Brain-penetrant LSD1 inhibitors can block memory consolidation

Area of Science:

• Neuroscience
• Epigenetics
• Pharmacology

Background:

• Histone modifications regulate gene expression and cellular functions.
• Lysine specific demethylase 1 (LSD1) is a key enzyme in histone modification.
• Existing inhibitors like Parnate target monoamine oxidases, prompting development of selective LSD1 inhibitors.

Purpose of the Study:

• To synthesize and characterize novel, selective LSD1 inhibitors.
• To assess the brain penetration of these inhibitors in rodents.
• To investigate the cognitive effects of LSD1 inhibition in a mouse model.

Main Methods:

• Synthesis and in vitro characterization of FAD-covalent LSD1 inhibitors.
• Radiosynthesis of a positron-emitting analog for bio-distribution studies.
• Assessment of cognitive function using the novel object recognition memory paradigm.

Main Results:

• Two potent and selective LSD1 inhibitors were identified.
• Systemic administration demonstrated brain penetration in rodents.
• LSD1 inhibition abolished long-term memory formation in mice without affecting short-term memory.

Conclusions:

• Novel FAD-covalent LSD1 inhibitors show promise for brain disorder therapy.
• These inhibitors effectively penetrate the brain and modulate cognitive function.
• Reversible histone methylation is crucial for nervous system function, particularly memory formation.