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

Abstract

BackgroundHallmarks 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 (SOD1G93A). 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. SOD1G93A mice were treated with saline, free methylprednisolone (MP, 10 mg/kg/week) or glutathione PEGylated liposomal MP (2B3-201, 10 mg/kg/week) and compared to saline treated wild-type animals. Animals were treated weekly with intravenous injections for 9 weeks from 60 days of age. Weights and motor performance were monitored during this period. At the end of the experimental period (116 days) mice were imaged using T2-weighted MRI for brainstem pathology; brain and spinal cord tissue were then collected for histological analysis.ResultsAll SOD1G93A groups showed a significant decrease in motor performance, compared to baseline, from ~100 days. SOD1G93A animals showed a significant increase in signal intensity on T2 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 T2 hyperintensity observed in SOD1G93A mice. Compared to saline-treated and free-MP-treated SOD1G93A mice, those animals given 2B3-201 displayed significantly improved histopathological outcomes in brainstem motor nuclei, which included reduced gliosis and neuronal loss.ConclusionsIn 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 SOD1G93A 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.

Characterization of human iPSC-derived astrocytes with potential for disease modeling and drug discovery

“…where an abnormal activation of astrocytes was initially suggested from the analysis of postmortem tissues, cerebrospinal fluids and blood samples from ALS patients [Schiffer et al, 1996;Anneser et al, 2004;Baron et al, 2005;Poloni et al, 2000]. In agreement with these observations, marked neuroinflammation was observed in the spinal cord and cranial motor nuclei of ALS transgenic mouse models [Schiffer et al, 1996;Ferraiuolo et al, 2007;Evans et al, 2014].…”

“…Astrocyte reactivation is a common event in virtually all neurological diseases [Li et al, 2019;Liddelow and Barres, 2017;Siracusa et al, 2019;Yamanaka and Komine, 2018]. For instance, hallmarks of astrocyte activation feature prominently in post-mortem tissues from amyotrophic lateral sclerosis (ALS) patients, as well as in the spinal cord and cranial motor nuclei in ALS transgenic mouse models [Anneser et al, 2004;Baron et al, 2005;Evans et al, 2014;Ferraiuolo et al, 2007;Poloni et al, 2000;Schiffer et al, 1996]. More importantly, increasing evidence suggests that reactive astrocytes contribute directly to the degeneration of motor circuits in ALS animal models by promoting non-cell autonomous mechanisms of motor neuron degeneration [Diaz-Amarilla et al, 2011;Ferraiuolo, 2014;Haidet-Phillips et al, 2011;Ouali Alami et al, 2018;Radford et al, 2015;Yamanaka and Komine, 2018].…”

Treatment with penicillin G and hydrocortisone reduces ALS-associated symptoms: a case series of three patients

“…https://www.medicines.org.uk/emc/medicine/10815, accessed July 27, 2016). Furthermore, glucocorticoids have been found to be efficacious in preclinical models of ALS 16 .…”

Syphilis may be a confounding factor, not a causative agent, in syphilitic ALS

“…Furthermore, hydrocortisone has been reported to affect the GABAergic system 10 , the GABAergic system has been reported to affect the release of cortisone, the natural form of hydrocortisone 11 . and glucocorticoids have been shown to be efficacious in preclinical models for ALS 12 .…”