TREM-1-targeting LP17 attenuates cerebral ischemia-induced neuronal injury by inhibiting oxidative stress and pyroptosis.

Stroke ranks as the second leading cause of disability and death globally. Trigger receptors expressed on myeloid cells (TREM) -1 are responsible for the activation of the innate immune response and also play a critical role in inflammation. In this study, we reported the contribution of TREM-1 after ischemic damage in a rat middle cerebral artery occlusion (MCAO) model. This study also demonstrated that TREM-1 expression was upregulated following cerebral infarction in rats. TREM-1 inhibition was determined using its selective inhibitor, LP17, which indicated a neuroprotective effect on cerebral infarction damage. The findings revealed that inhibition of TREM-1 by administering LP17 improved cerebral damage and decreased ischemic areas and brain water contents. Moreover, LP17 decreased MCAO-induced microglial activation and neurodegeneration, evidenced by a reduction in the expression of microglial Iba-1 and FJ-B positive cells, and reversed neuronal loss. Besides, the contribution of LP17 to ischemic neuronal damage may be associated with a decrease in the production of pro-inflammatory cytokines, and enhanced production of anti-inflammatory cytokine IL-10. Both in vivo and in vitro studies showed that inhibiting TREM-1 attenuated ROS accumulation, lipid per-oxidation (LPO) contents such as malondialdehyde (MDA) and enhanced the superoxide dismutase (SOD) activity after ischemia. Inhibiting TREM-1 alleviated inflammation and pyroptosis found in MCAO rats. This was achieved through the inhibition of the levels of NLRP3, caspase-1, ASC (an apoptosis-associated speck-like protein containing a CARD) and gasdermin D. These results confirmed that inhibiting TREM-1 protects against ischemia-induced neuronal damage and alleviates microglial mediated neuro-inflammation by reducing oxidative stress and pyroptosis. Therefore, blocking TREM-1 expression provides an effective intervention for improving ischemic stroke.

Memantine ameliorates tau protein deposition and secondary damage in the ipsilateral thalamus and sensory decline following focal cortical infarction in rats.

Previous studies have reported that memantine presents evidence of therapeutic benefits in several animal models of ischemic stroke and neurodegenerative diseases. However, the effect of memantine on secondary damage in the ipsilateral thalamus after focal cortical infarction remains undefined. Present study investigated whether memantine has a protective effect on secondary damage in the ipsilateral thalamus after focal cerebral infarction in rats. At 24 h after distal middle cerebral artery occlusion (MCAO), rats in the memantine and vehicle groups were intraperitoneal injected with memantine and isopycnic vehicle, respectively, was once daily administered for consecutive 7 days. Infarct size was evaluated through Nissl staining and sensory decline determined using adhesive removal test. Secondary thalamic damage was assessed using Nissl staining and immunofluorescence 8 days after MCAO. Immunoboltting was used to identify tau and apoptosis-associated proteins in the ipsilateral thalamus after MCAO. Results revealed that memantine ameliorated sensory decline compared to the vehicle controls. Subsequently, tau phosphorylated at threonine 231 (p-tau-231), glycogen synthase kinase3ßpY216 (GSK3ßpY216) and protein phosphatase 2A (PP2ApY307) were reduced by memantine, causing greater reduction in neuronal loss and inhibition of reactive astrogliosis in the ipsilateral ventroposterior thalamic nucleus (VPN) compared with the vehicle groups. In addition, increase in secondary damage-induced TUNEL-positive cells was blunted by memantine, as demonstrated by the significant reduction in expression of apoptosis-associated proteins. Our results suggest that memantine has a neuro-protective effect on secondary damage in the ipsilateral thalamus following MCAO by inhibiting the activity of GSK3ßpY216/PP2ApY307 and down regulating the levels of p-tau-231 protein.

Beneficial Role of Rosuvastatin in Blood-Brain Barrier Damage Following Experimental Ischemic Stroke.

Hemorrhage transformation is the most challenging preventable complication in thrombolytic therapy and is related to recombinant tissue plasminogen activator (rt-PA)-induced blood-brain barrier (BBB) damage. Intraperitoneal injections of normal or high doses of rosuvastatin were administered to Balb/c mice 20 min prior to middle cerebral artery occlusion (MCAO) surgery for 3 h followed by reperfusion with rt-PA thrombolytic therapy and cerebral blood flow monitoring to investigate whether a high or normal dose of rosuvastatin reduces BBB damage after brain ischemia and rt-PA reperfusion. The integrity of the BBB was ameliorated by normal and high doses of rosuvastatin as determined from Evans blue staining, ultrastructure assessments and immunochemistry at 24 h after reperfusion. The levels of TJ proteins were preserved, potentially by targeting platelet-derived growth factor receptor α (PDGFR-α) and low-density lipoprotein receptor-related protein 1 (LRP1) to inhibit the expression of matrix metalloproteinase proteins (MMPs) by reducing the levels of phosphorylated c-jun-N-terminal kinase (pJNK), phosphorylated mitogen-activated protein kinase (MAPK) p38 (pP38) and increasing the levels of phosphorylated extracellular regulated protein kinases (pERK), and tissue inhibitor of metalloproteinases (TIMPs), as inferred from Western blotting and molecular docking analyses. In summary, rosuvastatin reduced rt-PA therapy-associated BBB permeability by PDGFR-α- and LRP1-associated MAPK pathways to reduce the mortality of mice, and a normal dose of rosuvastatin exerted greater preventative effects on reducing BBB damage than did a high dose in the time window of thrombolytic therapy.

Traditional Chinese medicine's intervention in endothelial nitric oxide synthase activation and nitric oxide synthesis in cardiovascular system.

Cardiovascular disease (CVD) is one of the most dangerous diseases which has become a major cause of human death. Many researches evidenced that nitric oxide (NO)/endothelial nitric oxide synthase (eNOS) system plays a significant role in the occurrence and development of CVD. NO, an important signaling molecule, closely associated with the regulation of vasodilatation, blood rheology, blood clotting and other physiological and pathological processes. The synthesis of NO in the endothelial cells primarily depends on the eNOS activity, thus the exploration of the mechanisms and effects of the eNOS activation on NO production is of great significance. Recently, studies on the effects of traditional Chinese medicine (TCM) and its extracts on eNOS activation and NO synthesis have gradually attracted more and more attentions. In this paper, we reviewed the mechanisms of NO synthesis and eNOS activation in the vascular endothelial cells (VECs) and intervention of TCM, so as to provide reference and train of thought to the intensive study of NO/eNOS system and the research and development of new drug for the treatment of CVD.