Houshiheisan and its components promote axon regeneration after ischemic brain injury

Houshiheisan,a classic prescription in traditional Chinese medicine,contains Flos Chrysanthemi,Radix Saposhnikoviae,Ramulus Cinnamomi,Rhizoma Chuanxiong,Radix et Rhizoma Asari,Radix Platycodonis,Rhizoma Atractylodis macrocephalae,Poria,Rhizoma Zingiberis,Radix Angelicae sinensis,Radix et Rhizoma Ginseng,Radix Scutellariae and Concha Ostreae.According to traditional Chinese medicine theory,Flos Chrysanthemi,Radix Saposhnikoviae,Ramulus Cinnamomi,Rhizoma Chuanxiong,Radix et Rhizoma Asari and Radix Platycodonis are wind-dispelling drugs;Rhizoma Atractylodis macrocephalae,Poria,Rhizoma Zingiberis,Radix Angelicae sinensis and Radix et Rhizoma Ginseng are deficiency-nourishing drugs.A large number of randomized controlled trials have shown that Houshiheisan is effective in treating stroke,but its mechanism of action is unknown.Axonal remodeling is an important mechanism in neural protection and regeneration.Therefore,this study explored the effect and mechanism of action of Houshiheisan on the repair of axons after cerebral ischemia.Rat models of focal cerebral ischemia were established by ligating the right middle cerebral artery.At 6 hours after model establishment,rats were intragastrically administered 10.5 g/kg Houshiheisan or 7.7 g/kg wind-dispelling drug or 2.59 g/kg deficiency-nourishing drug.These medicines were intragastrically administered as above every 24 hours for 7 consecutive days.Houshiheisan,and its wind-dispelling and deficiency-nourishing components reduced the neurological deficit score and ameliorated axon and neuron lesions after cerebral ischemia.Furthermore,Houshiheisan,and its wind-dispelling and deficiency-nourishing components decreased the expression of proteins that inhibit axonal remodeling：amyloid precursor protein,neurite outgrowth inhibitor protein A（Nogo-A）,Rho family small GTPase A（Rho A） and Rho-associated kinase 2（Rock2）,and increased the expression of growth associated protein-43,microtubule-associated protein-2,netrin-1,Ras-related C3 botulinum toxin substrate 1（Rac1） and cell division cycle 42（Cdc42）.The effect of Houshiheisan was stronger than wind-dispelling drugs or deficiency-nourishing drugs alone.In conclusion,Houshiheisan,and wind-dispelling and deficiency-nourishing drugs promote the repair of axons and nerve regeneration after cerebral ischemia through Nogo-A/Rho A/Rock2 and Netrin-1/Rac1/Cdc42 signaling pathways.These effects are strongest with Houshiheisan.

Immunization with Cop-1 promotes neuroprotection and neurogenesis after ischemic stroke

Cerebrovascular diseases are considered to be amongst the most serious public health issues,since they are the third leading cause of death（WHO,2014）and the most common cause of disability worldwide.Its monetary significance is evidenced by the economic burden imposed on health care systems,given that the cost of medical care for a patient that has suffered a stroke is around$25,741US dollars every 5 years（Luengo-Fernandez et al.,2012）.A stroke occurs as a result of a disturbance or interruption of cerebral blood flow that significantly reduces the supply of oxygen and glucose to the neural tissue. Consequently, several cell death mechanisms （secondary lesion mechanisms） such as necrosis, excitotoxicity, free radical production and inflammation are triggered （Castillo, 2000）.

Sigma-1 receptor and neuroprotection:current outlook and potential therapeutic effects

Oxidative stress plays a major role in neurodegenerative disease since central nervous system is particularly vul- nerable to reactive oxygen species （ROS） due to several reasons： high consumption ROS and nitrosative species, of O2; high production of which originate from spe- cific neurochemical reactions （e.g., dopamine oxidation）; high deposition of metal ions in the brain with aging leading to Fenton＇s reactions; high abundance of lipids which are particularly sensitive to oxidation.

A protease-activated receptor 1 antagonist protects against global cerebral ischemia/reperfusion injury after asphyxial cardiac arrest in rabbits

Cerebral ischemia/reperfusion injury is partially mediated by thrombin, which causes brain damage through protease-activated receptor 1（PAR1）. However, the role and mechanisms underlying the effects of PAR1 activation require further elucidation. Therefore, the present study investigated the effects of the PAR1 antagonist SCH79797 in a rabbit model of global cerebral ischemia induced by cardiac arrest. SCH79797 was intravenously administered 10 minutes after the model was established. Forty-eight hours later, compared with those administered saline, rabbits receiving SCH79797 showed markedly decreased neuronal damage as assessed by serum neuron specific enolase levels and less neurological dysfunction as determined using cerebral performance category scores. Additionally, in the hippocampus, cell apoptosis, polymorphonuclear cell infiltration, and c-Jun levels were decreased, whereas extracellular signal-regulated kinase phosphorylation levels were increased. All of these changes were inhibited by the intravenous administration of the phosphoinositide 3-kinase/Akt pathway inhibitor LY29004（3 mg/kg） 10 minutes before the SCH79797 intervention. These findings suggest that SCH79797 mitigates brain injury via anti-inflammatory and anti-apoptotic effects, possibly by modulating the extracellular signal-regulated kinase, c-Jun N-terminal kinase/c-Jun and phosphoinositide 3-kinase/Akt pathways.

Necrostatin-1 protection of dopaminergic neurons

Necroptosis is characterized by programmed necrotic cell death and autophagic activation and might be involved in the death process of dopaminergic neurons in Parkinson＇s disease. We hypothesized that necrostatin-1 could block necroptosis and give protection to dopaminergic neurons. There is likely to be crosstalk between necroptosis and other cell death pathways, such as apoptosis and autophagy. PC12 cells were pretreated with necroststin-1 1 hour before exposure to 6-hydroxydopamine. We examined cell viability, mitochondrial membrane potential and expression patterns of apoptotic and necroptotic death signaling proteins. The results showed that the autophagy/lysosomal pathway is involved in the 6-hydroxydopamine-induced death process of PC12 cells. Mitochondrial disability induced overactive autophagy, increased cathepsin B expression, and diminished Bcl-2 expression. Necrostatin-1 within a certain concentration range（5–30 μM） elevated the viability of PC12 cells, stabilized mitochondrial membrane potential, inhibited excessive autophagy, reduced the expression of LC3-II and cathepsin B, and increased Bcl-2 expression. These findings suggest that necrostatin-1 exerted a protective effect against injury on dopaminergic neurons. Necrostatin-1 interacts with the apoptosis signaling pathway during this process. This pathway could be a new neuroprotective and therapeutic target in Parkinson＇s disease.

Neuroprotective effect of the Chinese medicine Tiantai No.1 and its molecular mechanism in the senescence-accelerated mouse prone 8

Tiantai No.1, a Chinese medicine predominantly composed of powdered Rhizoma Gastrodiae, Radix Ginseng, and Ginkgo leaf at a ratio of 2：1：2 and dissolved in pure water, is neuroprotective in animal models of various cognitive disorders, but its molecular mechanism remains unclear. We administered Tiantai No.1 intragastrically to senescence-accelerated mouse prone 8（SAMP8） mice（a model of Alzheimer＇s disease） at doses of 50, 100 or 150 mg/kg per day for 8 weeks and evaluated their behavior in the Morris water maze and expression of Alzheimer＇s disease-related proteins in the brain. Tiantai No.1 shortened the escape latency in the water maze training trials, and increased swimming time in the target quadrant during the spatial probe test, indicating that Tiantai No.1 improved learning and memory in SAMP8 mice. Immunohistochemistry revealed that Tiantai No.1 restored the proliferation potential of Ki67-positive cells in the hippocampus. In addition, mice that had received Tiantai No.1 had fewer astrocytes, and less accumulation of amyloid-beta and phosphorylated tau. These results suggest that Tiantai No.1 is neuroprotective in the SAMP8 mouse model of Alzheimer＇s disease and acts by restoring neuronal number and proliferation potential in the hippocampus, decreasing astrocyte infiltration, and reducing the accumulation of amyloid-beta and phosphorylated tau.

Oenanthe Javanica Extract Protects Against Experimentally Induced Ischemic Neuronal Damage via its Antioxidant Effects

Background： Water dropwort （Oenanthejavanica） as a popular traditional medicine in Asia shows various biological properties including antioxidant activity. In this study, we firstly examined the neuroprotective effect of Oenanthejavanica extract （OJE） in the hippocampal comus ammonis 1 region （CA 1 region） of the gerbil subjected to transient cerebral ischemia. Methods： Gerbils were established by the occlusion of common carotid arteries for 5 min. The neuroprotective effect of OJE was estimated by cresyl violet staining. In addition, 4 antioxidants （copper, zinc superoxide dismutase [SOD], manganese SOD, catalase, and glutathione peroxidase） immunoreactivities were investigated by immunohistochemistry. Results： Pyramidal neurons in the CA1 region showed neuronal death at 5 days postischemia; at this point in time, all antioxidants immunoreactivities disappeared in CA1 pyramidal neurons and showed 100 mg/kg, OJE protected CA 1 pyramidal neurons from ischemic damage in many nonpyramidal cells. Treatment with 200 mg/kg, not In addition, 200 mg/kg OJE treatment increased or maintained antioxidants immunoreactivities. Especially, among the antioxidants, glutathione peroxidase immunoreactivity was effectively increased in the CA 1 pyramidal neurons of the OJE-treated sham-operated and ischemia-operated groups. Conclusion： Our present results indicate that treatment with OJE can protect neurons from transient ischemic damage and that the neuroprotective effect may be closely associated with increased or maintained intracellular antioxidant enzymes by OJE.