Linh Thuy Luong

Background:  Amyotrophic lateral sclerosis (ALS) is a multifaceted neurodegenerative disease involving neuroinflammation, immune cell destruction, and oxidative stress that damages upper and lower motor neurons and their proximal astrocytes and microglia.^1,2 Glucocorticoids have thus been looked into as a therapy for neuroinflammatory modulation. Glucocorticoid receptor modulators (GRMs) have been exploited as adjunctive treatments for other inflammatory neurologic and neuromuscular disorders such as Duchenne muscular dystrophy and Alzheimer’s disease;^3,4 however, when used in the context of ALS, chronic stress and sustained glucocorticoid elevation create a proinflammatory environment.^4,5 This paradoxical effect may occur because prolonged exposure to glucocorticoids leads to resistance of the HPA axis to glucocorticoid-mediated feedback inhibition and reactive downregulation of glucocorticoid levels.^6,7 These pitfalls need to be addressed for future glucocorticoid receptor-targeted therapies.

Objective:  Selective glucocorticoid receptor modulators (SGRMs) may present a solution to the proinflammatory effects seen during chronic GRM administration. In this review, we explored the effects of glucocorticoids during neuroinflammation and assessed the results of long-term administration of SGRMs in ALS models.

Search Methods:  An online search was conducted in the PubMed database from 2020-2026 using the following search terms: “selective glucocorticoid receptor modulation”, “amyotrophic lateral sclerosis”, “ALS inflammasome”, and “ALS neuroinflammation”.

Results:  Studies have shown upregulation of NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome components and downstream factors, such as apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, cleaved gasdermin D (GSDMD), and IL-18, in SOD1 mice modeling ALS, indicating its critical role in motor neuron degeneration.^8,9 SGRM efficacy in decreasing inflammation during long-term usage was assessed via administration of CORT113176, an SGRM, to 5-month-old Wobbler mice demonstrating an ALS phenotype over the course of 21 days. Results demonstrated a reduction in neuropathophysiology in comparison to those treated with a vehicle. Treated mice comparatively had decreased vacuolated motoneurons, astro- and microgliosis, neuroinflammatory markers, and glutamine synthase. In addition, treated mice demonstrated less muscular atrophy and had improved rotarod test performance results, indicating an improvement in balance, coordination, and overall motor function. Spinal cord neuroinflammatory markers, including high mobility group box 1 (HMGB1), TLR4, MyD88, TNFR, p50/NF-κB, and IL-18 were decreased in treated Wobbler mice.¹⁰ Studies assessing another SGRM, CORT125329, yielded similar results. This study also found that SGRM administration resulted in a healthier functioning population of surviving motoneurons, indicated by increased levels of acetylcholine acetyltransferase (ChAT) motoneurons and brain-derived neurotrophic factor. It also suggested that treated Wobbler mice had a higher population of mature oligodendrocytes, indicated by increased 2’3’-cyclic-nucleotide 3’-phosphodiesterase (CNPase+) oligodendrocytes.⁸

Conclusion:  Studies have found that administration of SGRMs in Wobbler mice modeling ALS over a chronic period reduced multiple pathological features of ALS. Despite long-term administration, treated Wobbler mice demonstrated a reduction in neuropathophysiology, and the paradoxical neuroinflammatory state found normally with chronic GRM administration did not appear to occur. Thus, SGRMs demonstrated the potential to maintain anti-neuroinflammatory effects despite long-term administration, suggesting a possible avenue to investigate in the development of new therapeutics for ALS.^7,10

Works Cited

1. Goutman SA, Hardiman O, Al-Chalabi A, et al. Emerging insights into the complex genetics and pathophysiology of amyotrophic lateral sclerosis. Lancet Neurol. 2022;21(5):465-479.
2. Mead RJ, Shan N, Reiser HJ, Marshall F, Shaw PJ. Amyotrophic lateral sclerosis: a neurodegenerative disorder poised for successful therapeutic translation. Nat Rev Drug Discov. 2023;22(3):185-212.
3. Canet G, Zussy C, Vitalis M, et al. Advancing Alzheimer’s disease pharmacotherapy: efficacy of glucocorticoid modulation with dazucorilant (CORT113176) in preclinical mouse models. Br J Pharmacol. 2025;182(9):1930-1956. doi:10.1111/bph.17457
4. Liu X, Wang Y, Gutierrez JS, et al. Disruption of a key ligand-H-bond network drives dissociative properties in vamorolone for Duchenne muscular dystrophy treatment. Proc Natl Acad Sci U S A. 2020;117(39):24285-24293. doi:10.1073/pnas.2006890117
5. Goslinga JA, Terrelonge M, Bedlack R, et al. ALSUntangled #65: glucocorticoid corticosteroids. Amyotroph Lateral Scler Frontotemporal Degener. 2023;24(3-4):351-357.
6. De Nicola AF, Meyer M, Guennoun R, et al. Insights into the therapeutic potential of glucocorticoid receptor modulators for neurodegenerative diseases. Int J Mol Sci. 2020;21(6):2137.
7. Esperante I, Banzan C, Munuera JZ, et al. The selective glucocorticoid receptor modulator CORT125329 decreases neuroinflammation and gliosis and enhances myelination in the wobbler model of amyotrophic lateral sclerosis. Mol Neurobiol. 2025. PMID: 40381165.
8. Deora V, Lee JD, Albornoz EA, et al. The microglial NLRP3 inflammasome is activated by amyotrophic lateral sclerosis proteins. Glia. 2020;68(2):407-421. doi:10.1002/glia.23728
9. Van Schoor E, Ospitalieri S, Moonen S, et al. Increased pyroptosis activation in white matter microglia is associated with neuronal loss in ALS motor cortex. Acta Neuropathol. 2022;144(3):393-411. doi:10.1007/s00401-022-02466-9
10. Meyer M, Kruse MS, Garay L, et al. Long-term effects of the glucocorticoid receptor modulator CORT113176 in murine motoneuron degeneration. Brain Res. 2020;1727:146551. doi:10.1016/j.brainres.2019.146551