induced by MHC II. Therefore it is necessary to use immunosuppressants in brain transplantation.


Subject(s)
Brain Tissue Transplantation/immunology , Graft Rejection/immunology , Animals , Behavior, Animal , Female , Histocompatibility Antigens Class II/metabolism , Male , Movement , Neostriatum/immunology , Neostriatum/metabolism , Parkinson Disease/immunology , Parkinson Disease/pathology , Parkinson Disease/surgery , Rats , Transplantation, Homologous , Tyrosine 3-Monooxygenase/metabolism
12.
Neurosci Lett ; 349(3): 191-5, 2003 Oct 09.
Article in English | MEDLINE | ID: mdl-12951201

ABSTRACT

Injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice results in a retrograde nigrostriatal dopaminergic pathway denervation and subsequent tissue reorganization. Since the role of inflammatory mediators after MPTP remains unclear, proinflammatory cytokine and matrix metalloproteinase (MMP) expression were evaluated by comparative RT-PCR during denervation and tissue reorganization following a single-dose of MPTP (40 mg/kg, s.c.) in young (8-week-old) mice. The time-course of denervation/reorganization was assessed through [(3)H]GBR-12935 binding on dopamine transporter and tyrosine hydroxylase immunohistochemistry. In the striatum, TNF-alpha, IL-1alpha, IL-1beta, IL-6 and MMP-9 mRNA expression peaked on day 1. In the ventral mesencephalon, cytokines (TNF-alpha, IL-1alpha, IL-1beta) and MMP-9 mRNA expression peaked on day 3. During tissue reorganization (day 6 through 16), the only change observed in the striatum consisted of IL-1alpha mRNA and protein overexpression together with MMP-2 downregulation. Whereas the early expression of proinflammatory cytokines and MMP might participate in the retrograde nigrostriatal denervation, the late component of IL-1alpha expression suggests a possible role for this cytokine in the subsequent striatal reorganization.


Subject(s)
Cytokines/genetics , Encephalitis/physiopathology , Matrix Metalloproteinases/genetics , Membrane Glycoproteins , Neostriatum/physiopathology , Nerve Tissue Proteins , Neural Pathways/physiopathology , Parkinsonian Disorders/physiopathology , Substantia Nigra/physiopathology , Animals , Disease Models, Animal , Dopamine/metabolism , Dopamine Plasma Membrane Transport Proteins , Encephalitis/enzymology , Encephalitis/immunology , Inflammation Mediators/metabolism , Interleukin-1/genetics , Male , Membrane Transport Proteins/metabolism , Mice , Mice, Inbred C57BL , Neostriatum/enzymology , Neostriatum/immunology , Neural Pathways/enzymology , Neural Pathways/immunology , Parkinsonian Disorders/enzymology , Parkinsonian Disorders/immunology , Piperazines/pharmacology , RNA, Messenger/metabolism , Reaction Time/physiology , Substantia Nigra/enzymology , Substantia Nigra/immunology , Tyrosine 3-Monooxygenase/metabolism
13.
Mol Cell Neurosci ; 21(1): 15-28, 2002 Sep.
Article in English | MEDLINE | ID: mdl-12359148

ABSTRACT

Cerebral deposition of beta-amyloid (Abeta) is an invariant event of Alzheimer's disease (AD). We recently described that the brain of aged transgenic mice expressing anti-nerve growth factor (NGF) antibodies (AD11 mice) show a dramatic neurodegenerative phenotype, reminiscent of AD, which includes neuronal loss, cholinergic deficit, and tau hyperphosphorylation, associated with neurofibrillary pathology. We now report that brains of aged transgenic mice contain large amounts of beta-amyloid plaques and describe their morphology by a variety of approaches. In conclusion, the chronic deprivation of NGF leads to the formation and deposition of Abeta in AD11 mice, suggesting a direct link between NGF signaling and abnormal processing of amyloid precursor protein.


