Salvianolic Acids for Injection (SAFI) promotes functional recovery and neurogenesis via sonic hedgehog pathway after stroke in mice.

There is a pressing need of developing approaches for delayed post-stroke therapy for patients who fail to receive thrombolysis within the narrow time window. Neuroprotection of Salvianolic Acids for Injection (SAFI) for cerebral ischemia-reperfusion injury in acute phase has been well documented. The current study was to determine the influence of SAFI at the subacute phase after stroke in mice, and to elucidate the underlying mechanisms. Adult male C57BL/6 mice were subjected to permanent occlusion of the distal middle cerebral artery (dMCAO), followed by daily intraperitoneal injection of SAFI 24 h after stroke for 14 days. Motor behavior was measured by neurological function evaluations weekly, and proliferation, migration, survival and differentiation of neural progenitor cells (NPCs) were examined with immunohistochemistry. Sonic hedgehog (Shh) inhibitor cyclopamine (CYC) was injected to determine the involvement of Shh pathway in the therapeutic effects of SAFI. The results showed that SAFI led to dramatic brain functional improvement, elevated NPCs proliferation, and prompted long-term survival of newborn neurons in the subventricular zone (SVZ). Up-regulation of Shh, Ptch and nuclear translocation of Gli1 were observed in the peri-infarct region, accompanied with robust production of Brain derived neurotrophic factor (BDNF) and Nerve growth factor (NGF). Simultaneous administration with CYC strikingly attenuated the beneficial outcomes of SAFI as well as abolished SAFI induced BDNF and NGF production. Collectively, our study demonstrated SAFI significantly promoted long-term functional recovery and neurogenesis, which might be dependent on Shh signaling mediated BDNF and NGF production. Therefore, SAFI might serve as a potential clinically translatable therapy during recovery stage after stroke.

Ulinastatin downregulates TLR4 and NF-kB expression and protects mouse brains against ischemia/reperfusion injury.

BACKGROUND: Inflammatory damage plays an important role in ischemic stroke and provides potential targets for therapy. Ulinastatin (UTI), a drug used to treat shock and acute pancreatitis in clinic, has attracted attention for its protective effects through immunomodulatory and anti-inflammatory properties. However, the effect of UTI in the acute phase of cerebral ischemia/reperfusion (I/R) is not clear. This study is to investigate the potential neuroprotective effect of UTI and explore its underlying mechanisms. METHODS: Male CD-1 mice were subjected to transient middle cerebral artery occlusion (tMCAO) and randomly assigned into four groups: Sham (sham-operated) group, tMCAO (tMCAO + 0.9% saline) group, UTI-L (tMCAO + UTI 1500 U/100 g), and UTI-H (tMCAO + UTI 3000 U/100 g) group. UTI was administered immediately after reperfusion in the UTI-L and UTI-H groups. About 24 h after the reperfusion, the neurological deficit, brain water content, and infarct volume were detected. Immunohistochemistry, western blot and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used to detect the expression of TLR4 and NF-κB in the ischemic cerebral cortex. RESULTS: Compared with tMCAO group, both UTI-L and UTI-H groups dramatically ameliorated neurological deficit (p < 0.05), lessened the brain water content (p < 0.05) and infarct volume (p < 0.05), and decreased the expression of TLR4 and NF-κB. CONCLUSION: These results showed that UTI protected the brain against ischemic injury which may be due to the alleviation of inflammation reaction in early stage through downregulating TLR4 and NF-κB expression.

Cinnamaldehyde inhibits inflammation and brain damage in a mouse model of permanent cerebral ischaemia.

BACKGROUND AND PURPOSE: Recent findings suggest the importance of inflammation in the pathogenesis of cerebral ischaemia and its potential as a therapeutic target. Cinnamaldehyde is a diterpene with a wide range of anti-inflammatory effects thus may be advantageous in the treatment of cerebral ischaemia. The present study examined the potential therapeutic effects of cinnamaldehyde on cerebral ischaemia using a mouse model with permanent middle cerebral artery occlusion. EXPERIMENTAL APPROACH: Male CD-1 mice, which had the middle cerebral artery occluded, were treated (i.p.) with cinnamaldehyde. Neuroprotection by cinnamaldehyde was analysed by evaluating neurological deficit scores, brain oedema and infarct volume. Expressions of signal transduction molecules and inflammatory mediators were measured by Western blotting, qRT-PCR and immunohistochemical staining. Activation of NF-κB was assessed by Western blotting, immunohistochemistry and immunofluorescence. KEY RESULTS: Cinnamaldehyde reduced the neurological deficit scores, brain oedema and infarct volume. Cinnamaldehyde suppressed the activation of signal transduction molecules including toll-like receptor 4, tumour necrosis receptor-associated factor 6 and NF-κB, attenuated the increased levels of TNF-α, IL-1ß, CCL2 and endothelial-leukocyte adhesion molecule-1 and ultimately reduced leukocyte infiltration into the ischaemic brain areas after cerebral ischaemia. CONCLUSIONS AND IMPLICATIONS: Cinnamaldehyde protects against cerebral ischaemia injury by inhibiting inflammation, partly mediated by reducing the expression of toll-like receptor 4, tumour necrosis receptor-associated factor 6 and the nuclear translocation of NF-κB. Our findings suggest that cinnamaldehyde may serve as a new candidate for further development as a treatment for stroke.