- Email: [email protected]
Hydrogen sulfide, a novel neuroprotectant in the neurodegenerative diseases
Poster Presentations P3
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the oligomers of Ab was 10 kDa (equivalent to dimmer for Ab1-40 and decamers for Ab25-35) and that DHA dose-dependently reduced these decamers. Conclusions: DHA decreases the in vitro fibrillation of Ab by inhibiting the oligomeric amyloid species and, therefore, Ab-related neurotoxicity or behavioral impairment could be restrained by DHA. P3-261
CURRENT DRUG TARGET SITES IN CLINICAL PRACTICE OR CLINICAL TRIAL, EXTENT OF DISEASE MODIFICATION FOR ALZHEIMER’S DISEASE
Farhan Ul Haq Subhani, Bolam Medical College Quetta Balochistan Pakistan, Quetta, Pakistan. Contact e-mail: [email protected] Background: Alzheimer’s disease is most common form of dementia and one of complicated neurodegenerative diseases. Different therapeutic target sites are approved and number of drug target sites are under development for the treatment of Alzheimer’s disease. The disease modification is claimed by several drug developers for Alzheimer’s disease but the disease process has not been significantly affected by the available drugs either in clinical practice or clinical trials. In this review, discussion of the effects of different drug target sites on the disease modification will be compiled. Methods: It is a review to discuss in detail the efficacy of different drugs for the disease modifying effect of their respective target site. Results: Alzheimer’s disease have been know to scientifically community for almost 100 years and good therapeutic revaluation has been experienced during last 2 decades with respect to the treatment of this mysterious disease. Different drug target sites have been approved for the treatment of disease which includes cholinesterase inhibitors, NMDA receptor antagonist and products to elevate ketone bodies level in brain. Many drug target sites are in the process of development from discovery to phase III stage of clinical trail. These target sites are beta amyloid modulator, amyloid protein deposition inhibitors, nicotinic ACh modulator, muscarinic M1 agonist, muscarinic M2 antagonist, TrkA receptor modulator, proteasome inhibitor, AMPA receptor antagonist & modulator, anti-inflammatory cytokine synthesis inhibitor, caspase-3 inhibitor, PDE 4 inhibitor, tau aggregation inhibitor, beta & gamma-secretrase inhibitor, benzothiophene derivatives, COX-2 inhibitor, histamine H3 antagonist, antioxidant agents, imidazoline receptor antagonist, alpha 2 adrenoceptor antagonist, metal (Zn, Cu) chelating agent, free radical scavenger, MAO B inhibitor, 5-HT agonist and glycogen synthase kinase-3 inhibitor etc. Conclusions: In this review disease modification effect of few important drug targetsites for AD will be discussed. The modification process is not for sake of cure in all these target sites but we are being hopeful for having a definitive cure from this next generation of drug target sites in case of Alzheimer’s disease. P3-262
COGNITIVE AND PATHOLOGICAL BENEFITS OF Ab-SENSITIVE TH2 CELLS ARE INDEPENDENT OF ANTIGEN-SPECIFIC B CELL ACTIVATION
Douglas W. Ethell1, Chuanhai Cao2, Alexander Dickson3, Malgorzata B. Mamcarz3, Xiaoyang Lin2, Gary W. Arendash2,3, 1University of California Riverside, Riverside, CA, USA; 2Florida Alzheimer’s Disease Research Center, Tampa, FL, USA; 3Johnnie B. Byrd Alzheimer’s Center and Research Institute, Tampa, FL, USA. Contact e-mail: doug.ethell@ucr. edu Background: Boosting immune responses to Ab can reduce cognitive and pathology in mouse models of Alzheimer’s disease, but the role of Ab-specific antibodies in this process remains enigmatic. We have previously shown that Ab-specific T cells facilitate cognitive improvements without generating a measurable anti-Ab antibody responses. However, it is unclear whether Th1 and/or Th2 cells were necessary for this effect. Methods: Cognitively-impaired APP+PS1 mice received injections of Th2 cells isolated from Ab-vaccinated wild-type mice and re-stimulated in vitro with Ab, IL2 and IL-4. Mice were subjected to behavioral studies before and after receiving T cell injections, with extensive pathology and histology following the final behavioral studies. Results: APP+PS mice that received Ab-specific Th2 cells performed significantly better in working memory tasks, which
