Development of a Novel, Small-Molecule Brain-Penetrant Histone Deacetylase Inhibitor That Enhances Spatial Memory...

Area of Science:

• Neuroscience
• Epigenetics
• Pharmacology

Background:

• Histone acetylation is crucial for memory and is dysregulated in neurodegenerative diseases.
• Current histone deacetylase inhibitors (HDACi) have poor blood-brain barrier (BBB) penetration and toxicity issues.
• A new class of disulfide-based compounds was developed to overcome these limitations.

Purpose of the Study:

• To develop novel HDACi with improved BBB permeability and reduced toxicity.
• To evaluate the efficacy of a new compound, MJM-1, in enhancing histone acetylation and memory function.

Main Methods:

• Developed novel disulfide-based compounds inspired by romidepsin.
• Assessed histone 3 (H3) acetylation levels in a prostate cancer cell line treated with MJM-1.
• Administered MJM-1 intraperitoneally (i.p.) to mice and measured its BBB penetration in the hippocampus.
• Evaluated the effect of MJM-1 on hippocampus-dependent spatial memory consolidation.

Main Results:

• MJM-1 increased overall H3 acetylation in vitro.
• MJM-1 successfully crossed the BBB and was detected in the hippocampus of mice.
• Post-training i.p. administration of MJM-1 enhanced spatial memory consolidation in male mice.

Conclusions:

• MJM-1 demonstrates potential as a therapeutic agent for cognitive deficits.
• The novel compound effectively targets the central nervous system for epigenetic modulation.
• MJM-1 warrants further investigation for treating aging-related and neurodegenerative cognitive impairments.