MGCD 0103, a selective histone deacetylase inhibitor, coameliorates oligomeric Aβ 25‐35 ‐induced anxiety and cognitive deficits in a mouse model

Summary Aims Recently, histone deacetylase ( HDAC ) inhibitors are considered a possible therapeutic strategy in Alzheimer's disease ( AD ). However, HDAC i treatments exhibit diverse functions with unfavorable effects in AD . Thus, the development of selective HDAC i without side effects is urgently needed. Methods HDAC i, namely, BML 210, MGCD 0103, PXD 101, and Droxinostat, were screened in mouse hippocampal primary cultures incubated with oligomeric Aβ 25‐35 (50 μmol/L). MGCD 0103 was chosen for in vivo tests and was intraperitoneally injected into C57 BL /6J mice (0.5 mg/kg, once per day) for 4 weeks following an intrahippocampal CA 1 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 HDAC i, MGCD 0103 exhibited significant neuroprotection against the Aβ toxicity in primary cultures. MGCD 0103 coattenuated cognitive deficits and anxiety against Aβ damage in mice. MGCD 0103 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 MGCD 0103 treatment did not show liver or kidney toxicity in mice. Conclusions These results reveal MGCD 0103 could be a potential therapeutic agent against AD .