correlated with higher plasma levels of soluble Ab, but no detectable Ab antibody titer using a polyvalent antibody that evaluates IgA, IgG, and IgM. Pathological analysis of the hippocampus revealed a 30% decrease of plaqueassociated microglia and less vascular amyloidosis in Th2-treated mice. The infusion of Ab-specific Th2 cells also reduced plasma levels of IFN-g, TNFa, GM-CSF, IL-2 and IL-4, which are elevated in untreated APP+PS1 mice. These results demonstrate that Ab-specific Th2 cells are sufficient to reverse cognitive impairment and provide multiple pathological benefits in an Alzheimer’s mouse model. Conclusions: We have found that a small number of purified Ab-specific T cells (Th2-biased) are sufficient to provide cognitive and pathological benefits in an APP+PS1 mouse model for Alzheimer’s disease, without the production of Ab-specific antibodies. Supported by NIH and the California Institute for Regenerative Medicine. P3-263
HYDROGEN SULFIDE, A NOVEL NEUROPROTECTANT IN THE NEURODEGENERATIVE DISEASES
Lifang Hu, Jinsong Bian, National University of Singapore, Singapore. Contact e-mail: [email protected] Background: Hydrogen sulfide (H2S) has recently been proposed to be a novel neuromodulator. The present study was designed to investigate its therapeutic value in the neurodegenerative diseases. Methods: We observed the effects of NaHS, an H2S donor, on neuroinflammation induced by betaamyloid in BV-2 microglial cells and cell injury induced by rotenone in human-derived dopaminergic neuroblastoma cell line (SH-SY5Y). Results: NaHS concentration-dependently suppressed beta amyloid -induced nitrite accumulation in BV-2 microglial cells and rotenone-induced cellular injury and apoptotic cell death in SH-SY5Y cells. It was found that NaHS prevented p38-MAPK phosphorylation-induced by neurotoxins in both BV-2 and SHSY5Y cells. In addition, NaHS also attenuated rotenone-mediated changes in Bcl-2/Bax levels, mitochondrial membrane potential (DJm) dissipation, cytochrome c release, caspase-9/3 activation and poly (ADP-ribose) polymerase (PARP) cleavage. 5-hydroxydecanoate (5-HD), a selective blocker of mitochondrial ATP-sensitive potassium (mitoKATP) channel, attenuated the protective effects of NaHS against rotenone-induced cell apoptosis. Conclusions: H2S protects against neurotoxins-induced cellular injury via p38MAPK pathway in both microglial and neuronal cells. MitoKATP channels may also contribute to the anti-apoptotic effect of H2S in neuronal cells. Our findings suggest that H2S may have important implications in the treatment of neurodegenerative diseases (e.g.Parkinson’s disease and Alzheimer’s disease). P3-264
SELECTIVE MODULATION OF AB42 BY CALCIUM CHANNEL ANTAGONISTS. RELEVANCE OF CALCIUM DYNAMICS
Antonello D’Arrigo, Elda Del Giudice, Michele Fabris, Maurizio Dalle Carbonare, Davide Colavito, Alberta Leon, Research & Innovation S.P.A., Padova, Italy. Contact e-mail: [email protected] Background: Evidence for a modulatory activity of dihydropyridines (DHPs) on beta-amyloid (Ab) production has been reported previously by our group in immortalised cells overexpressing a FAD-linked APP mutation (Facchinetti et al. Neurobiology of Aging 27: 218, 2006). In that report, nimodipine and other DHPs were described to affect the levels of Ab released into the extracellular medium. In the present study, the action exerted by a panel of calcium antagonists on amyloidogenesis was explored and further characterised employing mouse primary cortical neurons. Methods: Experiments were conducted on primary neurons from hippocampi and frontal cortices of embryonic-day 16 18 (E16 18) mice carrying the Swedish mutation of human amyloid precursor protein (APP), KM670/671NL. Neurons were maintained in culture for 7-8 days before the experiment. Both intracellular and extracellular beta-amyloid levels were assessed under different experimental conditions. Results: Among the tested compounds, nimodipine was found to specifically modulate Ab42 levels. Moreover, some DHPs, but not others, significantly altered Ab42/Ab40 ratio. These effects were not entirely accounted for by the role of these molecules as calcium channel antagonists. Furthermore, structurally unrelated blockers of
