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Melatonin reduces MPP+-induced FGF9 down regulation and nigral dopaminergic neuronal death
862
Poster Session 1 Abstracts 2 June 2008 / Int. J. Devl Neuroscience 26 (2008) 841–866
overexpresssion (GOF) or downregulation (LOF) of ALDH1a1. Several degenerative stimuli are tested in such systems. We present preliminary results from an in vitro LOF and GOF study, supporting the hypothesis that ALDH1a1 exerts neuroprotective effects in midbrain DA neurons. doi: 10.1016/j.ijdevneu.2008.09.111 [P1.62] Essential role of TGFb-HIPK2 signaling pathway in survival and synapse formation in enteric neurons A. Tang 1,*, A. Chalazonitis 2, T. Pham 2, I. Hsieh 1, M. Gershon 2, E. Huang 1 1
University of California, San Francisco, USA Columbia University, USA *Corresponding author.
2
Keywords: Dopamine neuron; Survival; Synapse; Trophic factor
It is well-established that TGFb and BMP signaling pathways control neural development in Drosophila, Aplysia and vertebrates. However, it is unclear whether these molecules also influence vertebrate synaptogenesis. We have previously shown that HIPK2 is an essential component in TGFb-mediated survival of midbrain dopamine neurons in mouse (Zhang et al, Nature Neuroscience, 2007) and that BMP-2 and-4 regulate the number of enteric neurons (Chalazonitis et al., Journal of Neuroscience, 2004) as differentiation of a dopaminergic subset (submitted). In this study, we investigated the role of HIPK2 in the development of enteric neurons. We found that 40% of Hipk2/ mutant mice died within 7 days after birth, many of them showed no food in the GI tracts. Hipk2/ mutants that survived into adulthood showed increased total GI transit time, poor intestinal motility, and signs of constipation. Similar to midbrain dopamine neurons, loss of HIPK2 had no detectable effects in migration of neural crest cells into the intestinal wall or the initial differentiation of enteric neurons. Instead, Hipk2/ mutants show a progressive loss of neurons in myenteric and submucosal plexuses. In particular, there was greater than 50% loss of dopamine neurons in the submucosal plexus in ileum and colon. Many of the remaining enteric neurons in Hipk2/ mutants were reduced in size and showed much fewer intraganglionic synapses. Taken together, these results indicate that TGFb-HIPK2 signaling mechanism provides trophic factor supports for survival and differentiation of dopamine neurons in the enteric nervous system as well as in the ventral midbrain of mice. doi: 10.1016/j.ijdevneu.2008.09.112 [P1.63] Effects of complement 3 on the protection against dopaminergic neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine B.Y. Su *, Y.J. Liang, S.R. Li Chengdu Medical College, China *Corresponding author. Tel.: +86 28 68289158. Keywords: Complement 3; Parkinson’s disease; Dopaminergic toxicity; Neuroinflammation
Parkinson’s disease (PD) is a debilitating neurological disorder characterized by loss of dopaminergic neurons in the nigrostriatal pathway. Recent studies have highlighted the neuroinflammation plays an important role in the pathogenesis of Parkinson’s disease.
Mounting evidence indicated that components of complement system may be involved in such disorder and contribute to its development. We thus observed the influence of deficiency of activation of complement system, caused by knockout of the central component complement 3, on the death of dopaminergic neurons in substantia nigra pars compacta compact (SNpc) and the loss of dopaminergic fibers in striata induced by acute or chronic administration of MPTP. Immunohistochemical staining of dopaminergic neurons in SNpc and neurochemical analysis of dopamine and its metabolites in striata reveal that there is no significant difference between the two genotypes. Longer survival time also indicated that complement 3 may not mediate the spontaneous recovery of dopaminergic fibers in mouse striatum acutely challenged by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. We conclude that, despite growing evidence indicating the involvement of complement system in the pathology of PD, our data do not support this speculation in a well established mouse model of PD, as indicated by HPLC analysis and immunohistochemical staining. Acknowledgement This study was supported by the Major State Basic Research Development Program of China (973 Program, No. 2003CB515300).