Subject(s)
Aging/genetics , Alzheimer Disease/genetics , Amyloid beta-Peptides/metabolism , Autoantibodies/genetics , Nerve Growth Factor/deficiency , Plaque, Amyloid/genetics , Aging/immunology , Aging/pathology , Alzheimer Disease/immunology , Alzheimer Disease/physiopathology , Amyloid beta-Protein Precursor/metabolism , Animals , Autoantibodies/immunology , Autoantibodies/metabolism , Benzothiazoles , Brain/immunology , Brain/metabolism , Brain/pathology , Cerebellum/immunology , Cerebellum/metabolism , Cerebellum/pathology , Disease Models, Animal , Locus Coeruleus/immunology , Locus Coeruleus/metabolism , Locus Coeruleus/pathology , Mice , Mice, Transgenic , Neostriatum/immunology , Neostriatum/metabolism , Neostriatum/pathology , Nerve Growth Factor/genetics , Nerve Growth Factor/metabolism , Neurofibrillary Tangles/metabolism , Neurons/immunology , Neurons/metabolism , Neurons/pathology , Plaque, Amyloid/immunology , Plaque, Amyloid/metabolism , Signal Transduction/genetics , Signal Transduction/immunology , Silver Staining , Thiazoles
14.
Neuroreport ; 12(14): 3143-8, 2001 Oct 08.
Article in English | MEDLINE | ID: mdl-11568653

ABSTRACT

Although anatomical and biochemical properties of the rat entopeduncular nucleus (EPN) closely resemble those of the substantia nigra pars reticulata (SNr), the present study shows that, unlike in the SNr, focal cerebral ischemia does not cause trans-synaptic degeneration of EPN neurons, despite striatal infarction and a similar delayed glial activation in both nuclei. In this study, interleukin-6 (IL-6) expression was found within EPN neurons 3 and 7 days after striatal ischemia. Since it has been reported that neuroprotective properties seem to predominate IL-6 function and that distinct SNr regions which demonstrate low trans-synaptic neuronal degeneration show high IL-6 expression and vice versa, IL-6 expression within partially deafferentiated but surviving EPN neurons could represent an intrinsic neuroprotective mechanism.


Subject(s)
Antigens, CD , Antigens, Neoplasm , Antigens, Surface , Avian Proteins , Blood Proteins , Brain Ischemia/metabolism , Entopeduncular Nucleus/metabolism , Interleukin-6/metabolism , Neostriatum/metabolism , Nerve Degeneration/metabolism , Neural Pathways/metabolism , Neurons/metabolism , Animals , Astrocytes/cytology , Astrocytes/immunology , Astrocytes/metabolism , Basigin , Brain Ischemia/immunology , Brain Ischemia/pathology , Cell Count , Cell Survival/immunology , Entopeduncular Nucleus/immunology , Entopeduncular Nucleus/pathology , Glial Fibrillary Acidic Protein/metabolism , Gliosis/immunology , Gliosis/metabolism , Gliosis/pathology , Immunohistochemistry , Infarction, Middle Cerebral Artery/immunology , Infarction, Middle Cerebral Artery/metabolism , Infarction, Middle Cerebral Artery/pathology , Interleukin-6/immunology , Male , Membrane Glycoproteins/metabolism , Microglia/cytology , Microglia/immunology , Microglia/metabolism , Neostriatum/immunology , Neostriatum/pathology , Nerve Degeneration/immunology , Nerve Degeneration/pathology , Neural Pathways/immunology , Neural Pathways/pathology , Neurons/immunology , Neurons/pathology , Rats , Rats, Sprague-Dawley
15.
Neuroscience ; 106(1): 201-16, 2001.
Article in English | MEDLINE | ID: mdl-11564430

ABSTRACT

Intracerebral neural xenografts elicit a host immune response that results in their rapid rejection. This forms a key barrier to the therapeutic use of xenogeneic tissue transplantation for conditions such as Parkinson's disease. The current study sought to provide insight into the cellular components of donor cell suspensions that are important in stimulating the host rejection response and thereby to suggest rational manipulations of xenogeneic donor tissue that might ultimately enhance its clinical utility. The neural stem cell mitogens, epidermal growth factor and fibroblast growth factor-2, have been used to isolate and expand populations of primordial neural precursor cells from the embryonic pig brain. The immune response elicited by these cells on transplantation into the non-immunosuppressed rat has been fully characterised. In the first experiments, expanded neural precursors were grafted into the hemi-parkinsonian, non-immunosuppressed Sprague-Dawley rat and graft status and host response examined 10, 21, 35 and 60 days post-transplantation. While equivalent primary tissue grafts were completely eliminated at 35 days, grafts of expanded neural precursors with healthy neurofilament-positive projections were present at all time-points, and two large grafts remained even at 60 days. Some grafts appeared to elicit minimal host immune responses at the time-points they were examined, although most did appear to be undergoing a rejection process since a co-ordinated response involving host cytotoxic T-lymphocytes, microglia/macrophages, immunoglobulin M and complement could be demonstrated to varying degrees. Subsequent experiments went on to demonstrate further that expanded precursor populations and primary tissue suspensions differed in their immunogenic profile. Firstly, when primary tissue was injected intraperitoneally into immunocompetent rats a vigorous primary humoral response was generated. No such response was detected following injection of expanded neural precursors. Secondly, flow cytometric analysis revealed small but significant levels of class II porcine major histocompatibility complex expression in primary cell suspensions but no such expression in expanded precursor populations.The results of this study therefore demonstrate that the immunogenicity of porcine neural cell suspensions used for intracerebral grafting is reduced when neural stem cell mitogens are used to expand precursor cells. The implications of these findings in the development of novel xenogeneic cellular therapies for neurodegenerative conditions such as Parkinson's disease are discussed.


