Peroxisome Proliferator–Activated Receptor β/δ Alleviates Early Brain Injury After Subarachnoid Hemorrhage in Rats

Abstract

S ubarachnoid hemorrhage (SAH) is a devastating disease with high mortality and disability. Traditionally, cerebral vasospasm, which develops in large cerebral arteries 3 to 7 days after SAH, was considered the most crucial cause of serious consequences after SAH. However, recent studies have shown that there is little advance in improving the outcome of SAH by prevention of vasospasm. It is reported that 12% of SAH patients die before receiving medical attention and 33% within 48 hours of SAH and 50% survivors havepermanent disability.1 The primary determinant of poor outcome in SAH patients was proposed to be early brain injury (EBI).2,3 EBI was described as the immediate injury of the brain after SAH, including elevation of intracranial pressure, disruption of bloodbrain barrier (BBB), neuronal cell death, brain edema, and other pathophysiologic changes. 4,5 Several recent studies have indicated apoptosis might play an important role in the pathogenesis of EBI after SAH. 6Background and Purpose-Early brain injury is proposed to be the primary cause of the poor outcome after subarachnoid hemorrhage (SAH), which is closely related to the neural apoptosis. To date, the relationship between peroxisome proliferator-activated receptor β/δ (PPARβ/δ) and nuclear factor-κB/matrix metalloproteinase-9 (NF-κB/MMP-9) pathway, both of which are closely related to apoptotic effects, has been poorly studied in SAH. The present study was undertaken to evaluate the effects of PPARβ/δ on early brain injury and NF-κB/MMP-9 pathway after SAH in rats. Methods-SAH model was established by injecting nonheparinized autologous arterial blood into the prechiasmatic cistern in male Sprague-Dawley rats. Adenoviruses or small interfering RNAs were injected into the right lateral cerebral ventricle to, respectively, up-or downregulate PPARβ/δ expression before SAH. All animals were assessed with a neurological score and then killed at 24 hours after SAH surgery. The indexes of brain water content, blood-brain barrier permeability, and apoptosis were used to detect brain injury. The expression of PPARβ/δ, NF-κB, and MMP-9 were measured by immunohistochemistry, gelatin zymography, and Western Blot methods, respectively. In addition, GW0742, a specific agonist of PPARβ/δ, was used to treat SAH in rats, the effects of which were evaluated by neurological scoring and Evans blue extravasation. Results-Overexpression of PPARβ/δ by adenoviruses treatment significantly ameliorated brain injury with improvement in neurological deficits, brain edema, blood-brain barrier impairment, and neural cell apoptosis at 24 hours after SAH in rats, whereas downregulation of PPARβ/δ by small interfering RNAs administration resulted in the reverse effects of the above. The expression levels of NF-κB and MMP-9 were markedly downregulated when PPARβ/δ increased after PPARβ/δ adenovirus transfection and upregulated when PPARβ/δ decreased by PPARβ/δ small interfering RNAs treatment. Moreover, GW0742 improved neurological deficits and reduced Evans blue extravasation ...

PPARβ/δ, a Novel Regulator for Vascular Smooth Muscle Cells Phenotypic Modulation and Vascular Remodeling after Subarachnoid Hemorrhage in Rats

“…For example, our previously work showed that PPARβ/δ alleviates early inflammatory response after SAH through blocking inflammation signaling28. Rikuta Hamaya, et al .…”

“…The 25-guage needle was inserted into the left lateral ventricle through the burr hole, and 4.0 mm below the horizontal plane of bregma. Ten microliters diluted Ad-PPARβ/δ or Ad-GFP was then slowly injected into the lateral ventricle on the 6 days before SAH, so as to obtain the max amplification28. Thus, 24 rats were randomly divided into 4 groups for immunoblots of cerebral arteries: sham, SAH + Ad-GFP, SAH + Ad-PPARβ/δ and SAH group (n = 6/group).…”

X-linked inhibitor of apoptosis inhibits apoptosis and preserves the blood-brain barrier after experimental subarachnoid hemorrhage

“…This model has the advantage of low mortality and the severity of hemorrhage was similar among the rats. Furthermore, previous studies have shown that obvious disruption of the BBB and apoptosis occur in this model36. A hemorrhage scoring system was used to evaluate the severity of hemorrhage on necropsy according to previously reported methods15.…”

β-Caryophyllene/Hydroxypropyl-β-Cyclodextrin Inclusion Complex Improves Cognitive Deficits in Rats with Vascular Dementia through the Cannabinoid Receptor Type 2 -Mediated Pathway

“…The expression of the CB2 was determined by immunohistochemical staining in the brain as described in our previous study (Teng et al, 2016). The rats were anesthetized and then transcardially perfused with 0.9% sodium chloride and fixed with 4% paraformaldehyde.…”

“…The sections were processed using an in situ cell death detection kit (Roche, Switzerland; Teng et al, 2016). The sections were dewaxed in xylene, ethyl alcohol, distilled water, and PBS and then incubated with Proteinase K, 0.1% sodium citrate and H 2 O 2 .…”