doi: 10.1016/j.ijdevneu.2008.09.113 [P1.64] Melatonin reduces MPP+-induced FGF9 down regulation and nigral dopaminergic neuronal death J.Y. Huang, J.I. Chuang * National Cheng Kung University, Taiwan *Corresponding author. Keywords: Melatonin; FGF9; MPP+; Dopamine
Parkinson’s disease (PD) represented movement disorder is due to the nigrostriatal dopaminergic neurodegeneration. The reduction of trophic factors found in PD patients suggests their important roles in dopamine neuronal survival. Fibroblast growth factor 9 (FGF9), initially identified as a growth factor for astrocytes, is a survival factor for various cells. However, the protective role of FGF9 in nigrostriatal dopaminergic neurons has not been investigated. Our previous studies had demonstrated that melatonin by antioxidant effect prevented neurotoxin-induced nigrostriatal dopaminergic neurodegeneration. We therefore investigated the protective role of FGF9 and effect of melatonin on FGF9 expression in 1-methyl-4-phenylpyridine (MPP+)-induced dopaminergic neuronal loss in rats. Our in vivo studies demonstrated that 3 days after intra-striatal MPP+ infusion statistically decreased FGF9 mRNA expression and protein level in striatum and substantia nigra. The MPP+-down regulated nigrostriatal FGF9 mRNA expression and protein level was significantly attenuated by melatonin co-treatment. Supra-nigral administration of recombinant FGF9 prevented MPP+-caused tyrosine hydroxylase (TH, a marker enzyme of dopaminergic neurons)-positive neuronal loss in substantia nigra but not the immunoreactivity of dopamine transporter in striatum. In mesencephalic neuron culture, we found that MPP+ dose dependently induced TH-positive dopamine neuronal apoptosis 48 h after treatment, which can be significantly attenuated by FGF9 or melatonin co-treatment. In summary, our findings suggested that FGF9 served neuroprotective function in
Poster Session 1 Abstracts 2 June 2008 / Int. J. Devl Neuroscience 26 (2008) 841–866
MPP+-mediated neurotoxicity mediated neuroprotection.
and
involved
in
melatonin-
doi: 10.1016/j.ijdevneu.2008.09.114
863
initiate a series of self-perpetuating deleterious cascades leading to self-sustained progressive neurodegeneration in PD. Selective inhibitors of PGD2 synthases (PGD2 is the precursor of PGJ2) could be effective PD therapeutic targets since, contrary to COX-1 and COX-2 inhibitors, they will not halt production of all PGs including the cytoprotective and anti-inflammatory ones.
[P1.65] Mouse model of Parkinson’s disease mimicking neuroinflammation S. Pierre, M.E. Figueiredo-Pereira * City University of New York, USA *Corresponding author.
Keywords: Inflammation; Parkinson’; Prostaglandin J2; Ubiquitin/proteasome pathway
The importance of chronic inflammation in Parkinson’s (PD) disease is strengthened by clinical and epidemiological studies demonstrating that NSAIDs reduce the incidence of PD (Klegeris et al., 2007). NSAIDs inhibit cyclooxygenases, decreasing arachidonic acid oxidation. The drawback is that cyclooxygenase-dependent arachidonic acid oxidation yields an extensive variety of products some with pro-survival others with pro-death effects. We chose to model PD by lesioning the nigrostriatal pathway with prostaglandin J2 (PGJ2). The latter is derived from PGD2, the major prostaglandin in the mammalian CNS. PGD2 readily undergoes non-enzymatic first order dehydration reaction to yield highly reactive and neurotoxic cyclopentenone J2 prostaglandins (PGJ2). PGJ2 are unique among the prostaglandin family because they covalently and potently react with free sulfhydryls of glutathione and cysteine residues in cellular proteins via Michael addition (Uchida and Shibata, 2007). A recent review suggests that ‘‘formation of cyclopentenone eicosanoids [such as PGJ2] in the brain may represent a novel pathogenic mechanism that contributes to many neurodegenerative conditions’’ (Musiek et al., 2005). We focused on PGJ2 because it is an endogenous product of inflammation and in vitro studies showed that it induces pleiotropic changes that mimic many of the molecular and cellular pathologies observed in PD. We microinjected PGJ2 into the substantia nigra and striatum of adult FVB male mice and observed dopaminergic cell loss (figure) in the SNpc but the GABAergic neurons of the SNpr were spared. Furthermore we observed ubiquitin inclusions in the dopaminergic neurons and a dramatic microglial and astrocyte activation. PGJ2 infusion also caused changes in posture and locomotion. PGJ2 has the potential to
Acknowledgements Supported by NIH [SNRP NS41073 (from NINDS to Hunter College, M.E.F.-P., head of sub-project) and RCMI RR03037 (from NIGMS to Hunter College)] and the Louis Stokes AMP program.