Subject(s)
Brain Tissue Transplantation/adverse effects , Graft Rejection/immunology , Immunocompetence/immunology , Neostriatum/surgery , Parkinsonian Disorders/surgery , Stem Cell Transplantation , Transplantation, Heterologous/adverse effects , Animals , Antibodies/blood , Antibodies/immunology , Antigens, Heterophile/blood , Antigens, Heterophile/immunology , Biomarkers/blood , Brain Tissue Transplantation/methods , Cell Division/drug effects , Cell Division/immunology , Cerebral Cortex/cytology , Cerebral Cortex/immunology , Cerebral Cortex/transplantation , Female , Fetus , Flow Cytometry , Graft Rejection/metabolism , Graft Rejection/physiopathology , Graft Survival/immunology , Mitogens/pharmacology , Neostriatum/immunology , Neostriatum/physiopathology , Neurons/cytology , Neurons/immunology , Neurons/transplantation , Parkinsonian Disorders/metabolism , Parkinsonian Disorders/physiopathology , Rats , Rats, Sprague-Dawley , Stem Cells/cytology , Stem Cells/immunology , Swine , Transplantation, Heterologous/methods
16.
Brain Res ; 909(1-2): 187-93, 2001 Aug 03.
Article in English | MEDLINE | ID: mdl-11478935

ABSTRACT

To determine the role of immune/inflammatory factors in dopaminergic cell degeneration in parkinsonian substantia nigra, we assayed tyrosine hydroxylase (TH)-positive immunoreactive neuronal numbers with stereologic techniques and CD11b-positive immunoreactive microglial profiles following 6-hydroxydopamine (6-OHDA) injection into ipsilateral striatum of mice. We further investigated the effect of minocycline on the inhibition of microglial activation and subsequent protection of nigral cells. The relative number of microglial profiles in the substantia nigra (SN) ipsilateral to the injection increased from 31 to 32% 1-3 days after injection, and increased further to 55% by 7 days and 59% by 14 days, compared with the contralateral SN. These changes started prior to the decrease of TH immunoreactivity of 34% on day 7 and of 42% by day 14. In animals treated with minocycline, microglial activation was inhibited by 47%, and TH positive cells were protected by 21% at day 14 after 6-OHDA injection, compared with those parkinsonian animals without minocycline treatment. All these results suggest that microglial activation may be involved in the nigral cell degeneration in 6-OHDA induced parkinsonian mice.


Subject(s)
Anti-Bacterial Agents/pharmacology , Gliosis/drug therapy , Microglia/drug effects , Minocycline/pharmacology , Nerve Degeneration/drug therapy , Parkinsonian Disorders/drug therapy , Substantia Nigra/drug effects , Animals , Cell Death/drug effects , Cell Death/physiology , Disease Models, Animal , Gliosis/immunology , Gliosis/physiopathology , Immunohistochemistry , Macrophage-1 Antigen/immunology , Macrophage-1 Antigen/metabolism , Male , Mice , Mice, Inbred ICR , Microglia/immunology , Microglia/metabolism , Neostriatum/drug effects , Neostriatum/immunology , Neostriatum/physiopathology , Nerve Degeneration/immunology , Nerve Degeneration/physiopathology , Oxidopamine/pharmacology , Parkinsonian Disorders/immunology , Parkinsonian Disorders/physiopathology , Substantia Nigra/immunology , Substantia Nigra/physiopathology , Sympatholytics/pharmacology , Tyrosine 3-Monooxygenase/metabolism
17.
Neurosci Lett ; 289(3): 165-8, 2000 Aug 11.
Article in English | MEDLINE | ID: mdl-10961655

ABSTRACT

We compared in rats with 6-hydroxydopamine (6-OHDA)-induced hemiparkinsonism the content of tumor necrosis factor (TNF)-alpha in the nigrostriatal dopaminergic region of the control side with that of the 6-OHDA-injected experimental side, and explored the effects of 6-OHDA injection combined with the immunosuppressant FK506 treatment (0.5 or 4 mg/kg per day for 2 weeks). The ratios of the concentration of TNF-alpha in the striatum and substantia nigra on the 6-OHDA injection side to that on the control side in the 6-OHDA hemiparkinsonism rats were significantly higher than those in the control rats without 6-OHDA treatment, whereas those in the rats treated with 6-OHDA and FK506 were not significantly different from those in the control rats. Thus FK506 attenuated increased TNF-alpha level in the nigrostriatal dopaminergic region injured by 6-OHDA treatment.


