The histone deacetylase inhibitor, sodium butyrate, exhibits neuroprotective effects for ischemic stroke in middle-aged female rats

Abstract

BackgroundSodium butyrate (NaB) is a histone deacetylase (HDAC) inhibitor exhibiting anti-inflammatory and neuroprotective effects in a rat ischemic model of stroke as well as a myocardial ischemia model. Although clinical evidence shows that older women are at higher risk for stroke occurrence and greater stroke severity, no studies have evaluated the effectiveness of NaB either in females or in older animals.MethodsTo determine the effects of NaB on stroke in older females, acyclic middle-aged Sprague-Dawley female rats (9–11 months old, constant diestrus) were subject to middle cerebral artery occlusion (MCAo) by intracerebral injection of recombinant endothelin-1. Rats were treated with NaB (300 mg/kg, i.p.) at 6 and 30 h following ET-1 injection. Animals were sacrificed at the early (2 days) or late (5 days) acute phase after MCAo. Serum and tissue lysates were collected for biochemical analyses.ResultsNaB treatment reduced infarct volume and ameliorated sensory motor impairment in middle-aged female rats, when measured at 2 and 5 days post MCAo. At the early acute phase (2 days post stroke), NaB treatment decreased brain lipid peroxides, and reduced serum levels of GFAP, a surrogate marker of blood-brain barrier (BBB) permeability. NaB also reduced expression of the inflammatory cytokine IL-1beta in circulation and IL-18 in the ischemic hemisphere. At the late acute phase (5 days post stroke), NaB treatment further suppressed MCAo-induced increase of IL-1beta, IL-17A, and IL-18 in brain lysates (cortex and striatum) from the ischemic hemisphere, and decreased ischemia-induced upregulation of IL-1beta and IL-18 in circulation, indicating a potent anti-inflammatory effect of the HDAC inhibitor. Moreover, NaB treatment also increased expression of IGF-1, a known neuroprotectant, in peripheral tissue including serum, liver, and spleen at the late acute phase.ConclusionsThese data provide the first evidence that delayed (>6 h) NaB treatment post-stroke is neuroprotective in older female rats. Additionally, these data also show that in addition to its well-known anti-inflammatory actions, NaB may exert a biphasic effect after stroke, operating initially to reduce BBB permeability and oxidative stress in the brain, and later, elevating IGF-1 expression in peripheral tissues.

Possible Prophylaxes of Aloe Vera Gel Ingestion to Butyrate Metabolism

“…These findings support the HDAC inhibitor, NaB, exhibits neuroprotective effects against MCAoinduced brain damage. This is also the first report that NaB treatment post-stroke is neuroprotective in older female rats [19] . Bourassa MW.…”

Valproate and sodium butyrate attenuate manganese-decreased locomotor activity and astrocytic glutamate transporters expression in mice

“…Numerous studies have reported that NaB induces neuroprotection in various animal models of neurological disorders, suggesting a number of molecular mechanisms of action for NaB in its neuroprotection including anti-inflammatory effect (Park and Sohrabji, 2016), anti-oxidative effect, and anti-apoptotic properties (Sun et al, 2015). NaB has also been reported to modulate gene expression that is related to many behavior in the prefrontal cortex (Kratsman et al, 2016).…”

“…Due to its modulation on epigenetic mechanisms, NaB has been considered as a specific and efficacious therapeutic strategy for treatment of variety of diseases, including neurodegenerative disorders. In rats, NaB exhibits neuroprotective effects against ischemic stroke by anti-inflammatory effects (Park and Sohrabji, 2016), and antidepressant-like effects (Yamawaki et al, 2012). NaB also exerts neuroprotective effects by anti-apoptotic, -oxidative and -inflammatory effects in a mouse model of cerebral ischemic injury (Sun et al, 2015).…”

Roles of Pro- and Anti-inflammatory Cytokines in Traumatic Brain Injury and Acute Ischemic Stroke

“…Moreover, transgenic mice with a mutant ICE gene developed smaller infarcts, fewer neurological deficits, lower IL-1β levels and decreased DNA fragmentation after transient and permanent middle cerebral artery occlusion [124,125]. Furthermore, many studies testing therapeutics in animal models of AIS correlate declines in IL-1β levels post-drug administration to improved functional and histologic outcomes post-stroke [115,126,127]. Thus, levels of IL-1β and IL-1Ra can be important predictors of the degree of neuroinlammation following ischemic stroke, as increased levels of IL-1β worsened AIS whereas IL-1Ra provided brain protection [114].…”

“…In the acute phase of injury, IL-1β interacts with its receptors to enhance microglial activation, stimulate astrocytic production of vascular endothelial growth factor (VEGF), and MMP-9 from NG2-oligodendrocyte precursor cells (NG2-OPC) [114,115]. Evidence from human culture systems suggests that hypoxia itself induces the production of IL-1β in endothelial cells, which then upregulates leukocyte adhesion molecules by an autocrine mechanism [116].…”