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2.15.1 PSYCHOGENIC MOVEMENT DISORDERS (1)
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Tuesday, 13 December 2011 / Parkinsonism and Related Disorders 18S2 (2012) S81–S159
2.14.3 NEURORESTORATIVE, NEUROPROTECTIVE AND CELL CYCLE ARREST ACTIVITY OF NOVEL MULTI TARGET DRUGS IN ANIMAL MODELS OF PARKINSON’S DISEASE M.B.H. Youdim1,2,3 . 1 Eve Topf Center of Excellence For Neurodegenerative Diseases, Technion-Rappaport Faculty of Medicine, Haifa, Israel; 2 Department of Biology, Yonsei World Central University, Seoul, Republic of Korea; 3 Varienl Inc., Delaware, PA, USA Parkinson’s disease (PD) is initiated by cascade of neurotoxic events, which includes oxidative stress, brain iron dysregulation, glutamate excitotoxicity, inflammatory process, neurotxic processing misfolding and aggregation of a-synuclein, resulting from the demise of ubiquitin-proteasome system (UPS). PD subjects are benefiting from drugs developed to act on a single molecular target. Such drugs have symptomatic activity and current pharmacological approaches are limited in their ability to modify the course of the disease.. However, the new therapeutic strategies for PD are those in which drug candidates are designed expressly to act on multiple neural and neurochemical targets involved in the neurodegenerative process. Thus we have developed brain permeable molecular entities, M30, M30P, HLA-20and HLA-20A that combine two or more of cholinesterase inhibitor, brain selective MAO inhibitor, and iron chelating-radical scavenging moieties and are inhibitors of glutamate toxicity and possess anti apoptotic and neurorestroative activity in post MPTP, lacatcystin and 6-OHDA treatment models. The neurorestorative activity of these drugs has been identified as being associated with neurogenesis and activation of HIF (hypoxia inducing factor), which regulates the neurotrophins BDNF, VEGF, erythropoeitin and induces cell cycle arrests, resulting in neuronal differentiation. These drugs are currently being developed as disease modifying agents for PD. 2.14.4 TRADITIONAL CHINESE HERBAL MEDICINE AND ELECTRO-ACUPUNCTURE X.M. Wang. Department of Physiology, Capital Medical University, Beijing, China Traditional Chinese medicine (TCM), including herbal formula and acupuncture, has been demonstrated as an alternative therapy for Parkinson’s disease (PD), and may provide unique strategies in combating it. In recent years, our group has explored a new herbal medicine, the extracts of traditional Chinese herb Tripterygium wilfordii Hook F (T10 ). T10 significantly improved the abnormal behaviors of PD rodents, which was critically related with its anti-inflammation effect. T10 inhibited the microglial activation, reduced the release of pro-inflammatory cytokines from microglia, and inhibited the expression of cyclooxygenase 2. In addition, T10 promoted the secretion of nerve growth factor from astrocytes, playing its neurotrophic role. Further studies showed that T10 inhibited the transcriptional activity of NF-úB, and downregulated the JNK phosphorylation in MAPK signal transduction pathway. Probably these above mechanisms contributed to the antiinflammation effect of T10 in PD therapy. Acupuncture is another focused approach for PD treatment. Studies have shown that electro-acupuncture (EA) was effective in alleviating abnormal motor symptoms in both PD patients and animal models. EA stimulation at a high frequency of 100 Hz significantly improved motor coordination and reduced apomorphine-induced rotational behaviors in the medial forebrain bundle (MFB) lesioned rat model. Nonetheless, the dopamine concentration in the striatum was not restored to the normal level. Instead, a decreased level of substance P and increased expression of glutamate decarboxylase-67 (GAD 67) was detected following EA stimulations In hemiparkinsonian rhesus monkeys with 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced rigidity, EA procedures did not adversely alter the animal’s locomotor activities; rather, parkinsonian animals showed a significant improvement
in movement speed; and EMG detected significant differences in muscle activity between the arms with and without MPTP-induced rigidity. The results also indicate that animals, especially those with parkinsonian-like symptoms, could benefit from long-term EA stimulations. Meanwhile, multi-channel single-unit electrode system was applied to record the neural activities at the primary motor cortex (MI) and the substantia nigra pars reticulata (SNr) in 6-OHDA lesioned rats. The further analyses with high-throughput gene expression microarray uncovered a number of potential targets in the cortex and the striatum after 4-week EA treatment. The results were in support of our conclusion that the recovery of homeostasis as reflected many regulated functional clusters of the transcript network may contribute and explain the behavioral changes in PD rats after EA treatments Acknowledgments: This work was supported by National Basic Research Program of China (2011CB504100), Key Program from Ministry of Science and Technology of China (2011ZX09102– 003–01), National Natural Science Foundation of China (81030062, 30973540, 81072858), and Key Program from Beijing Education Committee (kz200910025001). Video-Supported Session Psychogenic Movement Disorders Chairperson: Mark Hallett, Bethesda, USA
