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P2.076 MANF: a new potential disease-modifying drug candidate for Parkinson's disease
Poster presentations / Parkinsonism and Related Disorders 15S2 (2009) S29–S199
P2.075 Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, protects dopaminergic neurons from neurotoxin-induced damage H.-M. Wu1,2,3 , S.-H. Chen1,2 , J.-S. Hong2 , R.-B. Lu1 . 1 Institute of Behavioral Medicine, National Cheng-Kung University, Tainan, Taiwan R.O.C., 2 Neuropharmacology Section, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA; 3 Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan R.O.C. Background and Aim: Parkinson’s disease (PD) is characterized by selective and progressive loss of dopaminergic (DA) neurons in the substantia nigra. Current available anti-Parkinson’s drugs are limited to symptom relief; they can not stop the disease progression in PD patients. Growing evidences showed that administration of histone deacetylase (HDAC) inhibitors is able to ameliorate wide ranges of neurologic and psychiatric disorders. To further explore the therapeutic potential of HDAC inhibitor in PD, we conducted studies with SAHA, a potent HDAC inhibitor. Methods: Mesencephalic neuron-glia cultures and reconstituted cultures were used to investigate neurotrophic and neuroprotective effects of SAHA. We measured DA neurotoxicity using DA uptake assay and neurotrophic substances expression by enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. Results: Our results showed that: 1. SAHA enhanced the survival of DA neurons from spontaneous neuronal death in midbrain neuron-glia culture in a dose dependent manner; 2. the neuroprotective effects are mediated in part by release of neurotrophic substances from astrocytes; 3. furthermore, SAHA could also protect DA neurons against neurotoxicity induced by 1-methyl-4-phenylpyridinium (MPP+ ), in rat primary mesencephalic neuron-glia cultures. Mechanistic studies revealed that the neurotrophic effect was partially abolished when the condition medium from SAHA-treated astrocytes was incubated with neutralizing antibody for glia cell line-derived neurotrophic factor (GDNF). Conclusion: Our results demonstrated that neurotrophic and neuroprotective effects of SAHA may be tested as a potential drug for treatment of neurodegenerative disorders such as PD. P2.076 MANF: a new potential disease-modifying drug candidate for Parkinson’s disease J. Commissiong. Cell Biology, CNS Protein Therapeutics, Sunnyvale, CA, USA MANF, or mesencephalic astrocyte-derived neurotrophic factor is an 18 kDa, human secreted protein derived from a type-1 astrocyte cell line, VMCL1. MANF was selectively neuroprotective for dopaminergic neurons in vitro. It did not protect GABAergic or serotonergic neurons in the same cell culture. In a slice preparation of the rat substantia nigra, MANF increased the release of GABA from presynaptic GABAergic terminals innervating nigral dopaminergic neurons. This action of MANF can dampen the potential neurotoxic action of glutamate by decreasing Ca2+ . A study i to determine the efficacy of MANF in the primate MPTP model of PD is planned. The MANF gene, like the endoplasmic reticulum (ER) resident, Ca2+ -binding chaperone proteins GRP78 and GRP94, is induced in the adaptive pathway of the unfolded protein response (UPR) in ER stress. Moreover, MANF is also secreted in this model, suggesting that it could be an autocrine/paracrine factor (Tadimalla et al., 2008). These neuroprotective actions of MANF and its actions in the adaptive pathway of the unfolded protein response suggest that MANF is a bifunctional molecule, as reported recently by Parkash et al. (2009). Secreted MANF may be endocytosed or may bind to a MANF receptor on the plasmamembrane and activate a signal transduction pathway. In summary, MANF up-regulates the
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expression of TH, can prevent glutamate-mediated toxic increase in Ca2+ and corrects stress-induced protein misfolding. These actions i of MANF may contribute in correcting the neurological deficits in the rodent model of PD. No other neurotrophic factor to date has exhibited this spectrum of effects. P2.077 First-in-class drugs with neuroprotective potential against Parkinson’s disease identified through biology-driven discovery approach T. Van Dooren1 , K. Coupet1 , E. Gomme´ 1 , H. Duhamel1 , A. Lauwers1 , E. Cuveliers1 , K. Princen1 , I. Bastiaens1 , J. Winderickx2 , V. Rojas de la Parra1 , I. Van der Auwera1 , S. Wera1 , G. Griffioen1 . 