Mechanisms underlying inflammation in neurodegeneration.

Dominant mutations in superoxide dismutase cause amyotrophic lateral sclerosis (ALS), a progressive paralytic disease characterized by loss of motor neurons. With the use of mice carrying a deletable mutant gene, expression within motor neurons was shown to be a primary determinant of disease onset and of an early phase of disease progression. Diminishing the mutant levels in microglia had little effect on the early disease phase but sharply slowed later disease progression. Onset and progression thus represent distinct disease phases defined by mutant action within different cell types to generate non-cell-autonomous killing of motor neurons; these findings validate therapies, including cell replacement, targeted to the non-neuronal cells.

https://science.sciencemag.org/content/sci/312/5778/1389.full.pdf

Onset and Progression in Inherited ALS Determined by Motor Neurons and Microglia

ALS: a disease of motor neurons and their nonneuronal neighbors.

Although Charcot described amyotrophic lateral sclerosis (ALS) more than 130 years ago, the mechanism underlying the characteristic selective degeneration and death of motor neurons in this common adult motor neuron disease has remained a mystery. There is no effective remedy for this progressive, fatal disorder. Modern genetics has now identified mutations in one gene [Cu/Zn superoxide dismutase (SOD1)] as a primary cause and implicated others [encoding neurofilaments, cytoplasmic dynein and its processivity factor dynactin, and vascular endothelial growth factor (VEGF)] as contributors to, or causes of, motor neuron diseases. These insights have enabled development of model systems to test hypotheses of disease mechanism and potential therapies. Along with errors in the handling of synaptic glutamate and the potential excitotoxic response this provokes, these model systems highlight the involvement of nonneuronal cells in disease progression and provide new therapeutic strategies.

/pdf/unraveling-the-mechanisms-involved-in-motor-neuron-3p76wp4vdw.pdf

Unraveling the mechanisms involved in motor neuron degeneration in ALS.

The most common inherited [correct] form of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting adult motor neurons, is caused by dominant mutations in the ubiquitously expressed Cu-Zn superoxide dismutase (SOD1) In chimeric mice that are mixtures of normal and SOD1 mutant-expressing cells, toxicity to motor neurons is shown to require damage from mutant SOD1 acting within nonneuronal cells Normal motor neurons in SOD1 mutant chimeras develop aspects of ALS pathology Most important, nonneuronal cells that do not express mutant SOD1 delay degeneration and significantly extend survival of mutant-expressing motor neurons

https://science.sciencemag.org/content/sci/302/5642/113.full.pdf

Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice.

Minocycline Slows Disease Progression in a Mouse Model of Amyotrophic Lateral Sclerosis

There is currently no effective pharmacological treatment for amyotrophic lateral sclerosis (ALS). Because evidence suggests that multiple pathways may contribute to ALS pathogenesis, we tested in a mouse model of ALS (SOD1(G37R) mice) a combination approach consisting of three drugs for distinct targets in the complex pathway to neuronal death: minocycline, an antimicrobial agent that inhibits microglial activation, riluzole, a glutamate antagonist, and nimodipine, a voltage-gated calcium channel blocker. The efficacy of this three-drug cocktail was remarkable when administered in the diet from late presymptomatic stage (8-9 months). It delayed the onset of disease, slowed the loss of muscle strength, and increased the average longevity of SOD1(G37R) mice by 6 weeks. The protective effect of the treatment was corroborated by the reduced immunodetection signals for markers of gliosis and neurodegeneration in the spinal cord of SOD1(G37R) mice. These results indicate that such three-drug combination may represent an effective strategy for ALS treatment.

Efficient three‐drug cocktail for disease induced by mutant superoxide dismutase

Pathways to motor neuron degeneration in transgenic mouse models.

The present invention relates to a method for reducing symptoms related to stroke, this therapy comprising the administration of a therapeutically effective amount of at least two compounds selected from the group of an inhibitor of microglial activation, an antiglutaminergic agent and a voltage gated calcium channel blocker to a patient suffering from a neurodegenerative disease. The present invention also relates to a composition for reducing symptoms related to stroke, comprising a therapeutically effective amount of at least two compounds selected from the group of an inhibitor of microglial activation, an antiglutaminergic agent and a voltage gated calcium channel blocker in association with a pharmaceutically acceptable carrier.

Therapy for stroke

The present invention relates to a method for reducing symptoms related to a neurodegenerative disease and/or treating a neurodegenerative disease, this therapy comprising the administration of a therapeutically effective amount of at least two compounds selected from the group of an inhibitor of microglial activation, an antiglutominergic agent and a voltage gated calcium channer blocker to a patient suffering from a neurodegenerative disease. The present invention also relates to a composition for reducing symptoms related to a neurodegenerative disease and/or treating a neurodegenerative disease, comprising a therapeutically effective amount of at least two compounds selected from the group of an inhibitor of microglial activation, an antiglutaminergic agent and a voltage gated calcium channel blocker in association with a pharmaceutically acceptable carrier.

Jasna Kriz

Papers

Minocycline Slows Disease Progression in a Mouse Model of Amyotrophic Lateral Sclerosis

Efficient three‐drug cocktail for disease induced by mutant superoxide dismutase

Pathways to motor neuron degeneration in transgenic mouse models.

Therapy for stroke

Therapy for neurodegenerative diseases