Subarachnoid Hemorrhage In Rat Model Research Articles

Glycyrrhizin suppresses the expressions of HMGB1 and ameliorates inflammative effect after acute subarachnoid hemorrhage in rat model

High-mobility group box 1 (HMGB1), a nuclear protein that has endogenous cytokine-like activity, is involved in early brain injury after subarachnoid hemorrhage (SAH) by mediating inflammatory response. This study was conducted to investigate the effect of glycyrrhizin as an inhibitor of HMGB1 in a rat SAH model. Experimental SAH was induced by using autologous blood injection to prechiasmatic cistern. 15 mg/kg glycyrrhizin was administered immediately after SAH induction, and then administered once at 6, 12 and 18 h. All the rats were sacrificed at 24 h after neurological assessment and frontal brain tissue was taken for assay. Blood–brain barrier (BBB) permeability was determined by Evans blue (EB) extravasation. The expression of HMGB1 were detected by immunofluorescence, western blot and quantitative real-time PCR. Inflammatory mediators (TNF-α, IL-1β) were measured using specific ELISA. Fluoro-Jade C staining and TUNEL staining was performed for the quantitative assessment of neuronal injury. We found the use of glycyrrhizin significantly improved neurological scores, reduced HMGB1-positive cells, down-regulated mRNA and protein levels of HMGB1, inhibited BBB permeability, and attenuated neuronal cell death and apoptosis after SAH. The up-regulations of inflammation-related molecules (TNF-α, IL-1β) in SAH rats were suppressed by glycyrrhizin treatment. These findings suggest that glycyrrhizin is a potential candidate for the treatment of inflammatory brain injury after SAH.

Neuroprotective Effects of a Smoothened Receptor Agonist against Early Brain Injury after Experimental Subarachnoid Hemorrhage in Rats

The sonic hedgehog (Shh) signaling pathway plays a fundamental role in the central nervous system (CNS) development, but its effects on neural cell survival and brain repair after subarachnoid hemorrhage (SAH) has not been well-investigated. The present study was undertaken to evaluate the influence of an agonist of the Shh co-receptor Smoothened (Smo), purmorphamine (PUR), on early brain injury (EBI) as well as the underlying mechanisms after SAH. PUR was administered via an intraperitoneal injection with a dose of 0.5, 1, and 5 mg/kg at 2, 6, 24, and 46 h after SAH in rat model. The results showed that PUR treatment significantly ameliorated brain edema, improved neurobehavioral function, and attenuated neuronal cell death in the prefrontal cortex (PFC), associated with a decrease in Bax/Bcl-2 ratio and suppression of caspase-3 activation at 48 h after SAH. PUR also promoted phospho-ERK levels. Additionally, PUR treatment markedly decreased MDA concentration accompanied with the elevation in the expression of nuclear factor erythroid 2-related factor 2 and heme oxygenase-1 in PFC. Notably, PUR treatment significantly reversed the changes of Shh pathway mediators containing Patched, Gli1, and Shh by SAH insult, and the neuroprotection of PUR on SAH was blocked by Smo antagonist cyclopamine. These results indicated that PUR exerts neuroprotection against SAH-evoked injury in rats, mediated in part by anti-apoptotic and anti-oxidant mechanism, up-regulating phospho-ERK levels, mediating Shh signaling molecules in the PFC.

Neuroprotective Effects of Hydrogen Sulfide Against Early Brain Injury and Secondary Cognitive Deficits Following Subarachnoid Hemorrhage.

Although the neuroprotective effects of hydrogen sulfide (H2 S) have been demonstrated in several studies, whether H2 S protects against early brain injury (EBI) and secondary cognitive dysfunction in subarachnoid hemorrhage (SAH) model remains unknown. This study was undertaken to evaluate the influence of H2 S on both acute brain injury and neurobehavioral changes as well as the underlying mechanisms after SAH. The H2 S donor, NaHS, was administered via an intraperitoneal injection at a dose of 5.6 mg/kg at 2 h, 6 h, 24 h, and 46 h after SAH in rat model. The results showed that NaHS treatment significantly improved brain edema and neurobehavioral function, and attenuated neuronal cell death in the prefrontal cortex, associated with a decrease in Bax/Bcl-2 ratio and suppression of caspase-3 activation at 48 h after SAH. NaHS also promoted phospho-Akt and phospho-ERK levels. Furthermore, NaHS treatment significantly enhanced the levels of brain-derived neurotrophic factor (BDNF) and phospho-CREB. Importantly, NaHS administration improved learning and memory performance in the Morris water maze test at 7 days post-SAH in rats. These results demonstrated that NaHS, as an exogenous H2 S donor, could significantly alleviate the development of EBI and cognitive dysfunction induced by SAH via Akt/ERK-related antiapoptosis pathway, and upregulating BDNF-CREB expression.