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The leaves of Toona sinensis, a well-known traditional oriental medicine, have been prescribed for the treatment of enteritis and infection. Recently, aqueous extracts of Toona sinensis leaves (TSL-1) have demonstrated many biological effects both in vitro and in vivo. In the central nervous system, microglial activation and their proinflammatory responses are considered an important therapeutic strategy for neuroinflammatory disorders such as cerebral ischemia, Alzheimer's disease, and Parkinson's disease. The present study attempted to validate the effect of TSL-1 on microglia-mediated neuroinflammation stimulated by lipopolysaccharide (LPS). As inflammatory parameters, the production of nitric oxide (NO), inducible NO synthase, and tumor necrosis factor-α were evaluated. Our results demonstrate that TSL-1 suppresses LPS-induced NO production, tumor necrosis factor-α secretion, and inducible NO synthase protein expression in a concentration-dependent manner, without causing cytotoxicity. In addition, the inhibitory effects of TSL-1 in LPS-stimulated BV-2 microglia were extended to post-treatment suggesting the therapeutic potential of TSL-1. Therefore, this work provides the future evaluation of the role of TSL-1 in the treatment of neurodegenerative diseases by inhibition of inflammatory mediator production in activated microglia.

Cerebral vasospasm is the leading cause of mortality and morbidity in patients after aneurysmal subarachnoid hemorrhage (SAH). However, the mechanism and adequate treatment of vasospasm are still elusive. In the present study, we evaluate the effect and possible mechanism of progesterone on SAH-induced vasospasm in a two-hemorrhage rodent model of SAH. Progesterone (8 mg/kg) was subcutaneously injected in ovariectomized female Sprague-Dawley rats one hour after SAH induction. The degree of vasospasm was determined by averaging the cross-sectional areas of basilar artery 7 days after first SAH. Expressions of endothelial nitric oxide synthase (eNOS) and phosphorylated Akt (phospho-Akt) in basilar arteries were evaluated. Prior to perfusion fixation, there were no significant differences among the control and treated groups in physiological parameters recorded. Progesterone treatment significantly(P<0.01)attenuated SAH-induced vasospasm. The SAH-induced suppression of eNOS protein and phospho-Akt were relieved by progesterone treatment. This result further confirmed that progesterone is effective in preventing SAH-induced vasospasm. The beneficial effect of progesterone might be in part related to upregulation of expression of eNOS via Akt signaling pathway after SAH. Progesterone holds therapeutic promise in the treatment of cerebral vasospasm following SAH.

Background Apoptosis is implicated in vasospasm and the long-term sequelae of subarachnoid hemorrhage (SAH). This study tested the hypothesis that attenuation of SAH-induced apoptosis after 17β-estradiol (E2) treatment is associated with an increase in phosphorylation of Akt via estrogen receptor-α (ER-α) in rats. Materials and methods We examined the expression of phospho-Akt, ERα and ERβ, and apoptosis in cerebral cortex, hippocampus, and dentate gyrus in a two-hemorrhage SAH model in rats. We subcutaneously implanted other rats with a silicone rubber tube containing E2; they received daily injections of nonselective estrogen receptor antagonist (ICI 182,780), selective ERα-selective antagonist (methyl-piperidino-pyrazole), or ERβ-selective antagonist (R,R-tetrahydrochrysene) after the first hemorrhage. Results At 7 d after the first SAH, protein levels of phospho-Akt and ERα were significantly decreased and caspase-3 was significantly increased in the dentate gyrus. The cell death assay revealed that DNA fragmentation was significantly increased in the dentate gyrus. Those actions were reversed by E2 and blocked by ICI 182,780 and methyl-piperidino-pyrazole, but not R,R-tetrahydrochrysene. However, there were no significant changes in the expression of the protein levels of phospho-Akt, ERα, ERβ, and caspase-3, and DNA fragmentation after SAH. Conclusions The present study shows that a beneficial effect of E2 in attenuating SAH-induced apoptosis is associated with activation of the expression of phospho-Akt and ERα, and alteration in caspase-3 protein expression via an ERα-dependent mechanism in the dentate gyrus. These data support further the investigation of E2 in the treatment of SAH in humans.