References Klegeris, A., McGeer, E.G., McGeer, P.L., 2007. Therapeutic approaches to inflammation in neurodegenerative disease. Current Opinion In Neurology 20, 351–357. Uchida, K., Shibata, T., 2007. 15-Deoxy-delta(12,14)-prostaglandin J2: an electrophilic trigger of cellular responses. Chemical Research In Toxicology. Musiek, E.S., Milne, G.L., McLaughlin, B., Morrow, J.D., 2005. Cyclopentenone eicosanoids as mediators of neurodegeneration: a pathogenic mechanism of oxidative stress-mediated and cyclooxygenase-mediated neurotoxicity. Brain Pathology 15, 149–158.
doi: 10.1016/j.ijdevneu.2008.09.115 [P1.66] The role of microRNAs in midbrain dopaminergic neurogenesis A. Anderegg *, B. Yun, M. Joksimovic, R. Awatramani Northwestern University, USA *Corresponding author. Keywords: microRNA; Midbrain; Dopamine; Neurogenesis
Stem cell based therapeutics offer promising opportunity for the treatment of Parkinson’s disease. However, generating an optimal population of dopamine neurons for cell replacement requires a comprehensive understanding of the molecules that initially direct embryonic stem cells (ESCs) toward the dopaminergic fate. Thus, we have investigated the potential role of microRNAs (a recently identified class of evolutionarily conserved, non-coding, regulatory RNAs) in orchestrating the birth, specification, and maturation of midbrain dopamine neurons (mDAs).
Poster Session 1 Abstracts 2 June 2008 / Int. J. Devl Neuroscience 26 (2008) 841–866
overexpresssion (GOF) or downregulation (LOF) of ALDH1a1. Several degenerative stimuli are tested in such systems. We present preliminary results from an in vitro LOF and GOF study, supporting the hypothesis that ALDH1a1 exerts neuroprotective effects in midbrain DA neurons. doi: 10.1016/j.ijdevneu.2008.09.111 [P1.62] Essential role of TGFb-HIPK2 signaling pathway in survival and synapse formation in enteric neurons A. Tang 1,*, A. Chalazonitis 2, T. Pham 2, I. Hsieh 1, M. Gershon 2, E. Huang 1 1
University of California, San Francisco, USA Columbia University, USA *Corresponding author.
2
Keywords: Dopamine neuron; Survival; Synapse; Trophic factor
It is well-established that TGFb and BMP signaling pathways control neural development in Drosophila, Aplysia and vertebrates. However, it is unclear whether these molecules also influence vertebrate synaptogenesis. We have previously shown that HIPK2 is an essential component in TGFb-mediated survival of midbrain dopamine neurons in mouse (Zhang et al, Nature Neuroscience, 2007) and that BMP-2 and-4 regulate the number of enteric neurons (Chalazonitis et al., Journal of Neuroscience, 2004) as differentiation of a dopaminergic subset (submitted). In this study, we investigated the role of HIPK2 in the development of enteric neurons. We found that 40% of Hipk2/ mutant mice died within 7 days after birth, many of them showed no food in the GI tracts. Hipk2/ mutants that survived into adulthood showed increased total GI transit time, poor intestinal motility, and signs of constipation. Similar to midbrain dopamine neurons, loss of HIPK2 had no detectable effects in migration of neural crest cells into the intestinal wall or the initial differentiation of enteric neurons. Instead, Hipk2/ mutants show a progressive loss of neurons in myenteric and submucosal plexuses. In particular, there was greater than 50% loss of dopamine neurons in the submucosal plexus in ileum and colon. Many of the remaining enteric neurons in Hipk2/ mutants were reduced in size and showed much fewer intraganglionic synapses. Taken together, these results indicate that TGFb-HIPK2 signaling mechanism provides trophic factor supports for survival and differentiation of dopamine neurons in the enteric nervous system as well as in the ventral midbrain of mice. doi: 10.1016/j.ijdevneu.2008.09.112 [P1.63] Effects of complement 3 on the protection against dopaminergic neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine B.Y. Su *, Y.J. Liang, S.R. Li Chengdu Medical College, China *Corresponding author. Tel.: +86 28 68289158. Keywords: Complement 3; Parkinson’s disease; Dopaminergic toxicity; Neuroinflammation
Parkinson’s disease (PD) is a debilitating neurological disorder characterized by loss of dopaminergic neurons in the nigrostriatal pathway. Recent studies have highlighted the neuroinflammation plays an important role in the pathogenesis of Parkinson’s disease.
