3,6'- and 1,6'-Dithiopomalidomide Mitigate Ischemic Stroke in Rats and Blunt Inflammation

Area of Science:

• Neuroscience
• Pharmacology
• Immunology

Background:

• Stroke is often accompanied by neuroinflammation, a process that exacerbates brain damage.
• Pomalidomide, an immunomodulatory imide drug (IMiD), reduces tumor necrosis factor-alpha (TNF-α) and possesses anti-inflammatory properties.
• Developing well-tolerated IMiD analogs could offer new stroke treatments and help elucidate the role of neuroinflammation in ischemic brain injury.

Purpose of the Study:

• To evaluate two novel pomalidomide derivatives, 3,6 -dithiopomalidomide (3,6 -DP) and 1,6 -dithiopomalidomide (1,6 -DP), as potential stroke therapeutics.
• To characterize the anti-inflammatory actions of these derivatives in a preclinical stroke model.
• To assess the safety profile of the novel derivatives compared to pomalidomide.

Main Methods:

• A rat middle cerebral artery occlusion (MCAo) model was used to simulate stroke.
• Administration of pomalidomide, 3,6 -DP, and 1,6 -DP post-MCAo.
• Measurement of pro-inflammatory cytokines (TNF-α, IL1-β), assessment of neurological deficits (postural asymmetry), infarct size quantification, cereblon binding assays, evaluation of teratogenic intermediates (Ikaros, Aiolos, SALL4), and standard toxicology assays (chromosome aberration, AMES, hERG).
• In vitro studies using primary rat neuron-microglia cultures and mouse RAW 264.7 cells challenged with α-synuclein or LPS.

Main Results:

• All tested drugs reduced TNF-α and IL1-β levels, decreased stroke-induced postural asymmetry, and diminished infarct size.
• 3,6 -DP and 1,6 -DP, similar to pomalidomide, bound to cereblon.
• Unlike pomalidomide, 3,6 -DP did not affect Ikaros, Aiolos, or SALL4 levels, indicating a potentially safer profile.
• The novel derivatives passed key regulatory safety assays (chromosome aberration, AMES, hERG).
• Both 3,6 -DP and 1,6 -DP demonstrated anti-inflammatory effects in cellular models.

Conclusions:

• Neuroinflammation, particularly TNF-α mediated, significantly impacts stroke outcomes.
• 3,6 -DP and 1,6 -DP exhibit promising therapeutic potential for stroke.
• These novel compounds warrant further preclinical investigation as stroke treatments due to their efficacy and improved safety profile.