Abstract
Histone deacetylase inhibitors (HDACi) are a promising therapeutic intervention for stroke. The involvement of the anti-inflammatory effects of HDACi in their neuroprotection has been reported, but the underlying mechanisms are still uncertain. Given the post-stroke inflammation is a time-dependent process, starting with acute and intense inflammation, and followed by a prolonged and mild one, we proposed whether target the early inflammatory response could achieve the neuroprotection of HDACi? To test this hypothesis, a single dose of suberoylanilide hydroxamic acid (SAHA) (50 mg/kg), a pan HDACi, was intraperitoneally (i.p.) injected immediately or 12 h after ischemia onset in a transient middle cerebral artery occlusion (tMCAO) mouse model. Compared with delayed injection, immediate SAHA treatment provided more protection, evidenced by smaller infarction volume, and a better outcome. This protection was accompanied by suppression of pro-inflammatory cytokines and reduction of activated microglia in the early stage of post-stroke inflammation. Moreover, SAHA treatment suppressed M1 cytokine expression (IL-6, TNF-α, and iNOS) while promoted the transcription of M2 cytokines (Arg-1 and IL-10) in LPS-challenged mouse microglia, and enhanced CD206 (M2 marker) but decreased CD86 (M1 markers) levels in microglia isolated from the ipsilateral hemisphere of MCAO mice. Collectively, our data suggested that the protection of SAHA on ischemic brain injury was closely associated with its inhibition on the early inflammatory response, and this inhibition was related to its reducing microglia activation and priming the activated microglia toward a more protective phenotype.
Highlights
Ischemic stroke is a leading cause of death and adult disability worldwide [1]; aside from tissue plasminogen activator, available treatments are minimal [2, 3]
A similar result was reported in human plasma, where the mean half-life (t1/2) of suberoylanilide hydroxamic acid (SAHA) ranged from 91.6 to 127 min, and acetylated histone H3 accumulation was observed in peripheral blood mononuclear cells from 2 to 10 h, depending on the dose [28]
Normal mice i.p. injected with a single dose of 12.5, 25, and 50 mg/kg SAHA or vehicle were sacrificed at 6 h after injection (Figure 1A)
Summary
Ischemic stroke is a leading cause of death and adult disability worldwide [1]; aside from tissue plasminogen activator (tPA), available treatments are minimal [2, 3]. Accumulating in vivo and in vitro evidence proved modulation of protein acetylation by HDACi could mitigate ischemia-induced brain damage and promote endogenous regeneration and recovery [8, 9]. They are considered a promising therapeutic intervention for stroke and a variety of neurodegenerative diseases. The resident macrophages of the brain, and macrophages derived from infiltrated peripheral monocytes/macrophages are the two main elements participating in this immune response [14] These are two ontogenetically distinct cell populations and are activated or recruited with distinct kinetics after the onset of ischemia [14, 15]
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