Differences
This shows you the differences between two versions of the page.
| Both sides previous revision Previous revision Next revision | Previous revision | ||
|
group_1_presentation_1_-_als [2019/02/01 16:51] chens60 [Amyotrophic Lateral Sclerosis (ALS)] |
group_1_presentation_1_-_als [2019/02/01 21:26] (current) achunaia [Riluzole] |
||
|---|---|---|---|
| Line 2: | Line 2: | ||
| - | <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)? ====== | ||
| Line 37: | Line 37: | ||
| ("What is ALS? - ALS Society of Canada," n.d.) | ("What is ALS? - ALS Society of Canada," n.d.) | ||
| - | {{ :als_in_hospital.jpg?500 |}} | + | <box 45% width centre|> {{ :als_in_hospital.jpg?500 |}}</box| Figure 2. ALS patient in hospital.> |
| Line 72: | Line 73: | ||
| Glutamate is a neurotransmitter that plays a major role in the neurotransmission process. Glutamate is made in the presynaptic terminal and released into the synaptic cleft (Zariei et al., 2015). It travels through the cleft to activate the postsynaptic receptors. Once the postsynaptic receptors have been activated, the glutamate neurotransmitter is removed using the excitatory amino acid transporters (EAATs) (Zariei et al., 2015). The picture on the right side displays the maintenance of glutamate molecules through the use of healthy EAATs. The picture on the left shows the absences of EAATs in an individual with ALS and the accumulation of Glutamate. This continuous cycle of release and elimination of glutamate is important in maintaining a gradient and avoiding excitotoxic neuronal damage (Zariei et al., 2015). Researchers have observed a decrease in function of the EEATs in ALS patients and transgenic SOD1 mouse models (Zariei et al., 2015). This is extremely harmful as it increases the amount of glutamate present in the synaptic cleft, which causes over-stimulation of the glutamate receptors. The over-stimulation leads to excitotoxicity and neuronal degeneration (Zariei et al., 2015). | Glutamate is a neurotransmitter that plays a major role in the neurotransmission process. Glutamate is made in the presynaptic terminal and released into the synaptic cleft (Zariei et al., 2015). It travels through the cleft to activate the postsynaptic receptors. Once the postsynaptic receptors have been activated, the glutamate neurotransmitter is removed using the excitatory amino acid transporters (EAATs) (Zariei et al., 2015). The picture on the right side displays the maintenance of glutamate molecules through the use of healthy EAATs. The picture on the left shows the absences of EAATs in an individual with ALS and the accumulation of Glutamate. This continuous cycle of release and elimination of glutamate is important in maintaining a gradient and avoiding excitotoxic neuronal damage (Zariei et al., 2015). Researchers have observed a decrease in function of the EEATs in ALS patients and transgenic SOD1 mouse models (Zariei et al., 2015). This is extremely harmful as it increases the amount of glutamate present in the synaptic cleft, which causes over-stimulation of the glutamate receptors. The over-stimulation leads to excitotoxicity and neuronal degeneration (Zariei et al., 2015). | ||
| - | {{ :als.png?nolink&550 |}} | + | <box 50% width centre|> {{ :als.png?nolink&550 |}}</box| Figure 3. Mechanism of glutamate excitotoxicity.> |
| ==== 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). |
| Line 85: | Line 85: | ||
| 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 ==== | ||
| Line 115: | Line 117: | ||
| ==== 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). | ||
| - | + | | |
| - | {{ :playground:advancedriluzole.png?400 |}} | + | |
| + | <box 40% width centre|> {{ :playground:advancedriluzole.png?400 |}}</box| Figure 6. The mechanism of Riluzole.> | ||
| Line 126: | Line 129: | ||
| 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). | ||
| + | |||
| + | |||
| + | <box 80% width centre|> {{ :stem_cell_report_photo.jpg?730 |}}</box| Figure 7. Article exploring the use of stem cells in ALS treatment.> | ||
| + | |||
| + | |||
| + | |||
| ==== 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). | ||
| + | |||
| + | <box 30% width centre|> {{ :cuatsm.png?300 |}}</box| Figure 8. Structure of CuATSM.> | ||
| ====== ALS PowerPoint ====== | ====== ALS PowerPoint ====== | ||
| Line 150: | Line 161: | ||
| 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. | ||
| + | |||
| + | 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. | ||
| Line 180: | Line 193: | ||
| 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/ | ||
| + | |||
| + | 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. | ||
| Line 188: | Line 203: | ||
| 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 | ||
| + | |||
| + | 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 | ||
| Line 195: | Line 212: | ||
| 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 | ||
| + | |||
| + | 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/ | ||