1 reMYND, Leuven-Heverlee, 2 Katholieke Universiteit Leuven, Leuven, Belgium Introduction: Neuronal degeneration in Parkinson’s disease (PD) entails an elusive cascade of events involving noxious aggregation of alpha-synuclein. Therefore, therapeutic intervention by inhibiting protein aggregation-triggered cytotoxicity may represent an effective way of decelerating disease progression. Aims: The aims of the studies are discovery and development of innovative, disease-modifying therapeutics for treating PD. Results: A family of small molecules (ReS9-S) has been developed with potent, cytoprotective properties in a human neuronal cell model of alpha-synucleopathy. Lead compound ReS9-S7 rescued nigro-striatal dopaminergic degeneration in chemicallyinduced and transgenic alpha-synuclein mouse models of PD. Moreover, abnormal dopaminergic-controlled anxiety and motoric dysfunctioning were rescued. Biochemical characterisation revealed ReS9-S7 facilitates clearance of noxious alpha-synuclein species of the striatum, hence explaining its neuroprotective properties. Regulatory toxicology and ADME studies have demonstrated excellent safety, plasma exposure and brain penetration allowing a once-a-day oral dosing regimen. A chemo-genetic screen in cell-based models of PD was carried out to identify genes and pathways required for compound action. The approach identified genes operating in sorting misfolded proteins to the lysosome, the protein degradation organelle of the cell. Conclusions: ReS9-S7 holds a huge promise as a therapeutic agent for treatment of Parkinson’s disease and related alpha-synucleopathies. ReS9-S7 modulates lysosomal-dependent clearance of pathological alpha-synuclein in order to reduce its toxicological burden in dopaminergic neurons. P2.078 Usage and cost of complementary therapies in hemifacial spasm P. Ratnagopal1 , S. Hameed1 , E.K. Tan1 , K. Hussein2 . 1 Neurology, National Neuroscience Institute, 2 Neurology, Singapore General Hospital, Singapore, Singapore Objective: To determine the pattern and cost of complementary therapies in patients with hemifacial spasm. Background: Hemifacial spasm (HFS) is common among Asians and cosmetically unacceptable to many patients. Complementary therapies (CompTh) are frequently sought after by patients with neurological disorders. The use of CompTh in HFS has not been reported. Methods: Consecutive patients with HFS were administered a structured questionnaire on the frequency of usage of CompTh and to investigate factors influencing usage. Results: A total of 96 patients were included. 49 (51%) used one or more forms of CompTh. Thirty-five (71.4%) used one type only and 9 (18.4%) and 5 (10.2%) used 2 and 3 types of CompTh respectively. Different types of CompTh were used by 49 participants, with acupuncture (52.9%) being the most common, then facial massage (17.6%) and others. Interestingly, only 2 (4.1%) of CompTh users reported the therapies as very helpful, forty-three percent reported the therapies as being sometimes helpful and the
P2.075 Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, protects dopaminergic neurons from neurotoxin-induced damage H.-M. Wu1,2,3 , S.-H. Chen1,2 , J.-S. Hong2 , R.-B. Lu1 . 1 Institute of Behavioral Medicine, National Cheng-Kung University, Tainan, Taiwan R.O.C., 2 Neuropharmacology Section, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA; 3 Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan R.O.C. Background and Aim: Parkinson’s disease (PD) is characterized by selective and progressive loss of dopaminergic (DA) neurons in the substantia nigra. Current available anti-Parkinson’s drugs are limited to symptom relief; they can not stop the disease progression in PD patients. Growing evidences showed that administration of histone deacetylase (HDAC) inhibitors is able to ameliorate wide ranges of neurologic and psychiatric disorders. To further explore the therapeutic potential of HDAC inhibitor in PD, we conducted studies with SAHA, a potent HDAC inhibitor. Methods: Mesencephalic neuron-glia cultures and reconstituted cultures were used to investigate neurotrophic and neuroprotective effects of SAHA. We measured DA neurotoxicity using DA uptake assay and neurotrophic substances expression by enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. Results: Our results showed that: 1. SAHA enhanced the survival of DA neurons from spontaneous neuronal death in midbrain neuron-glia culture in a dose dependent manner; 2. the neuroprotective effects are mediated in part by release of neurotrophic substances from astrocytes; 3. furthermore, SAHA could also protect DA neurons against neurotoxicity induced by 1-methyl-4-phenylpyridinium (MPP+ ), in rat primary mesencephalic neuron-glia cultures. Mechanistic studies revealed that the neurotrophic effect was partially abolished when the condition medium from SAHA-treated astrocytes was incubated with neutralizing antibody for glia cell line-derived neurotrophic factor (GDNF). Conclusion: Our results demonstrated that neurotrophic and neuroprotective effects of SAHA may be tested as a potential drug for treatment of neurodegenerative disorders such as PD. P2.076 MANF: a new potential disease-modifying drug candidate for Parkinson’s disease J. Commissiong. Cell Biology, CNS Protein Therapeutics, Sunnyvale, CA, USA MANF, or mesencephalic astrocyte-derived neurotrophic