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the oligomers of Ab was 10 kDa (equivalent to dimmer for Ab1-40 and decamers for Ab25-35) and that DHA dose-dependently reduced these decamers. Conclusions: DHA decreases the in vitro fibrillation of Ab by inhibiting the oligomeric amyloid species and, therefore, Ab-related neurotoxicity or behavioral impairment could be restrained by DHA. P3-261
CURRENT DRUG TARGET SITES IN CLINICAL PRACTICE OR CLINICAL TRIAL, EXTENT OF DISEASE MODIFICATION FOR ALZHEIMER’S DISEASE
Farhan Ul Haq Subhani, Bolam Medical College Quetta Balochistan Pakistan, Quetta, Pakistan. Contact e-mail: [email protected] Background: Alzheimer’s disease is most common form of dementia and one of complicated neurodegenerative diseases. Different therapeutic target sites are approved and number of drug target sites are under development for the treatment of Alzheimer’s disease. The disease modification is claimed by several drug developers for Alzheimer’s disease but the disease process has not been significantly affected by the available drugs either in clinical practice or clinical trials. In this review, discussion of the effects of different drug target sites on the disease modification will be compiled. Methods: It is a review to discuss in detail the efficacy of different drugs for the disease modifying effect of their respective target site. Results: Alzheimer’s disease have been know to scientifically community for almost 100 years and good therapeutic revaluation has been experienced during last 2 decades with respect to the treatment of this mysterious disease. Different drug target sites have been approved for the treatment of disease which includes cholinesterase inhibitors, NMDA receptor antagonist and products to elevate ketone bodies level in brain. Many drug target sites are in the process of development from discovery to phase III stage of clinical trail. These target sites are beta amyloid modulator, amyloid protein deposition inhibitors, nicotinic ACh modulator, muscarinic M1 agonist, muscarinic M2 antagonist, TrkA receptor modulator, proteasome inhibitor, AMPA receptor antagonist & modulator, anti-inflammatory cytokine synthesis inhibitor, caspase-3 inhibitor, PDE 4 inhibitor, tau aggregation inhibitor, beta & gamma-secretrase inhibitor, benzothiophene derivatives, COX-2 inhibitor, histamine H3 antagonist, antioxidant agents, imidazoline receptor antagonist, alpha 2 adrenoceptor antagonist, metal (Zn, Cu) chelating agent, free radical scavenger, MAO B inhibitor, 5-HT agonist and glycogen synthase kinase-3 inhibitor etc. Conclusions: In this review disease modification effect of few important drug targetsites for AD will be discussed. The modification process is not for sake of cure in all these target sites but we are being hopeful for having a definitive cure from this next generation of drug target sites in case of Alzheimer’s disease. P3-262
COGNITIVE AND PATHOLOGICAL BENEFITS OF Ab-SENSITIVE TH2 CELLS ARE INDEPENDENT OF ANTIGEN-SPECIFIC B CELL ACTIVATION
Douglas W. Ethell1, Chuanhai Cao2, Alexander Dickson3, Malgorzata B. Mamcarz3, Xiaoyang Lin2, Gary W. Arendash2,3, 1University of California Riverside, Riverside, CA, USA; 2Florida Alzheimer’s Disease Research Center, Tampa, FL, USA; 3Johnnie B. Byrd Alzheimer’s Center and Research Institute, Tampa, FL, USA. Contact e-mail: doug.ethell@ucr. edu Background: Boosting immune responses to Ab can reduce cognitive and pathology in mouse models of Alzheimer’s disease, but the role of Ab-specific antibodies in this process remains enigmatic. We have previously shown that Ab-specific T cells facilitate cognitive improvements without generating a measurable anti-Ab antibody responses. However, it is unclear whether Th1 and/or Th2 cells were necessary for this effect. Methods: Cognitively-impaired APP+PS1 mice received injections of Th2 cells isolated from Ab-vaccinated wild-type mice and re-stimulated in vitro with Ab, IL2 and IL-4. Mice were subjected to behavioral studies before and after receiving T cell injections, with extensive pathology and histology following the final behavioral studies. Results: APP+PS mice that received Ab-specific Th2 cells performed significantly better in working memory tasks, which
