Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects upper motor neurons (MNs) comprising the corticospinal tract and lower MNs arising from the brain stem nuclei and ventral roots of the spinal cord, leading to fatal paralysis. Currently, there are no effective therapies for ALS. Increasing evidence indicates that neuroinflammation plays an important role in ALS pathogenesis. The neuroinflammation in ALS is characterized by infiltration of lymphocytes and macrophages, activation of microglia and reactive astrocytes, as well as the involvement of complement. In this review, we focus on the key cellular players of neuroinflammation during the pathogenesis of ALS by discussing not only their detrimental roles but also their immunomodulatory actions. We will summarize the pharmacological therapies for ALS that target neuroinflammation, as well as recent advances in the field of stem cell therapy aimed at modulating the inflammatory environment to preserve the remaining MNs in ALS patients and animal models of the disease.
Highlights
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons (MNs) in the brain and spinal cord
The pathogenesis involved in MN death in ALS is complex, and neuroinflammation has been accepted as a key contributor to MN degeneration and disease progression
Several issues should be taken into consideration when designing therapeutic strategies targeting neuroinflammation in ALS
Summary
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons (MNs) in the brain and spinal cord. The expression level of P2X7 was increased in activated microglia from postmortem spinal cord of ALS patients [59], as well as in SOD1G93A mice [58]. Apolloni et al found that constitutive deletion of P2X7 receptor aggravated disease progression, exacerbated astrogliosis, microgliosis, and motoneuron loss, activated MAPKs pathway, as well as increased the release of proinflammatory markers such as nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) and inducible nitric oxide synthase in the lumbar spinal cord of end-stage (23 weeks of age) SOD1G93A mice [63] These studies demonstrated that only the administration of P2X7 antagonist, Brilliant Blue G, starting at late presymptomatic stage (100 days/14 weeks of age) significantly enhanced MN survival in lumbar spinal cord through reducing microgliosis and modulating the expression of inflammatory markers, accompanied by delayed onset and improved motor functions [64]. Another recent study has observed macrophage-mediated inflammation in the skeletal muscle of familial ALS rats [106], which might be another therapeutic target for novel treatment of ALS
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