16:00–17:30
2.15.1 PSYCHOGENIC MOVEMENT DISORDERS (1) M. Hallett1 , W.J. Weiner2 , K. Kompoliti3 . 1 Human Motor Control Section, National Institute of Neurological Disorders and Stroke, Bethesda, 2 Neurology, University of Maryland School of Medicine, Baltimore, MD, 3 Neurology, Rush University Medical Center, Chicago, IL, USA Psychogenic movement disorders are common, but the diagnosis may be difficult. Visual appearance alone is typically not sufficient to make a diagnosis, but such information is certainly important. That a movement is bizarre can be helpful, but still must be considered thoughtfully since organic movement disorders can have endless variety. The diagnosis should rest on positive findings such as paroxysmal nature, maximal severity at or near onset, variability of tremor frequency, direction and amplitude, entrainment of tremor, distractability and suggestibility, and wildly swaying gait or balance problems without falls. Psychogenic parkinsonism often causes a problem because of the relatively high frequency of overlap of psychogenic and organic disease. In regard psychogenic parkinsonism, there are special features to look for. There might be tremor with kinetic movement as well as rest and posture, and finger tremor might be absent. With sequential movements, the sequence effect is typically lacking. Extreme slowness and grunting with great effort may be seen. Improvement of arm swing with running compared with walking, a feature of organic parkinsonism, might not be seen. 2.15.2 PSYCHOGENIC MOVEMENT DISORDERS (2) K. Kompoliti. Neurological Sciences, Rush University Medical Center, Chicago, IL, USA Psychogenic movement disorders (PMDs) are clinical syndromes presenting with various, often complex involuntary movements that cannot be attributed to any known structural or neurochemical disease but can be associated to an underlying psychiatric illness. They encompass the full range of abnormal involuntary movements, can affect gait and/or speech and can be associated with other somatizations. Most PMDs fulfill psychiatric criteria for a somatoform disorder, in most instances conversion or other somatization disorder. Occasionally they can be associated with a factitious disorder or malingering, although the latter is not considered a psychiatric diagnosis. PMDs can be disabling
Tuesday, 13 December 2011 / Parkinsonism and Related Disorders 18S2 (2012) S81–S159
2.14.3 NEURORESTORATIVE, NEUROPROTECTIVE AND CELL CYCLE ARREST ACTIVITY OF NOVEL MULTI TARGET DRUGS IN ANIMAL MODELS OF PARKINSON’S DISEASE M.B.H. Youdim1,2,3 . 1 Eve Topf Center of Excellence For Neurodegenerative Diseases, Technion-Rappaport Faculty of Medicine, Haifa, Israel; 2 Department of Biology, Yonsei World Central University, Seoul, Republic of Korea; 3 Varienl Inc., Delaware, PA, USA Parkinson’s disease (PD) is initiated by cascade of neurotoxic events, which includes oxidative stress, brain iron dysregulation, glutamate excitotoxicity, inflammatory process, neurotxic processing misfolding and aggregation of a-synuclein, resulting from the demise of ubiquitin-proteasome system (UPS). PD subjects are benefiting from drugs developed to act on a single molecular target. Such drugs have symptomatic activity and current pharmacological approaches are limited in their ability to modify the course of the disease.. However, the new therapeutic strategies for PD are those in which drug candidates are designed expressly to act on multiple neural and neurochemical targets involved in the neurodegenerative process. Thus we have developed brain permeable molecular entities, M30, M30P, HLA-20and HLA-20A that combine two or more of cholinesterase inhibitor, brain selective MAO inhibitor, and iron chelating-radical scavenging moieties and are inhibitors of glutamate toxicity and possess anti apoptotic and neurorestroative activity in post MPTP, lacatcystin and 6-OHDA treatment models. The neurorestorative activity of these drugs has been identified as being associated with neurogenesis and activation of HIF (hypoxia inducing factor), which regulates the neurotrophins BDNF, VEGF, erythropoeitin and induces cell cycle arrests, resulting in neuronal differentiation. These drugs are currently being developed as disease modifying agents for PD. 2.14.4 TRADITIONAL CHINESE HERBAL MEDICINE AND ELECTRO-ACUPUNCTURE X.M. Wang. Department of Physiology, Capital Medical University, Beijing, China Traditional Chinese medicine (TCM), including herbal formula and acupuncture, has been demonstrated as an alternative therapy for Parkinson’s disease (PD), and may provide unique strategies in combating it. In recent years, our group has explored a new herbal medicine, the extracts of traditional Chinese herb Tripterygium wilfordii Hook F (T10 ). T10 significantly improved the abnormal