correlated with higher plasma levels of soluble Ab, but no detectable Ab antibody titer using a polyvalent antibody that evaluates IgA, IgG, and IgM. Pathological analysis of the hippocampus revealed a 30% decrease of plaqueassociated microglia and less vascular amyloidosis in Th2-treated mice. The infusion of Ab-specific Th2 cells also reduced plasma levels of IFN-g, TNFa, GM-CSF, IL-2 and IL-4, which are elevated in untreated APP+PS1 mice. These results demonstrate that Ab-specific Th2 cells are sufficient to reverse cognitive impairment and provide multiple pathological benefits in an Alzheimer’s mouse model. Conclusions: We have found that a small number of purified Ab-specific T cells (Th2-biased) are sufficient to provide cognitive and pathological benefits in an APP+PS1 mouse model for Alzheimer’s disease, without the production of Ab-specific antibodies. Supported by NIH and the California Institute for Regenerative Medicine. P3-263
HYDROGEN SULFIDE, A NOVEL NEUROPROTECTANT IN THE NEURODEGENERATIVE DISEASES
Lifang Hu, Jinsong Bian, National University of Singapore, Singapore. Contact e-mail: [email protected] Background: Hydrogen sulfide (H2S) has recently been proposed to be a novel neuromodulator. The present study was designed to investigate its therapeutic value in the neurodegenerative diseases. Methods: We observed the effects of NaHS, an H2S donor, on neuroinflammation induced by betaamyloid in BV-2 microglial cells and cell injury induced by rotenone in human-derived dopaminergic neuroblastoma cell line (SH-SY5Y). Results: NaHS concentration-dependently suppressed beta amyloid -induced nitrite accumulation in BV-2 microglial cells and rotenone-induced cellular injury and apoptotic cell death in SH-SY5Y cells. It was found that NaHS prevented p38-MAPK phosphorylation-induced by neurotoxins in both BV-2 and SHSY5Y cells. In addition, NaHS also attenuated rotenone-mediated changes in Bcl-2/Bax levels, mitochondrial membrane potential (DJm) dissipation, cytochrome c release, caspase-9/3 activation and poly (ADP-ribose) polymerase (PARP) cleavage. 5-hydroxydecanoate (5-HD), a selective blocker of mitochondrial ATP-sensitive potassium (mitoKATP) channel, attenuated the protective effects of NaHS against rotenone-induced cell apoptosis. Conclusions: H2S protects against neurotoxins-induced cellular injury via p38MAPK pathway in both microglial and neuronal cells. MitoKATP channels may also contribute to the anti-apoptotic effect of H2S in neuronal cells. Our findings suggest that H2S may have important implications in the treatment of neurodegenerative diseases (e.g.Parkinson’s disease and Alzheimer’s disease). P3-264
SELECTIVE MODULATION OF AB42 BY CALCIUM CHANNEL ANTAGONISTS. RELEVANCE OF CALCIUM DYNAMICS
Antonello D’Arrigo, Elda Del Giudice, Michele Fabris, Maurizio Dalle Carbonare, Davide Colavito, Alberta Leon, Research & Innovation S.P.A., Padova, Italy. Contact e-mail: [email protected] Background: Evidence for a modulatory activity of dihydropyridines (DHPs) on beta-amyloid (Ab) production has been reported previously by our group in immortalised cells overexpressing a FAD-linked APP mutation (Facchinetti et al. Neurobiology of Aging 27: 218, 2006). In that report, nimodipine and other DHPs were described to affect the levels of Ab released into the extracellular medium. In the present study, the action exerted by a panel of calcium antagonists on amyloidogenesis was explored and further characterised employing mouse primary cortical neurons. Methods: Experiments were conducted on primary neurons from hippocampi and frontal cortices of embryonic-day 16 18 (E16 18) mice carrying the Swedish mutation of human amyloid precursor protein (APP), KM670/671NL. Neurons were maintained in culture for 7-8 days before the experiment. Both intracellular and extracellular beta-amyloid levels were assessed under different experimental conditions. Results: Among the tested compounds, nimodipine was found to specifically modulate Ab42 levels. Moreover, some DHPs, but not others, significantly altered Ab42/Ab40 ratio. These effects were not entirely accounted for by the role of these molecules as calcium channel antagonists. Furthermore, structurally unrelated blockers of