Subject(s)
Immunosuppressive Agents/pharmacology , Neostriatum/immunology , Neural Pathways/immunology , Parkinsonian Disorders/drug therapy , Parkinsonian Disorders/immunology , Substantia Nigra/immunology , Tacrolimus/pharmacology , Tumor Necrosis Factor-alpha/drug effects , Animals , Dopamine/metabolism , Functional Laterality/drug effects , Functional Laterality/physiology , Male , Neostriatum/drug effects , Neostriatum/physiopathology , Neural Pathways/drug effects , Neural Pathways/physiopathology , Neurons/drug effects , Neurons/metabolism , Neurons/pathology , Neuroprotective Agents/pharmacology , Oxidopamine/adverse effects , Parkinsonian Disorders/chemically induced , Parkinsonian Disorders/physiopathology , Rats , Rats, Sprague-Dawley , Substantia Nigra/drug effects , Substantia Nigra/physiopathology , Tumor Necrosis Factor-alpha/metabolism
18.
Brain Pathol ; 10(1): 1-15, 2000 Jan.
Article in English | MEDLINE | ID: mdl-10668891

ABSTRACT

Theiler's murine encephalomyelitis virus (TMEV) induces acute neuronal disease followed by chronic demyelination in susceptible strains of mice. In this study we examined the role of a limited immune defect (deletion or blocking of CD40 ligand [CD40L]) on the extent of brain disease, susceptibility to demyelination, and the ability of demyelinated mice to spontaneously remyelinate following TMEV infection. We demonstrated that CD40L-dependent immune responses participate in pathogenesis in the cerebellum and the spinal cord white matter but protect the striatum of susceptible SJL/J mice. In mice on a background resistant to TMEV-induced demyelination (C57BL/6), the lack of CD40L resulted in increased striatal disease and meningeal inflammation. In addition, CD40L was required to maintain resistance to demyelination and clinical deficits in H-2b mice. CD40L-mediated interactions were also necessary for development of protective H-2b-restricted cytotoxic T cell responses directed against the VP2 region of TMEV as well as for spontaneous remyelination of the spinal cord white matter. The data presented here demonstrated the critical role of this molecule in both antibody- and cell-mediated protective immune responses in distinct phases of TMEV-mediated pathology.


Subject(s)
Demyelinating Diseases/immunology , Disease Models, Animal , Membrane Glycoproteins/immunology , Multiple Sclerosis/immunology , Myelin Sheath/immunology , Neuroprotective Agents/immunology , Animals , CD40 Ligand , Capsid/immunology , Capsid Proteins , Cerebellum/immunology , Cerebellum/pathology , Cytotoxicity, Immunologic/immunology , Demyelinating Diseases/pathology , Demyelinating Diseases/physiopathology , Female , Histocompatibility Antigens Class I/immunology , Immunoglobulin G/immunology , Mice , Mice, Inbred Strains , Mice, Knockout , Minor Histocompatibility Antigens , Multiple Sclerosis/pathology , Multiple Sclerosis/physiopathology , Myelin Sheath/pathology , Myelin Sheath/ultrastructure , Neostriatum/immunology , Neostriatum/pathology , Theilovirus/immunology
19.
Neuroscience ; 77(2): 599-609, 1997 Mar.
Article in English | MEDLINE | ID: mdl-9472415

