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group_1_presentation_1_-_als [2019/02/01 16:54] chens60 [Glutamate Excitotoxicity] |
group_1_presentation_1_-_als [2019/02/01 21:26] (current) achunaia [Riluzole] |
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| - | <box 40% width centre|> {{ :alsneurons.png?nolink&400 |}}</box| Figure 1. Neuron.> | + | <box 40% width centre|> {{ :alsneurons.png?nolink&400 |}}</box| Figure 1. Motor Neuron.> |
| ====== What is Amyotrophic Lateral Sclerosis (ALS)? ====== | ====== What is Amyotrophic Lateral Sclerosis (ALS)? ====== | ||
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| ==== Impairment of Axonal Structure or Transport Defects ==== | ==== Impairment of Axonal Structure or Transport Defects ==== | ||
| - | Impairment of axonal transport and structure can be caused by many different pathways triggered by mutant SOD1. Mechanisms such as the lack of mitochondrial function, disruption of kinesin function, energy depletion, and excitotoxicity caused by glutamate, lead to the impairment of axonal transport/structure. Many experiments conducted on mice with mutant SOD1 displayed loss of defects in axonal transport in the early process of the disease. The impairment of the structure leads to build up of mitochondria, autophagosomes, and neurofilaments in the damaged motor neurons, which eventually causes the death of the neurons. | + | Impairment of axonal transport and structure can be caused by many different pathways triggered by mutant SOD1 (Zariei et al., 2015). Mechanisms such as the lack of mitochondrial function, disruption of kinesin function, energy depletion, and excitotoxicity caused by glutamate, lead to the impairment of axonal transport/structure (Zariei et al., 2015). Many experiments conducted on mice with mutant SOD1 displayed loss of defects in axonal transport in the early process of the disease. The impairment of the structure leads to build up of mitochondria, autophagosomes, and neurofilaments in the damaged motor neurons, which eventually causes the death of the neurons (Zariei et al., 2015). |
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| There is no distinct biological marker that is available for study in the diagnosis of ALS. Due to this, various medical and laboratory tests need to be completed to rule out other diseases that exhibit identical or similar symptoms (e.g. electrophysiological studies, neuroimaging studies, nerve conduction studies, etc.). The El Escorial criteria was typically used as the international standard of guidelines for diagnosing ALS. However, a conference held in April 1998 in Warrenton, Virginia by the World Federation of Neurology Research Committee on Motor Neuron Diseases. The figure below is an excerpt of the consensus document that was produced at the conference stating the following requirements for proper ALS diagnosis (Brooks et al., 2000). | There is no distinct biological marker that is available for study in the diagnosis of ALS. Due to this, various medical and laboratory tests need to be completed to rule out other diseases that exhibit identical or similar symptoms (e.g. electrophysiological studies, neuroimaging studies, nerve conduction studies, etc.). The El Escorial criteria was typically used as the international standard of guidelines for diagnosing ALS. However, a conference held in April 1998 in Warrenton, Virginia by the World Federation of Neurology Research Committee on Motor Neuron Diseases. The figure below is an excerpt of the consensus document that was produced at the conference stating the following requirements for proper ALS diagnosis (Brooks et al., 2000). | ||
| - | {{ :figure_aa.png?nolink&350 |}} | + | <box 40% width centre|> {{ :figure_aa.png?nolink&350 |}}</box| Figure 4. Requirements for ALS Diagnosis.> |
| Renamed as the Airlie House criteria in 1998 after the El Escorial was revised, these set of guidelines went under further revision to produce Awaji-Shima criteria. This was introduced in 2008, which requires clinical or electrophysiological evidence with more regional specifications (e.g. signs in bulbar, spinal regions etc.) to ensure that an accurate ALS diagnosis is being made. The table below compares the original 1994 El Escorial criteria with the revised 1998 Airlie House (incorporated with the 2008 Awaji-Shima criteria) to demonstrate how there has been an increase in the specificity of diagnosing ALS. (Source: Hardiman et al., 2011) | Renamed as the Airlie House criteria in 1998 after the El Escorial was revised, these set of guidelines went under further revision to produce Awaji-Shima criteria. This was introduced in 2008, which requires clinical or electrophysiological evidence with more regional specifications (e.g. signs in bulbar, spinal regions etc.) to ensure that an accurate ALS diagnosis is being made. The table below compares the original 1994 El Escorial criteria with the revised 1998 Airlie House (incorporated with the 2008 Awaji-Shima criteria) to demonstrate how there has been an increase in the specificity of diagnosing ALS. (Source: Hardiman et al., 2011) | ||