behaviors of PD rodents, which was critically related with its anti-inflammation effect. T10 inhibited the microglial activation, reduced the release of pro-inflammatory cytokines from microglia, and inhibited the expression of cyclooxygenase 2. In addition, T10 promoted the secretion of nerve growth factor from astrocytes, playing its neurotrophic role. Further studies showed that T10 inhibited the transcriptional activity of NF-úB, and downregulated the JNK phosphorylation in MAPK signal transduction pathway. Probably these above mechanisms contributed to the antiinflammation effect of T10 in PD therapy. Acupuncture is another focused approach for PD treatment. Studies have shown that electro-acupuncture (EA) was effective in alleviating abnormal motor symptoms in both PD patients and animal models. EA stimulation at a high frequency of 100 Hz significantly improved motor coordination and reduced apomorphine-induced rotational behaviors in the medial forebrain bundle (MFB) lesioned rat model. Nonetheless, the dopamine concentration in the striatum was not restored to the normal level. Instead, a decreased level of substance P and increased expression of glutamate decarboxylase-67 (GAD 67) was detected following EA stimulations In hemiparkinsonian rhesus monkeys with 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced rigidity, EA procedures did not adversely alter the animal’s locomotor activities; rather, parkinsonian animals showed a significant improvement
in movement speed; and EMG detected significant differences in muscle activity between the arms with and without MPTP-induced rigidity. The results also indicate that animals, especially those with parkinsonian-like symptoms, could benefit from long-term EA stimulations. Meanwhile, multi-channel single-unit electrode system was applied to record the neural activities at the primary motor cortex (MI) and the substantia nigra pars reticulata (SNr) in 6-OHDA lesioned rats. The further analyses with high-throughput gene expression microarray uncovered a number of potential targets in the cortex and the striatum after 4-week EA treatment. The results were in support of our conclusion that the recovery of homeostasis as reflected many regulated functional clusters of the transcript network may contribute and explain the behavioral changes in PD rats after EA treatments Acknowledgments: This work was supported by National Basic Research Program of China (2011CB504100), Key Program from Ministry of Science and Technology of China (2011ZX09102– 003–01), National Natural Science Foundation of China (81030062, 30973540, 81072858), and Key Program from Beijing Education Committee (kz200910025001). Video-Supported Session Psychogenic Movement Disorders Chairperson: Mark Hallett, Bethesda, USA
16:00–17:30
2.15.1 PSYCHOGENIC MOVEMENT DISORDERS (1) M. Hallett1 , W.J. Weiner2 , K. Kompoliti3 . 1 Human Motor Control Section, National Institute of Neurological Disorders and Stroke, Bethesda, 2 Neurology, University of Maryland School of Medicine, Baltimore, MD, 3 Neurology, Rush University Medical Center, Chicago, IL, USA Psychogenic movement disorders are common, but the diagnosis may be difficult. Visual appearance alone is typically not sufficient to make a diagnosis, but such information is certainly important. That a movement is bizarre can be helpful, but still must be considered thoughtfully since organic movement disorders can have endless variety. The diagnosis should rest on positive findings such as paroxysmal nature, maximal severity at or near onset, variability of tremor frequency, direction and amplitude, entrainment of tremor, distractability and suggestibility, and wildly swaying gait or balance problems without falls. Psychogenic parkinsonism often causes a problem because of the relatively high frequency of overlap of psychogenic and organic disease. In regard psychogenic parkinsonism, there are special features to look for. There might be tremor with kinetic movement as well as rest and posture, and finger tremor might be absent. With sequential movements, the sequence effect is typically lacking. Extreme slowness and grunting with great effort may be seen. Improvement of arm swing with running compared with walking, a feature of organic parkinsonism, might not be seen. 2.15.2 PSYCHOGENIC MOVEMENT DISORDERS (2) K. Kompoliti. Neurological Sciences, Rush University Medical Center, Chicago, IL, USA Psychogenic movement disorders (PMDs) are clinical syndromes presenting with various, often complex involuntary movements that cannot be attributed to any known structural or neurochemical disease but can be associated to an underlying psychiatric illness. They encompass the full range of abnormal involuntary movements, can affect gait and/or speech and can be associated with other somatizations. Most PMDs fulfill psychiatric criteria for a somatoform disorder, in most instances conversion or other somatization disorder. Occasionally they can be associated with a factitious disorder or malingering, although the latter is not considered a psychiatric diagnosis. PMDs can be disabling