scholarly journals Adipose-derived Stem Cell Conditioned Media Extends Survival time of a mouse model of Amyotrophic Lateral Sclerosis

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Christine V. Fontanilla ◽  
Huiying Gu ◽  
Qingpeng Liu ◽  
Timothy Z. Zhu ◽  
Changwei Zhou ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Mouse Model ◽  
Survival Time ◽  
Neuronal Death ◽  
Immunohistochemical Analysis ◽  
Mitogen Activated Protein Kinase ◽  
Trophic Factors ◽  
Mitogen Activated Protein ◽  
Adipose Derived Stem Cell ◽  
Lateral Sclerosis

Abstract Adipose stromal cells (ASC) secrete various trophic factors that assist in the protection of neurons in a variety of neuronal death models. In this study, we tested the effects of human ASC conditional medium (ASC-CM) in human amyotrophic lateral sclerosis (ALS) transgenic mouse model expressing mutant superoxide dismutase (SOD1G93A). Treating symptomatic SOD1G93A mice with ASC-CM significantly increased post-onset survival time and lifespan. Moreover, SOD1G93A mice given ASC-CM treatment showed high motor neuron counts, less activation of microglia and astrocytes at an early symptomatic stage in the spinal cords under immunohistochemical analysis. SOD1G93A mice treated with ASC-CM for 7 days showed reduced levels of phosphorylated p38 (pp38) in the spinal cord, a mitogen-activated protein kinase that is involved in both inflammation and neuronal death. Additionally, the levels of α-II spectrin in spinal cords were also inhibited in SOD1G93A mice treated with ASC-CM for 3 days. Interestingly, nerve growth factor (NGF), a neurotrophic factor found in ASC-CM, played a significant role in the protection of neurodegeneration inSOD1G93A mouse. These results indicate that ASC-CM has the potential to develop into a novel and effective therapeutic treatment for ALS.

scholarly journals Mitogen-Activated Protein Kinase Pathway in Amyotrophic Lateral Sclerosis

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 969
Author(s):  
TG Sahana ◽  
Ke Zhang
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Protein Kinase ◽  
Mapk Pathway ◽  
Signal Transduction Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Spinal Cord Tissue ◽  
Disease Manifestation ◽  
Drug Candidates ◽  
Mitogen Activated Protein ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis is a fatal motor neuron degenerative disease. Multiple genetic and non-genetic risk factors are associated with disease pathogenesis, and several cellular processes, including protein homeostasis, RNA metabolism, vesicle transport, etc., are severely impaired in ALS conditions. Despite the heterogeneity of the disease manifestation and progression, ALS patients show protein aggregates in the motor cortex and spinal cord tissue, which is believed to be at least partially caused by aberrant phase separation and the formation of persistent stress granules. Consistent with this notion, many studies have implicated cellular stress, such as ER stress, DNA damage, oxidative stress, and growth factor depletion, in ALS conditions. The mitogen-activated protein kinase (MAPK) pathway is a fundamental mitogen/stress-activated signal transduction pathway that regulates cell proliferation, differentiation, survival, and death. Here we summarize the fundamental role of MAPK in physiology and ALS pathogenesis. We also discuss pharmacological inhibitors targeting this pathway tested in pre-clinical models, suggesting their role as potential drug candidates.

Understanding correlation of abnormal c-JNK/p38MAPK signaling in amyotrophic lateral sclerosis: Potential drug targets and influences on neurological disorders

2021 ◽  
Vol 20 ◽  
Author(s):  
Rajeshwar Kumar Yadav ◽  
Elizabeth Minj ◽  
Sidharth Mehan
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Diseases ◽  
Motor Neuron ◽  
Drug Targets ◽  
Management Strategies ◽  
Mitogen Activated Protein Kinase ◽  
Glutamate Excitotoxicity ◽  
Mitogen Activated Protein ◽  
P38mapk Signaling ◽  
Lateral Sclerosis

: c-JNK (c-Jun N-terminal kinase) and p38 mitogen-activated protein kinase (MAPK) family members work in a cell-specific manner to incorporate neuronal signals that cause glutamate excitotoxicity, impaired protein homeostasis, defective axonal transport, and synaptic dysfunctions. Consistent with the importance of these cellular events in the up-regulation of c-JNK/p38MAPK signaling is associated with neurodegenerative diseases in various clinical and pre-clinical studies. Exceptionally, a large number of experimental evidence has recently shown that c-JNK/p38MAPK has also been involved in the development of the central nervous system in a variety of neuropathological conditions, including amyotrophic lateral sclerosis (ALS). Overall, the currently available information has shown that c-JNK/p38MAPK signaling inhibitors can be a promising therapeutic solution for modifying histopathological, functional, and demyelination defects associated with motor neuron disabilities. Understanding the correlation between c-JNK/p38MAPK signaling and prediction of motor neuron degradation can help identify significant therapeutic measures that may avoid neuro complications. Therefore, in the current study, we explore the manifestations of disease utilizing the c-JNK/p38MAPK upregulation that could potentially cause ALS and other neurodegenerative diseases, as well as providing data on pre-clinical trials, accessible and successful drug treatment, and disease management strategies.

Life span extension and reduced neuronal death after weekly intraventricular cyclosporin injections in the G93A transgenic mouse model of amyotrophic lateral sclerosis

2004 ◽  
Vol 101 (1) ◽  
pp. 128-137 ◽  
Author(s):  
Jenny Karlsson ◽  
Keith S. K. Fong ◽  
Magnus J. Hansson ◽  
Eskil Elmàr ◽  
Katalin Csiszar ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Mouse Model ◽  
Life Span ◽  
Transgenic Mouse ◽  
Physical Performance ◽  
Neuronal Death ◽  
Transgenic Mouse Model ◽  
Content Type ◽  
Lateral Sclerosis ◽  
Fine Print

Object. The authors investigated whether cyclosporin A (CsA), a cyclophilin ligand with mitochondrial permeability transition pore-blocking and calcineurin-inhibiting properties, affects motor function, neuronal death, and life span in the G93A transgenic mouse model of familial amyotrophic lateral sclerosis (FALS). Methods. The G93A mice received weekly intracerebroventricular injections of CsA (20 µg/mouse/week) starting at the age of 65 days, and physical performance on an exercise wheel was monitored beginning at 84 days of age. Mice were allowed to survive for clinical observation of body weight, hindlimb weakness, and life span or until a defined end stage or were killed at 110 days of age for histological analysis. Conclusions. Treatment with CsA significantly delayed the onset of hindlimb weakness and also extended the time from its onset to paralysis. The overall life span of CsA-treated G93A mice was significantly extended, by 12% compared with vehicle-treated transgenic littermates. The CsA also prolonged physical performance on the exercise wheel and delayed weight loss. Histologically, there was significant preservation of both cervical and lumbar spine motor neurons and also tyrosine hydroxylase—positive dopaminergic substantia nigra neurons in 110-day-old CsA-treated mice compared with their transgenic littermates. The local administration of CsA directly into the brain ventricles is an effective means of central nervous system drug delivery (because CsA does not readily cross the blood—brain barrier), which in this study ameliorated clinical and neuropathological features of FALS in G93A mice. The remarkably low intrathecal CsA dose required for neuroprotection reduces potential adverse effects of systemic immunosuppression or nephrotoxicity seen with chronic systemic delivery of the drug.

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