| - | {{ :figure_cc.png?nolink&660 |}} | + | <box 60% width centre|> {{ :figure_cc.png?nolink&660 |}}</box| Figure 5. Criteria for diagnosis of ALS.> |
| ==== Potential ALS Biomarkers in Research ==== | ==== Potential ALS Biomarkers in Research ==== | ||
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| ==== Riluzole ==== | ==== Riluzole ==== | ||
| Riluzole is the main drug that is utilized for treating ALS. Riluzole specifically works in blocking the release of glutamate from one neuron to the next as shown in the figure below (Rothstein, 1996). Glutamate is the neurotransmitter that is used for majority of the excitatory functions in the brain. Many of the functions of glutamate include increase cell membrane permeability, and activating cell surface receptors (Stephen et al., 2010). However, when there is an excessive release of glutamate it can result in excitotoxicity due to the large influx of calcium in the the neuron (Lewerenz & Maher, 2015). Motor neurons specifically are more sensitive to calcium release, as a result, causing neuron death. Hence, Riluzole inhibits the release of glutamate from the presynaptic neuron, stopping the influx of calcium into the neuron (Rothstein, 1996). Riluzole is not a cure to ALS, however, the drug can help prolong life by delaying the onset of muscle weakness and paralysis. This would also include the reduction of the reliance of patients to tracheostomy, which is a procedure in which an incision is created in a patients neck to place a tube in, as an alternative method of breathing (Bryson, Fulton & Benfield, 1996). | Riluzole is the main drug that is utilized for treating ALS. Riluzole specifically works in blocking the release of glutamate from one neuron to the next as shown in the figure below (Rothstein, 1996). Glutamate is the neurotransmitter that is used for majority of the excitatory functions in the brain. Many of the functions of glutamate include increase cell membrane permeability, and activating cell surface receptors (Stephen et al., 2010). However, when there is an excessive release of glutamate it can result in excitotoxicity due to the large influx of calcium in the the neuron (Lewerenz & Maher, 2015). Motor neurons specifically are more sensitive to calcium release, as a result, causing neuron death. Hence, Riluzole inhibits the release of glutamate from the presynaptic neuron, stopping the influx of calcium into the neuron (Rothstein, 1996). Riluzole is not a cure to ALS, however, the drug can help prolong life by delaying the onset of muscle weakness and paralysis. This would also include the reduction of the reliance of patients to tracheostomy, which is a procedure in which an incision is created in a patients neck to place a tube in, as an alternative method of breathing (Bryson, Fulton & Benfield, 1996). | ||
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| - | {{ :playground:advancedriluzole.png?400 |}} | + | |
| + | <box 40% width centre|> {{ :playground:advancedriluzole.png?400 |}}</box| Figure 6. The mechanism of Riluzole.> | ||
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| One potential treatment that is currently being studied in mice is associated with stem cell therapy. Kondo et al. (2014), transplanted glial-rich neural progenitors from human induced pluripotent cells into the lumbar spinal cord of mice with ALS. These diseased mice had mutant superoxide dismutase 1 (SOD1) enzymes that promotes ALS development and the loss of function in motor neurons. After transplantation with hiPSCs, the cells were able to differentiate into astrocytes resulting in an increased life span. Researchers further explains that this therapy is beneficial because the AKT signaling pathway in astrocytes is activated which promotes the survival of cells in ALS. This is because it replaces mutated ALS astrocytes, which originally mediates the