Object Cerebral vasospasm remains a major complication in patients who have suffered a subarachnoid hemorrhage (SAH). Previous studies have shown that 17β-estradiol (E2) attenuates experimental SAH–induced cerebral vasospasm. Moreover, E2 has been shown to reduce neuronal apoptosis and secondary injury following cerebral ischemia. Adenosine A1 receptor (AR-A1) expression is increased following ischemia and may represent an endogenous neuroprotective effect. This study was designed to evaluate the efficacy of E2 in preventing cerebral vasospasm and reducing secondary injury, as evidenced by DNA fragmentation and AR-A1 expression, following SAH. Methods A double-hemorrhage model of SAH in rats was used, and the degree of vasospasm was determined by averaging the cross-sectional areas of the basilar artery 7 days after the first SAH. A cell death assay was used to detect apoptosis. Changes in the protein expression of AR-A1 in the cerebral cortex, hippocampus, and dentate gyrus were compared with levels in normal controls and E2-treated groups (subcutaneous E2, 0.3 mg/ml). Results The administration of E2 prevented vasospasm (p < 0.05). Seven days after the first SAH, DNA fragmentation and protein levels of AR-A1 were significantly increased in the dentate gyrus. The E2 treatment decreased DNA fragmentation and prevented the increase in AR-A1 expression in the dentate gyrus. There were no significant changes in DNA fragmentation and the expression of AR-A1 after SAH in the cerebral cortex and hippocampus in the animals in the control and E2-treated groups. Conclusions The E2 was effective in attenuating SAH-induced cerebral vasospasm, decreasing apoptosis in the dentate gyrus, and reducing the expression of AR-A1 in the dentate gyrus after SAH. Interestingly, E2 appears to effectively prevent cerebral vasospasm subsequent to SAH as well as attenuate secondary injury by reducing both apoptosis and a compensatory increase in AR-A1 expression in the dentate gyrus.

Object Apoptosis is implicated in vasospasm and long-term sequelae of subarachnoid hemorrhage (SAH). The authors observed that 17β-estradiol (E2) can attenuate cerebral vasospasm, lower endothelin-1 production, and preserve normal endothelial nitric oxide synthase expression by reduction of inducible NO synthase expression in experimental SAH. The authors investigated the potential antiapoptotic effects of E2 in an experimental rat model of SAH. Methods The authors examined the antiapoptotic effects of E2 in a double-hemorrhage SAH model in male Sprague-Dawley rats. The rats underwent subcutaneous implantation of a Silastic tube containing corn oil either with or without E2, and some E2-treated animals also received ICI 182,780 (a nonselective estrogen receptor [ER] antagonist) for 7 days after SAH. The degree of vasospasm was determined by averaging the cross-sectional areas of the basilar artery 7 days after SAH. The expression of apoptotic indicators, including TNF-α, caspase 3, Bcl-2, Bax, terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick end labeling (TUNEL), and cell death assays were used for detection of apoptosis. Results Treatment with E2 significantly attenuated SAH-induced vasospasm. Seven days after the induction of SAH, positive TUNEL-staining was seen, and DNA fragmentation was increased in the dentate gyrus. Increased TNF-α and cleaved caspase-3 protein expression and decreased Bcl-2 protein expression in the dentate gyrus were also observed. These changes were reversed with E2-treatment but not in the presence of ICI 182,780. However, the expression of Bax did not change after SAH either with or without E2 treatment. Conclusions The authors found that E2 appears to confer an antiapoptotic effect that reduces secondary brain injury after SAH via estrogen receptor–dependent mechanisms. This finding provides support for possible future applications of E2 treatment for the reduction of secondary injury after SAH in patients.

