Investigating the Therapeutic Potential of LSD1 Enzyme Activity-Specific Inhibition by TAK-418 for Social and Memory Deficits in Rodent Disease Models.
ACS Chem Neurosci
; 13(3): 313-321, 2022 02 02.
Article
in En
| MEDLINE
| ID: mdl-35061371
ABSTRACT
Inhibition of lysine-specific demethylase 1 (LSD1) enzyme activity is a promising approach to treat diseases associated with epigenetic dysregulation, such as neurodevelopmental disorders. However, this concept has not been fully validated because genetic LSD1 deletion causes embryonic lethality and conventional LSD1 inhibitors cause thrombocytopenia via the dissociation of LSD1-cofactor complex. To characterize the therapeutic potential of LSD1 enzyme inhibition, we used TAK-418 and T-448, the LSD1 enzyme activity-specific inhibitors with minimal impact on the LSD1-cofactor complex. TAK-418 and T-448, by inhibiting brain LSD1 enzyme activity, consistently improved social deficits in animal models of neurodevelopmental disorders without causing thrombocytopenia. Moreover, TAK-418 improved memory deficits caused by aging or amyloid precursor protein overexpression. In contrast, TAK-418 did not improve memory deficits caused by miR-137 overexpression. Thus, miR-137 modulation may be involved in memory improvement by LSD1 inhibition. TAK-418 warrants further investigation as a novel therapeutic agent for diseases with epigenetic dysregulation.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
MicroRNAs
/
Enzyme Inhibitors
/
Histone Demethylases
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Memory Disorders
Limits:
Animals
Language:
En
Journal:
ACS Chem Neurosci
Year:
2022
Document type:
Article
Affiliation country: