The key target of neuroprotection after the onset of ischemic stroke: secretory pathway Ca^(2+)-ATPase 1

The regulatory mechanisms of cytoplasmic Ca2＋ after myocardial infarction-induced Ca2＋ overload involve secretory pathway Ca2＋-ATPase 1 and the Golgi apparatus and are well understood. However, the effect of Golgi apparatus on Ca2＋ overload after cerebral ischemia and reperfusion remains unclear. Four-vessel occlusion rats were used as animal models of cerebral ischemia. The expression of secretory pathway Ca2＋-ATPase 1 in the cortex and hippocampus was detected by immunoblotting, and Ca2＋ concentrations in the cytoplasm and Golgi vesicles were determined. Results showed an overload of cytoplasmic Ca2＋ during ischemia and reperfusion that reached a peak after reperfusion. Levels of Golgi Ca2＋ showed an opposite effect. The expression of Golgi-specific secretory pathway Ca2＋-ATPase 1 in the cortex and hippocampus decreased before ischemia and reperfusion, and increased after reperfusion for 6 hours. This variation was similar to the alteration of calcium in separated Golgi vesicles. These results indicate that the Golgi apparatus participates in the formation and alleviation of calcium overload, and that secretory pathway Ca2＋-ATPase 1 tightly responds to ischemia and reperfusion in nerve cells. Thus, we concluded that secretory pathway Ca2＋-ATPase 1 plays an essential role in cytosolic calcium regulation and its expression can be used as a marker of Golgi stress, responding to cerebral ischemia and reperfusion. The secretory pathway Ca2＋-ATPase 1 can be an important neuroprotective target of ischemic stroke.

Protection of 3'-methoxy-puerarin against focal brain ischemia and its association with c-fos expression

The present study established a rat model of focal brain ischemia by occlusion of the middle cerebral artery covered with FeCl3, and investigated the protective effect of 3＇-methoxy-puerarin. Hippocampal and cortical c-fos gene expression was determined using in situ hybridization. Results showed that 3＇-methoxy-puerarin reduced neurological deficit scores, cerebral infarcted zone and water content of brain tissues, dramatically increased the activity of catalase and glutathione peroxidase in the ischemia zone of the hippocampus, increased the activity of catalase in the cortex, decreased lipid peroxide and lactic acid contents in the hippocampus and cerebral cortex, and down-regulated c-fos gene expression in brain ischemic rats. Results demonstrated that 3＇-methoxy-puerarin exhibited cerebroprotective effects against focal brain ischemia, which involved c-fos gene expression.

Fingolimod protects against neurovascular unit injury in a rat model of focal cerebral ischemia/reperfusion injury

Recent research on the underlying mechanisms of cerebral ischemia indicates that the neurovascular unit can be used as a novel subject for general surveys of neuronal damage and protein mechanisms.Fingolimod(FTY-720)is a newly developed immunosuppressant isolated from Cordyceps sinensis that exhibits a wide range of biological activities,and has recently attracted much attention for the treatment of ischemic cerebrovascular diseases.In the current research,the role of FTY-720 and its possible mechanisms were assessed from an neurovascular unit perspective using a rat cerebral ischemia model.Our results revealed that FTY-720 markedly decreased infarct volume,promoted neurological function recovery,and weakened the blood-brain barrier permeability of ischemic rats.The protective roles of FTY-720 in ischemic stroke are ascribed to a combination of sphingosin-1-phosphate receptor-1 and reduced expression of sphingosin-1-phosphate receptor-1 in microvessels and reduction of interleukin-17A protein levels.These findings indicate that FTY-720 has promise as a new therapy for neurovascular protection and functional recovery after ischemic stroke.

Estrogen receptor beta treats Alzheimer's disease

In vitro studies have shown that estrogen receptor β can attenuate the cytotoxic effect of amyloid protein on PC12 cells through the Akt pathway without estrogen stimulation. In this study, we aimed to observe the effect of estrogen receptor β in Alzheimer＇s disease rat models established by intraventricular injection of amyloid β protein. Estrogen receptor β lentiviral particles delivered via intraventricular injection increased Akt content in the hippocampus, decreased interleukin-1β mRNA tumor necrosis factor a mRNA and amyloid β protein levels in the hippocampus, and improved the learning and memory capacities in AIzheimer＇s disease rats. Estrogen receptor β short hairpin RNA lentiviral particles delivered via intraventricular injection had none of the above impacts on AIzheimer＇s disease rats. These experimental findings indicate that estrogen receptor β, independent from estrogen, can reduce inflammatory reactions and amyloid β deposition in the hJppocampus of AIzheimer＇s disease rats, and improve learning and memory capacities. This effect may be mediated through activation of the Akt pathway.

Triptolide protects astrocytes from hypoxia/reoxygenation injury

Astrocytes in an in vitro murine astrocyte model of oxygen and glucose deprivation/hypoxia and reoxygenation were treated with different concentrations of triptolide （250, 500, 1 000 ng/mL） in a broader attempt to elucidate the protection and mechanism underlying triptolide treatment on astrocytes exposed to hypoxia/reoxygenation injury. The results showed that the matrix metalloproteinase-9, interleukin-1β, tumor necrosis factor α and interleukin-6 expressions were significantly decreased after triptolide treatment in the astrocytes exposed to hypoxia/ reoxygenation injury, while interleukin-10 expression was upregulated. In addition, the vitality of the injured astrocytes was enhanced, the triptolide＇s effect was apparent at 500 ng/mL. These experimental findings indicate that triptolide treatment could protect astrocytes against hypoxia/ reoxygenation injury through the inhibition of inflammatory response and the reduction of matrix metalloproteinase-9 expression.

Hypothermic intervention for 3 hours inhibits apoptosis in neonatal rats with hypoxic-ischemic brain damage

A neonatal rat model of hypoxic-ischemic brain damage was designed and implemented in this study. Rats were subjected to hypothermia at 31℃ immediately following hypoxia-ischemia for either 3, 6 or 15 hours. TdT-mediated dUTP nick end labeling demonstrated that the number of apoptotic cells was reduced in the rat cerebral cortex, hippocampus and periventricular white matter following hypothermia. Immunohistochemistry revealed that Bcl-2 and p16 expression were decreased. Inhibition of apoptosis was greatest with the 3 hour hypothermic treatment, followed by hypothermia for 6 hours. In contrast, hypothermia for 15 hours led to a decrease in neuronal number in the cerebral cortex. The results demonstrate that hypothermic intervention at 31℃ protects brain tissue against hypoxic-ischemic brain damage by inhibiting apoptosis, and that the optimal length of treatment is 3 hours.

Schisandrin B protects PC12 cells by decreasing the expression of amyloid precursor protein and vacuolar protein sorting 35

PC12 cell injury was induced using 20 μM amyloid β-protein 25-35 to establish a model of Alzheimer＇s disease. The cells were then treated with 5, 10, and 25 μM Schisandrin B. Methylthiazolyldiphenyl-tetrazolium bromide assays and Hoechst 33342 staining results showed that with increasing Schisandrin B concentration, the survival rate of PC12 cells injured by amyloid β-protein 25-35 gradually increased and the rate of apoptosis gradually decreased. Reverse transcription-PCR, immunocytochemical staining and western blot results showed that with increasing Schisandrin B concentration, the mRNA and protein expression of vacuolar protein sorting 35 and amyloid precursor protein were gradually decreased. Vacuolar protein sorting 35 and amyloid precursor protein showed a consistent trend for change. These findings suggest that 5, 10, and 25 μM Schisandrin B antagonizes the cellular injury induced by amyloid β-protein 25-35 in a dose-dependent manner. This may be caused by decreasing the expression of vacuolar protein sorting 35 and amyloid precursor protein.

Hyperbaric oxygen preconditioning improves postoperative cognitive dysfunction by reducing oxidant stress and inflammation

Postoperative cognitive dysfunction is a crucial public health issue that has been increasingly studied in efforts to reduce symptoms or prevent its occurrence. However, effective advances remain lacking. Hyperbaric oxygen preconditioning has proved to protect vital organs, such as the heart, liver, and brain. Recently, it has been introduced and widely studied in the prevention of postoperative cognitive dysfunction, with promising results. However, the neuroprotective mechanisms underlying this phenomenon remain controversial. This review summarizes and highlights the definition and application of hyperbaric oxygen preconditioning, the perniciousness and pathogenetic mechanism underlying postoperative cognitive dysfunction, and the effects that hyperbaric oxygen preconditioning has on postoperative cognitive dysfunction. Finally, we conclude that hyperbaric oxygen preconditioning is an effective and feasible method to prevent, alleviate, and improve postoperative cognitive dysfunction, and that its mechanism of action is very complex, involving the stimulation of endogenous antioxidant and anti-inflammation defense systems.