Mounting evidence indicated that components of complement system may be involved in such disorder and contribute to its development. We thus observed the influence of deficiency of activation of complement system, caused by knockout of the central component complement 3, on the death of dopaminergic neurons in substantia nigra pars compacta compact (SNpc) and the loss of dopaminergic fibers in striata induced by acute or chronic administration of MPTP. Immunohistochemical staining of dopaminergic neurons in SNpc and neurochemical analysis of dopamine and its metabolites in striata reveal that there is no significant difference between the two genotypes. Longer survival time also indicated that complement 3 may not mediate the spontaneous recovery of dopaminergic fibers in mouse striatum acutely challenged by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. We conclude that, despite growing evidence indicating the involvement of complement system in the pathology of PD, our data do not support this speculation in a well established mouse model of PD, as indicated by HPLC analysis and immunohistochemical staining. Acknowledgement This study was supported by the Major State Basic Research Development Program of China (973 Program, No. 2003CB515300).
doi: 10.1016/j.ijdevneu.2008.09.113 [P1.64] Melatonin reduces MPP+-induced FGF9 down regulation and nigral dopaminergic neuronal death J.Y. Huang, J.I. Chuang * National Cheng Kung University, Taiwan *Corresponding author. Keywords: Melatonin; FGF9; MPP+; Dopamine
Parkinson’s disease (PD) represented movement disorder is due to the nigrostriatal dopaminergic neurodegeneration. The reduction of trophic factors found in PD patients suggests their important roles in dopamine neuronal survival. Fibroblast growth factor 9 (FGF9), initially identified as a growth factor for astrocytes, is a survival factor for various cells. However, the protective role of FGF9 in nigrostriatal dopaminergic neurons has not been investigated. Our previous studies had demonstrated that melatonin by antioxidant effect prevented neurotoxin-induced nigrostriatal dopaminergic neurodegeneration. We therefore investigated the protective role of FGF9 and effect of melatonin on FGF9 expression in 1-methyl-4-phenylpyridine (MPP+)-induced dopaminergic neuronal loss in rats. Our in vivo studies demonstrated that 3 days after intra-striatal MPP+ infusion statistically decreased FGF9 mRNA expression and protein level in striatum and substantia nigra. The MPP+-down regulated nigrostriatal FGF9 mRNA expression and protein level was significantly attenuated by melatonin co-treatment. Supra-nigral administration of recombinant FGF9 prevented MPP+-caused tyrosine hydroxylase (TH, a marker enzyme of dopaminergic neurons)-positive neuronal loss in substantia nigra but not the immunoreactivity of dopamine transporter in striatum. In mesencephalic neuron culture, we found that MPP+ dose dependently induced TH-positive dopamine neuronal apoptosis 48 h after treatment, which can be significantly attenuated by FGF9 or melatonin co-treatment. In summary, our findings suggested that FGF9 served neuroprotective function in
Poster Session 1 Abstracts 2 June 2008 / Int. J. Devl Neuroscience 26 (2008) 841–866
MPP+-mediated neurotoxicity mediated neuroprotection.
and
involved
in
melatonin-
doi: 10.1016/j.ijdevneu.2008.09.114
863
initiate a series of self-perpetuating deleterious cascades leading to self-sustained progressive neurodegeneration in PD. Selective inhibitors of PGD2 synthases (PGD2 is the precursor of PGJ2) could be effective PD therapeutic targets since, contrary to COX-1 and COX-2 inhibitors, they will not halt production of all PGs including the cytoprotective and anti-inflammatory ones.