accumulation of glutamate and ultimately cell death (Pehar, Harlan, Killoy, & Vargas, 2018). Kondo et al. (2014), explains that although this experiment only shows an improvement in the motor abilities of the lower limb, there is a possibility of targeting different areas of the spinal cord to treat different symptoms (Kondo et al., 2014). | One potential treatment that is currently being studied in mice is associated with stem cell therapy. Kondo et al. (2014), transplanted glial-rich neural progenitors from human induced pluripotent cells into the lumbar spinal cord of mice with ALS. These diseased mice had mutant superoxide dismutase 1 (SOD1) enzymes that promotes ALS development and the loss of function in motor neurons. After transplantation with hiPSCs, the cells were able to differentiate into astrocytes resulting in an increased life span. Researchers further explains that this therapy is beneficial because the AKT signaling pathway in astrocytes is activated which promotes the survival of cells in ALS. This is because it replaces mutated ALS astrocytes, which originally mediates the accumulation of glutamate and ultimately cell death (Pehar, Harlan, Killoy, & Vargas, 2018). Kondo et al. (2014), explains that although this experiment only shows an improvement in the motor abilities of the lower limb, there is a possibility of targeting different areas of the spinal cord to treat different symptoms (Kondo et al., 2014). | ||
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| + | <box 80% width centre|> {{ :stem_cell_report_photo.jpg?730 |}}</box| Figure 7. Article exploring the use of stem cells in ALS treatment.> | ||
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| ==== CuATSM ==== | ==== CuATSM ==== | ||
| Treatment with a drug called diacetylbis(N(4)-methylthiosemicarbazonato) copper II (CuATSM) has the potential to reduce the symptoms, and slow the advancement of familial ALS. The role of this drug is to penetrate the blood-brain barrier and deliver copper to body cells that are copper deficient (Irving, 2019). According to ALS Therapy Development Institute (2016), this is significant as these cells are able to use copper to prevent the misfolding of proteins that causes ALS (ALS Therapy Development Institute, 2016). According to Xia (n.d.), In humans it is specifically to prevent the misfolding of the SOD1 protein which would affect motor neurons by causing endoplasmic reticulum, proteasome, and mitochondrial stress that influences cell death (Xia, n.d.). Furthermore, mutated SOD1 modifies many cellular pathways and functions including axonal transport, RNA processing, etc. which leads to muscle atrophy (Xia, n.d.). Carvalho (2019), concluded that CuATSM improves lung and cognitive function during Phase 1 human clinical trials (Carvalho, 2019). This was measured using the forced vital capacity and Edinburgh cognitive and behavioural ALS Screen (ECAS) scoring system (Carvalho, 2019). Patients with lower doses of CuATSM experienced minor improvements in these scores over 24 weeks compared to those with higher doses (Carvalho, 2019). Phase 2 clinical trials will be held in 2019 to confirm its impact on biological activities using larger and randomized sample sizes, implementing placebo controls, and using a double-blind experiment (Irving, 2019). | Treatment with a drug called diacetylbis(N(4)-methylthiosemicarbazonato) copper II (CuATSM) has the potential to reduce the symptoms, and slow the advancement of familial ALS. The role of this drug is to penetrate the blood-brain barrier and deliver copper to body cells that are copper deficient (Irving, 2019). According to ALS Therapy Development Institute (2016), this is significant as these cells are able to use copper to prevent the misfolding of proteins that causes ALS (ALS Therapy Development Institute, 2016). According to Xia (n.d.), In humans it is specifically to prevent the misfolding of the SOD1 protein which would affect motor neurons by causing endoplasmic reticulum, proteasome, and mitochondrial stress that influences cell death (Xia, n.d.). Furthermore, mutated SOD1 modifies many cellular pathways and functions including axonal transport, RNA processing, etc. which leads to muscle atrophy (Xia, n.d.). Carvalho (2019), concluded that CuATSM improves lung and cognitive function during Phase 1 human clinical trials (Carvalho, 2019). This was measured using the forced vital capacity and Edinburgh cognitive and behavioural ALS Screen (ECAS) scoring system (Carvalho, 2019). Patients with lower doses of CuATSM experienced minor improvements in these scores over 24 weeks compared to those with higher doses (Carvalho, 2019). Phase 2 clinical trials will be held in 2019 to confirm its impact on biological activities using larger and randomized sample sizes, implementing placebo controls, and using a double-blind experiment (Irving, 2019). | ||