factor is an 18 kDa, human secreted protein derived from a type-1 astrocyte cell line, VMCL1. MANF was selectively neuroprotective for dopaminergic neurons in vitro. It did not protect GABAergic or serotonergic neurons in the same cell culture. In a slice preparation of the rat substantia nigra, MANF increased the release of GABA from presynaptic GABAergic terminals innervating nigral dopaminergic neurons. This action of MANF can dampen the potential neurotoxic action of glutamate by decreasing Ca2+ . A study i to determine the efficacy of MANF in the primate MPTP model of PD is planned. The MANF gene, like the endoplasmic reticulum (ER) resident, Ca2+ -binding chaperone proteins GRP78 and GRP94, is induced in the adaptive pathway of the unfolded protein response (UPR) in ER stress. Moreover, MANF is also secreted in this model, suggesting that it could be an autocrine/paracrine factor (Tadimalla et al., 2008). These neuroprotective actions of MANF and its actions in the adaptive pathway of the unfolded protein response suggest that MANF is a bifunctional molecule, as reported recently by Parkash et al. (2009). Secreted MANF may be endocytosed or may bind to a MANF receptor on the plasmamembrane and activate a signal transduction pathway. In summary, MANF up-regulates the
S109
expression of TH, can prevent glutamate-mediated toxic increase in Ca2+ and corrects stress-induced protein misfolding. These actions i of MANF may contribute in correcting the neurological deficits in the rodent model of PD. No other neurotrophic factor to date has exhibited this spectrum of effects. P2.077 First-in-class drugs with neuroprotective potential against Parkinson’s disease identified through biology-driven discovery approach T. Van Dooren1 , K. Coupet1 , E. Gomme´ 1 , H. Duhamel1 , A. Lauwers1 , E. Cuveliers1 , K. Princen1 , I. Bastiaens1 , J. Winderickx2 , V. Rojas de la Parra1 , I. Van der Auwera1 , S. Wera1 , G. Griffioen1 . 1 reMYND, Leuven-Heverlee, 2 Katholieke Universiteit Leuven, Leuven, Belgium Introduction: Neuronal degeneration in Parkinson’s disease (PD) entails an elusive cascade of events involving noxious aggregation of alpha-synuclein. Therefore, therapeutic intervention by inhibiting protein aggregation-triggered cytotoxicity may represent an effective way of decelerating disease progression. Aims: The aims of the studies are discovery and development of innovative, disease-modifying therapeutics for treating PD. Results: A family of small molecules (ReS9-S) has been developed with potent, cytoprotective properties in a human neuronal cell model of alpha-synucleopathy. Lead compound ReS9-S7 rescued nigro-striatal dopaminergic degeneration in chemicallyinduced and transgenic alpha-synuclein mouse models of PD. Moreover, abnormal dopaminergic-controlled anxiety and motoric dysfunctioning were rescued. Biochemical characterisation revealed ReS9-S7 facilitates clearance of noxious alpha-synuclein species of the striatum, hence explaining its neuroprotective properties. Regulatory toxicology and ADME studies have demonstrated excellent safety, plasma exposure and brain penetration allowing a once-a-day oral dosing regimen. A chemo-genetic screen in cell-based models of PD was carried out to identify genes and pathways required for compound action. The approach identified genes operating in sorting misfolded proteins to the lysosome, the protein degradation organelle of the cell. Conclusions: ReS9-S7 holds a huge promise as a therapeutic agent for treatment of Parkinson’s disease and related alpha-synucleopathies. ReS9-S7 modulates lysosomal-dependent clearance of pathological alpha-synuclein in order to reduce its toxicological burden in dopaminergic neurons. P2.078 Usage and cost of complementary therapies in hemifacial spasm P. Ratnagopal1 , S. Hameed1 , E.K. Tan1 , K. Hussein2 . 1 Neurology, National Neuroscience Institute, 2 Neurology, Singapore General Hospital, Singapore, Singapore Objective: To determine the pattern and cost of complementary therapies in patients with hemifacial spasm. Background: Hemifacial spasm (HFS) is common among Asians and cosmetically unacceptable to many patients. Complementary therapies (CompTh) are frequently sought after by patients with neurological disorders. The use of CompTh in HFS has not been reported. Methods: Consecutive patients with HFS were administered a structured questionnaire on the frequency of usage of CompTh and to investigate factors influencing usage. Results: A total of 96 patients were included. 49 (51%) used one or more forms of CompTh. Thirty-five (71.4%) used one type only and 9 (18.4%) and 5 (10.2%) used 2 and 3 types of CompTh respectively. Different types of CompTh were used by 49 participants, with acupuncture (52.9%) being the most common, then facial massage (17.6%) and others. Interestingly, only 2 (4.1%) of CompTh users reported the therapies as very helpful, forty-three percent reported the therapies as being sometimes helpful and the