HDACi protects against vascular cognitive impairment from CCH injury via induction of BDNF-related AMPA receptor activation

Abstract

We previously showed a hydroxamic acid-based histone deacetylase inhibitor (HDACi), compound 13, provides neuroprotection against chronic cerebral hypoperfusion (CCH) both in vitro under oxygen-glucose deprivation (OGD) conditions and in vivo under bilateral common carotid artery occlusion (BCCAO) conditions. Intriguingly, the protective effect of this HDACi is via H3K14 or H4K5 acetylation-mediated differential BDNF isoform activation. BDNF is involved in cell proliferation and differentiation in development, synaptic plasticity and in learning and memory related with receptors or synaptic proteins. B6 mice underwent BCCAO and were randomized into 4 groups; a sham without BCCAO (sham), BCCAO mice injected with DMSO (DMSO), mice injected with HDACi-compound 13 (compound 13) and mice injected with suberoylanilide hydroxamic acid (SAHA). The cortex and hippocampus of mice were harvested at 3 months after BCCAO, and levels of BDNF, AMPA receptor and dopamine receptors (D1, D2 and D3) were studied using Western blotting analysis or immunohistochemistry. We found that the AMPA receptor plays a key role in the molecular mechanism of this process by modulating HDAC. This protective effect of HDACi may be through BDNF; therefore, activation of this downstream signalling molecule, for example by AMPA receptors, could be a therapeutic target or intervention applied under CCH conditions.

Keywords: AMPA; BDNF; CCH; HDAC; OGD; vascular dementia.

FIGURE 1

Increased BDNF in the hippocampus at 3 mo following chronic cerebral hypoperfusion (CCH). A and B, The region and immunostaining of BDNF in the hippocampus. C, Semiquantitative analytic data of immunostaining image. Each bar represents the mean ± SEM of four independent experiments (n = 4, *P <.05, **P <.01 vs indicated group)

FIGURE 2

Effect of compound 13 on the levels of BDNF in the cortex of CCH mice. A and B, The region and immunostaining of BDNF in the cortex. C, Semiquantitative analytic data of immunostaining image. Each bar represents the mean ± SEM of four independent experiments (n = 4, *P <.05, **P <.01 vs indicated group)

FIGURE 3

Effect of compound 13 on the levels of glutamatergic, and dopaminergic receptor in the hippocampus (H) of CCH mice. The protein levels of AMPA receptor A, and dopamine receptors 1 B, 2 C and 3 D were measured statistically after BCCAO for 3 mo. β‐actin served as the loading control. A representative Western blot showing the levels of AMPA receptor, and dopamine receptors in the hippocampus E. The densities were normalized to β‐actin, and each bar represents the mean ± SEM of independent experiments (*P < .05, **P < .01 vs the indicated group)

FIGURE 4

Effect of compound 13 on the levels of glutamatergic, and dopaminergic receptor in the cortex of CCH mice. The protein levels of AMPA receptor A, and dopamine receptors 1 B, 2 C and 3 D were measured statistically after BCCAO for 3 mo. β‐actin served as the loading control. E, Representative Western blot images of AMPA receptor and dopamine receptors in the cortex. The densities were normalized to β‐actin, and each bar represents the mean ± SEM of independent experiments (n = 4, *P < .05, **P < .01 vs the indicated group)

FIGURE 5

Proposed mechanism by which the HDACi‐induced brain‐derived neurotrophic factor and AMPA receptor activation mediate cognitive function in CCH mice