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| + | <box 30% width centre|> {{ :cuatsm.png?300 |}}</box| Figure 8. Structure of CuATSM.> | ||
| ====== ALS PowerPoint ====== | ====== ALS PowerPoint ====== | ||
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| Bogdanov, M., Brown Jr, R. H., Matson, W., Smart, R., Hayden, D., O’Donnell, H., ... & Cudkowicz, M. (2000). Increased oxidative damage to DNA in ALS patients. Free Radical Biology and Medicine, 29(7), 652-658. | Bogdanov, M., Brown Jr, R. H., Matson, W., Smart, R., Hayden, D., O’Donnell, H., ... & Cudkowicz, M. (2000). Increased oxidative damage to DNA in ALS patients. Free Radical Biology and Medicine, 29(7), 652-658. | ||
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| + | Bryson, H. M., Fulton, B., & Benfield, P. (1996). Riluzole. Drugs, 52(4), 549–563. https://doi.org/10.2165/00003495-199652040-00010 | ||
| Brooks, B. R., Miller, R. G., Swash, M., & Munsat, T. L. (2000). El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis and other motor neuron disorders, 1(5), 293-299. | Brooks, B. R., Miller, R. G., Swash, M., & Munsat, T. L. (2000). El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis and other motor neuron disorders, 1(5), 293-299. | ||
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| Learning, L. (n.d.). Biology for Majors I. Retrieved from https://courses.lumenlearning.com/wm-biology1/chapter/reading- electron-transport-chain/ | Learning, L. (n.d.). Biology for Majors I. Retrieved from https://courses.lumenlearning.com/wm-biology1/chapter/reading- electron-transport-chain/ | ||
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| + | Lewerenz, J., & Maher, P. (2015). Chronic Glutamate Toxicity in Neurodegenerative Diseases—What is the Evidence? Frontiers in Neuroscience, 9. https://doi.org/10.3389/fnins.2015.00469 | ||
| Mitsumoto, H. (1997). Diagnosis and progression of ALS. Neurology, 48(4 Suppl 4), 2S-8S. | Mitsumoto, H. (1997). Diagnosis and progression of ALS. Neurology, 48(4 Suppl 4), 2S-8S. | ||
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| Riluzole Oral : Uses, Side Effects, Interactions, Pictures, Warnings & Dosing - WebMD. (n.d.). Retrieved from | Riluzole Oral : Uses, Side Effects, Interactions, Pictures, Warnings & Dosing - WebMD. (n.d.). Retrieved from | ||
| https://www.webmd.com/drugs/2/drug-12138/riluzole-oral/details | https://www.webmd.com/drugs/2/drug-12138/riluzole-oral/details | ||
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| + | Rothstein, J. D. (1996). Therapeutic horizons for amyotrophic lateral sclerosis. Current Opinion in Neurobiology, 6(5), 679–687. https://doi.org/10.1016/S0959-4388(96)80103-6 | ||
| Seals, R. M., Hansen, J., Gredal, O., & Weisskopf, M. G. (2016). Physical Trauma and Amyotrophic Lateral Sclerosis: A Population-Based Study Using Danish National Registries. //American Journal of Epidemiology,183//(4), 294-301. doi:10.1093/aje/kwv169 | Seals, R. M., Hansen, J., Gredal, O., & Weisskopf, M. G. (2016). Physical Trauma and Amyotrophic Lateral Sclerosis: A Population-Based Study Using Danish National Registries. //American Journal of Epidemiology,183//(4), 294-301. doi:10.1093/aje/kwv169 | ||
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| Swash, M. (2018). Physical activity as a risk factor in ALS. //Journal of Neurology, Neurosurgery & Psychiatry,89//(8), 793-793. doi:10.1136/jnnp-2018-318147 | Swash, M. (2018). Physical activity as a risk factor in ALS. //Journal of Neurology, Neurosurgery & Psychiatry,89//(8), 793-793. doi:10.1136/jnnp-2018-318147 | ||
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| + | Traynelis, S. F., Wollmuth, L. P., McBain, C. J., Menniti, F. S., Vance, K. M., Ogden, K. K., … Dingledine, R. (2010). Glutamate Receptor Ion Channels: Structure, Regulation, and Function. Pharmacological Reviews, 62(3), 405–496. https://doi.org/10.1124/pr.109.002451 | ||
| What is ALS? - ALS Society of Canada. (n.d.). Retrieved from https://www.als.ca/about-als/what-is-als/ | What is ALS? - ALS Society of Canada. (n.d.). Retrieved from https://www.als.ca/about-als/what-is-als/ | ||