ABSTRACT

To address the importance of antigen-presenting cells for the survival of intracerebral neural allografts, allogeneic spleen cells were added to the graft tissue before transplantation. Dissociated embryonic, dopamine-rich mesencephalic and adult spleen tissues were prepared from either inbred Lewis or Sprague-Dawley rats. A mixture of neural and spleen cells was sterotaxically transplanted into the right striatum of adult Sprague-Dawley rats. Controls were neural allografts without addition of allogeneic spleen cells and syngeneic neural grafts with or without the addition of syngeneic spleen cells. Six weeks after transplantation, brain sections were processed immunocytochemically for tyrosine hydroxylase, specific for grafted dopamine neurons, and a bank of markers for various components in the immune and inflammatory responses. The neural allografts which were mixed with allogeneic spleen cells were rejected. In these rats, there were high levels of expression of major histocompatibility complex class I and II antigens, intense cellular infiltration including macrophages and activated microglial cells, and a presence of cluster of differentiation 4- and 8-immunoreactive cells in the graft sites. Moreover, there were increased levels of intercellular adhesion molecule-1, tumour necrosis factor-alpha and interleukin-6 in and around the grafts which were undergoing rejection. In contrast, syngeneic neural grafts survived well regardless of whether they were mixed with syngeneic spleen cells or not, and control neural allografts also exhibited unimpaired survival. No significant difference was observed in the number of grafted dopamine neurons among these three latter groups. The levels of expression of the different markers for inflammation and rejection were generally lower in these grafts than in implants of combined allogeneic neural and spleen cells. In summary, intrastriatal neural allografts, which normally survive well in our animal model, were rejected if allogeneic spleen cells from the same donor were added to the graft tissue. The added spleen cells caused strong host immune and inflammatory responses. The study gave support to the notion that immunological privilege of the brain does not provide absolute protection to immunogenetically histoincompatible neural grafts.


Subject(s)
Brain Tissue Transplantation/immunology , Cell Transplantation/physiology , Fetal Tissue Transplantation/immunology , Graft Rejection/immunology , Mesencephalon/transplantation , Neostriatum/physiology , Spleen/immunology , Transplantation, Homologous/immunology , Animals , Antigen-Presenting Cells/immunology , CD4 Antigens/immunology , CD8 Antigens/immunology , Female , Immunohistochemistry , Major Histocompatibility Complex/immunology , Mesencephalon/immunology , Neostriatum/immunology , Rats , Rats, Sprague-Dawley , Receptors, Complement/immunology , Receptors, Complement/metabolism , Spleen/cytology , Spleen/physiology , Tyrosine 3-Monooxygenase/immunology , Tyrosine 3-Monooxygenase/metabolism
20.
J Chem Neuroanat ; 10(3-4): 209-12, 1996 Jun.
Article in English | MEDLINE | ID: mdl-8811425

ABSTRACT

Systemically administered 3-nitropropionic acid (3-NPA) that inhibits the mitochondrial oxidative phosphorylation induces selective lesions in the striatum. To investigate the nature of these selective lesions, we administered 3-NPA (20 mg/kg, s.c. daily for 2 or 3 days) to Wistar rats and investigated the behavioral disturbance, striatal lesions and their variations after modulating the activity of nitric oxide synthase (NOS). On the second or third day of 3-NPA administration, half the animals manifested behavioral disturbances (paddling, rolling, tremor, abnormal gait, and recumbence). A strong extravasation of immunoglobulin G (IgG) and a decrease in immunoreaction for glial fibrillary acidic protein (GFAP) were detected, and iNOS-like (iNOS-L) immunoreactive small cells appeared in the lateral and central striatum especially around the vessels. A week later, lesions lacking GFAP-immunoreaction were detected in the striatum in survived animals. Pretreatment with N-nitro-L-arginine methyl ester (L-NAME) along with each injection of 3-NPA did not improve the behavioral disturbances nor the survival rate, but attenuated the extravasation of IgG and iNOS-L immunoreaction. Pretreatment with aminoguanidine or FK506 improved the behavioral symptoms and survival rate. Extravasation of IgG and expression of iNOS-L immunoreactivity were attenuated, and the striatal lesion was reduced. Data indicate the involvement of NO in the high vulnerability of the striatum, and that iNOS, one of inflammatory markers, is induced following exposure to 3-NPA.


Subject(s)
Antihypertensive Agents/pharmacology , Neostriatum/drug effects , Nitric Oxide Synthase/metabolism , Propionates/pharmacology , Animals , Astrocytes/chemistry , Behavior, Animal/drug effects , Cell Death/drug effects , Dyspnea/chemically induced , Enzyme Inhibitors/pharmacology , Glial Fibrillary Acidic Protein/analysis , Guanidines/pharmacology , Immunohistochemistry , Immunosuppressive Agents/pharmacology , Injections, Subcutaneous , Male , NG-Nitroarginine Methyl Ester/pharmacology , Neostriatum/immunology , Neostriatum/metabolism , Neuritis/chemically induced , Neurotoxins/pharmacology , Nitric Oxide/metabolism , Nitric Oxide Synthase/antagonists & inhibitors , Nitric Oxide Synthase/immunology , Nitro Compounds , Rats , Rats, Wistar , Tacrolimus/pharmacology
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