Cerebral vasospasm remains a major complication in patients who have suffered a subarachnoid hemorrhage (SAH). Previous studies have shown that 17beta-estradiol (E2) attenuates experimental SAH-induced cerebral vasospasm. Moreover, E2 has been shown to reduce neuronal apoptosis and secondary injury following cerebral ischemia. Adenosine A1 receptor (AR-A1) expression is increased following ischemia and may represent an endogenous neuroprotective effect. This study was designed to evaluate the efficacy of E2 in preventing cerebral vasospasm and reducing secondary injury, as evidenced by DNA fragmentation and AR-A1 expression, following SAH.A double-hemorrhage model of SAH in rats was used, and the degree of vasospasm was determined by averaging the cross-sectional areas of the basilar artery 7 days after the first SAH. A cell death assay was used to detect apoptosis. Changes in the protein expression of AR-A1 in the cerebral cortex, hippocampus, and dentate gyrus were compared with levels in normal controls and E2-treated groups (subcutaneous E2, 0.3 mg/ml).The administration of E2 prevented vasospasm (p0.05). Seven days after the first SAH, DNA fragmentation and protein levels of AR-A1 were significantly increased in the dentate gyrus. The E2 treatment decreased DNA fragmentation and prevented the increase in AR-A1 expression in the dentate gyrus. There were no significant changes in DNA fragmentation and the expression of AR-A1 after SAH in the cerebral cortex and hippocampus in the animals in the control and E2-treated groups.The E2 was effective in attenuating SAH-induced cerebral vasospasm, decreasing apoptosis in the dentate gyrus, and reducing the expression of AR-A1 in the dentate gyrus after SAH. Interestingly, E2 appears to effectively prevent cerebral vasospasm subsequent to SAH as well as attenuate secondary injury by reducing both apoptosis and a compensatory increase in AR-A1 expression in the dentate gyrus.

Background Our previous study showed that 17β-estradiol (E2) and an adenosine A2A receptor (AR-A2A) agonist could attenuate subarachnoid hemorrhage (SAH)-induced cerebral vasospasm via preventing the augmentation of iNOS expression and preserving the normal eNOS expression. This study tests the hypothesis that E2 attenuates SAH-induced vasospasm and apoptosis by activating adenosine AR-A2A and extracellular signal-regulated kinase 1 and 2 (ERK1/2), and by altering antiapoptotic and proapoptotic protein expression (Bcl-2 and Bax, respectively). Materials and Methods The two-hemorrhage SAH model in rat was used. Animals were treated with E2 with or without a nonselective estrogen receptor (ER) antagonist (ICI182,780). The cross sectional areas of the basilar artery and terminal dUTP nick-end labeling (TUNEL) were used to determine the degree of vasospasm and apoptosis, respectively. The expressions of Bcl-2, Bax, AR-A2A, and ERK1/2 in the cerebral cortex, hippocampus, and dentate gyrus were investigated. Results E2 significantly attenuated vasospasm. Seven days after the first SAH, TUNEL scores were significantly increased, and protein levels of AR-A2A, ERK1/2, and Bcl-2 were significantly decreased in the dentate gyrus only but not in the cortex and hippocampus. These changes were reversed by E2 while ICI182,780 abrogated the antiapoptotic and anti-spastic effects of E2. The expression of Bax did not change in the dentate gyrus after SAH with or without treatment. Conclusions The down-regulated AR-A2A and ERK may play a role in vasospasm and apoptosis after SAH. The beneficial effect of E2 in the attenuating SAH-induced vasospasm and apoptosis may be due to an increased expression of AR-A2A and ERK via ER-dependent mechanisms. These data may support further investigation of E2 in the treatment of SAH in humans.

Toona sinensis (TS) leaves are used as a vegetable and in traditional Chinese medicine. However, in vivo experiments regarding the anti-inflammatory function of TS leaves have not previously been conducted. The aim of this study was to investigate the potential role of TS leaf extract (TSL) in the prevention of sepsis-induced lung injury in vivo and on macrophage activation in vitro. The results showed that oral gavage pretreatment with TSL in rats for 30 days improved the survival of cecal ligation and puncture-induced sepsis, potentially by attenuating sepsis-induced histological lung damage rather than inflammatory cell infiltration. Furthermore, we demonstrated that pretreatment with TSL attenuated the lipopolysaccharide (LPS)-induced expression of inducible nitric oxide synthase, thereby inhibiting nitric oxide production and release in murine macrophage-like RAW 264.7 cells. Interestingly, TSL did not affect the LPS-induced release of other cytokines (e.g., tumor necrosis factor α and interleukin 1β) but increased LPS-induced heme-oxygenase-1 expression. In conclusion, the study provides preliminary data for TSL on cecal ligation and puncture-induced sepsis. The beneficial impact of TSL needs extensive study to get solid evidence.