[P1.65] Mouse model of Parkinson’s disease mimicking neuroinflammation S. Pierre, M.E. Figueiredo-Pereira * City University of New York, USA *Corresponding author.
Keywords: Inflammation; Parkinson’; Prostaglandin J2; Ubiquitin/proteasome pathway
The importance of chronic inflammation in Parkinson’s (PD) disease is strengthened by clinical and epidemiological studies demonstrating that NSAIDs reduce the incidence of PD (Klegeris et al., 2007). NSAIDs inhibit cyclooxygenases, decreasing arachidonic acid oxidation. The drawback is that cyclooxygenase-dependent arachidonic acid oxidation yields an extensive variety of products some with pro-survival others with pro-death effects. We chose to model PD by lesioning the nigrostriatal pathway with prostaglandin J2 (PGJ2). The latter is derived from PGD2, the major prostaglandin in the mammalian CNS. PGD2 readily undergoes non-enzymatic first order dehydration reaction to yield highly reactive and neurotoxic cyclopentenone J2 prostaglandins (PGJ2). PGJ2 are unique among the prostaglandin family because they covalently and potently react with free sulfhydryls of glutathione and cysteine residues in cellular proteins via Michael addition (Uchida and Shibata, 2007). A recent review suggests that ‘‘formation of cyclopentenone eicosanoids [such as PGJ2] in the brain may represent a novel pathogenic mechanism that contributes to many neurodegenerative conditions’’ (Musiek et al., 2005). We focused on PGJ2 because it is an endogenous product of inflammation and in vitro studies showed that it induces pleiotropic changes that mimic many of the molecular and cellular pathologies observed in PD. We microinjected PGJ2 into the substantia nigra and striatum of adult FVB male mice and observed dopaminergic cell loss (figure) in the SNpc but the GABAergic neurons of the SNpr were spared. Furthermore we observed ubiquitin inclusions in the dopaminergic neurons and a dramatic microglial and astrocyte activation. PGJ2 infusion also caused changes in posture and locomotion. PGJ2 has the potential to
Acknowledgements Supported by NIH [SNRP NS41073 (from NINDS to Hunter College, M.E.F.-P., head of sub-project) and RCMI RR03037 (from NIGMS to Hunter College)] and the Louis Stokes AMP program.
References Klegeris, A., McGeer, E.G., McGeer, P.L., 2007. Therapeutic approaches to inflammation in neurodegenerative disease. Current Opinion In Neurology 20, 351–357. Uchida, K., Shibata, T., 2007. 15-Deoxy-delta(12,14)-prostaglandin J2: an electrophilic trigger of cellular responses. Chemical Research In Toxicology. Musiek, E.S., Milne, G.L., McLaughlin, B., Morrow, J.D., 2005. Cyclopentenone eicosanoids as mediators of neurodegeneration: a pathogenic mechanism of oxidative stress-mediated and cyclooxygenase-mediated neurotoxicity. Brain Pathology 15, 149–158.
doi: 10.1016/j.ijdevneu.2008.09.115 [P1.66] The role of microRNAs in midbrain dopaminergic neurogenesis A. Anderegg *, B. Yun, M. Joksimovic, R. Awatramani Northwestern University, USA *Corresponding author. Keywords: microRNA; Midbrain; Dopamine; Neurogenesis
Stem cell based therapeutics offer promising opportunity for the treatment of Parkinson’s disease. However, generating an optimal population of dopamine neurons for cell replacement requires a comprehensive understanding of the molecules that initially direct embryonic stem cells (ESCs) toward the dopaminergic fate. Thus, we have investigated the potential role of microRNAs (a recently identified class of evolutionarily conserved, non-coding, regulatory RNAs) in orchestrating the birth, specification, and maturation of midbrain dopamine neurons (mDAs).