CNS-targeted glucocorticoid reduces pathology in mouse model of amyotrophic lateral sclerosis

Abstract

Background: Hallmarks of CNS inflammation, including microglial and astrocyte activation, are prominent features in post-mortem tissue from amyotrophic lateral sclerosis (ALS) patients and in mice overexpressing mutant superoxide dismutase-1 (SOD1 G93A). Administration of non-targeted glucocorticoids does not significantly alter disease progression, but this may reflect poor CNS delivery. Here, we sought to discover whether CNS-targeted, liposomal encapsulated glucocorticoid would inhibit the CNS inflammatory response and reduce motor neuron loss. SOD1 G93A mice were treated with saline, free methylprednisolone (MP, 10mg/kg/week) or glutathione PEGylated liposomal MP (2B3-201, 10mg/kg/week) and compared to saline treated wild-type animals. Animals were treated weekly with intravenous injections for 9weeks from 60days of age. Weights and motor performance were monitored during this period. At the end of the experimental period (116days) mice were imaged using T 2-weighted MRI for brainstem pathology; brain and spinal cord tissue were then collected for histological analysis. Results: All SOD1 G93A groups showed a significant decrease in motor performance, compared to baseline, from ~100days. SOD1 G93A animals showed a significant increase in signal intensity on T 2 weighted MR images, which may reflect the combination of neuronal vacuolation and glial activation in these motor nuclei. Treatment with 2B3-201, but not free MP, significantly reduced T 2 hyperintensity observed in SOD1 G93A mice. Compared to saline-treated and free-MP-treated SOD1 G93A mice, those animals given 2B3-201 displayed significantly improved histopathological outcomes in brainstem motor nuclei, which included reduced gliosis and neuronal loss. Conclusions: In contrast to previous reports that employed free steroid preparations, CNS-targeted anti-inflammatory agent 2B3-201 (liposomal methylprednisolone) has therapeutic potential, reducing brainstem pathology in the SOD1 G93A mouse model of ALS. 2B3-201 reduced neuronal loss and vacuolation in brainstem nuclei, and reduced activation preferentially in astrocytes compared with microglia. These data also suggest that other previously ineffective therapies could be of therapeutic value if delivered specifically to the CNS.