MGCD0103, a selective histone deacetylase inhibitor, coameliorates oligomeric Aβ_25-35-induced anxiety and cognitive deficits in a mouse model

Aims: Recently, histone deacetylase (HDAC) inhibitors are considered a possible therapeutic strategy in Alzheimer's disease (AD). However, HDACi treatments exhibit diverse functions with unfavorable effects in AD. Thus, the development of selective HDACi without side effects is urgently needed. Methods: HDACi, namely, BML210, MGCD0103, PXD101, and Droxinostat, were screened in mouse hippocampal primary cultures incubated with oligomeric Aβ_25-35 (50 μmol/L). MGCD0103 was chosen for in vivo tests and was intraperitoneally injected into C57BL/6J mice (0.5 mg/kg, once per day) for 4 weeks following an intrahippocampal CA1 injection of oligomeric Aβ_25-35. Brain samples were collected for pathological analyses after the behavioral analyses including open- field test (OFT), elevated plus maze (EPM), Y-maze, and Morris water maze (MWM). Results: Among the HDACi, MGCD0103 exhibited significant neuroprotection against the Aβ toxicity in primary cultures. MGCD0103 coattenuated cognitive deficits and anxiety against Aβ damage in mice. MGCD0103 further ameliorated pathological features such as the levels of acetylated histone 3 at Lys 9 site (H3K9) and α-tubulin, synaptophysin, Aβ, tau protein phosphorylation, and serotonergic neuron loss against Aβ toxicity. Furthermore, chronic MGCD0103 treatment did not show liver or kidney toxicity in mice. Conclusions: These results reveal MGCD0103 could be a potential therapeutic agent against AD.