Myricetin protects hippocampal CA3 pyramidal neurons and improves learning and memory impairments in rats with Alzheimer's disease

There is currently no treatment for effectively slowing the progression of Alzheimer's disease, so early prevention is very important. Numerous studies have shown that flavonoids can improve memory impairment. The present study investigated the effects of myricetin, a member of the flavonoids, on intracerebroventricular streptozotocin induced neuronal loss and memory impairment in rat models of Alzheimer's disease. Myricetin at 5 or 10 mg/kg was intraperitoneally injected into rats over 21 days. Control rats were treated with 10 m L/kg saline. Behavioral test(the shuttle box test) was performed on day 22 to examine learning and memory in rats. Immediately after that, hematoxylin-eosin staining was performed to observe the morphological change in hippocampal CA3 pyramidal neurons. Myricetin greatly increased the number of hippocampal CA3 pyramidal neurons and improved learning and memory impairments in rats with Alzheimer's disease. These findings suggest that myricetin is beneficial for treatment of Alzheimer's disease.     

Effects of MCI-186 on intracellular calcium ion concentration and membrane fluidity of hippocampal neurons in a rat model of Alzheimer's disease

The present study observed the effects of MCI-186 on the intracellular calcium ion concentra-tion ([Ca2+]i) and membrane fluidity of hippocampal neurons in Alzheimer’s disease (AD) model rats to validate the neuroprotective effects of MCI-186.Compared with normal and sham-operated rats,the escape latency was obviously prolonged,spanning platform times were obviously reduced,[Ca2+]i was increased,and microviscosity η value was increased in AD rats.MCI-186 at 0.5 mg/mL and 0.2 mg/mL obviously shortened escape latency,increased spanning platform times and decreased [Ca2+]i and microviscosity η values in AD rats at 7 and 17 days after induction of the model.The differences in the above-mentioned indices between normal and MCI-186-treated rats were statistically significant.MCI-186 at 0.2 mg/mL yielded better curative effects than 0.5 mg/mL MCI-186.These findings suggest that MCI-186 improves learning and memory abilities in AD rats by decreasing [Ca2+]i and increasing membrane fluidity of hippocampal neurons.     

Pretreatment with scutellaria baicalensis stem-leaf total flavonoid protects against cerebral ischemia/ reperfusion injury in hippocampal neurons

Previous experimental studies have shown that cerebral infarction can be effectively reduced following treatment with scutellaria baicalensis stem-leaf total flavonoid （SSTF）. However, the mechanism of action of SSTF as a preventive drug to treat cerebral infarction remains unclear. In this study, Sprague-Dawley rats were pretreated with 50, 100, 200 mg/kg SSTF via intragastric ad- ministration for 1 week prior to the establishment of focal cerebral ischemia/reperfusion injury. The results showed that pretreatment with SSTF effectively improved neurological function, reduced brain water content and the permeability of blood vessels, ameliorated ischemia-induced morphology changes in hippocampal microvessels, down-regulated Fas and FasL protein expression, elevated the activity of superoxide dismutase and glutathione peroxidase, and decreased malondialdehyde content. In contrast to low-dose SSTF pretreatment, the above changes were most obvious after pretreatment with moderateand high-doses of SSTF. Experimental findings indicate that SSTF pretreatment can exert protective effects on the brain against cerebral ischemia/reperfusion injury. The underlying mechanisms may involve reducing brain water content, increasing microvascular recanalization, inhibiting the apoptosis of hippocampal neurons, and attenuating free radical damage.     

Protective effects of Bushen Tiansui decoction on hippocampal synapses in a rat model of Alzheimer's disease

Bushen Tiansui decoction is composed of six traditional Chinese medicines:Herba Epimedii,Radix Polygoni multiflori,Plastrum testudinis,Fossilia Ossis Mastodi,Radix Polygalae,and Rhizoma Acorus tatarinowii.Because Bushen Tiansui decoction is effective against amyloid beta(Aβ) toxicity,we hypothesized that it would reduce hippocampal synaptic damage and improve cognitive function in Alzheimer's disease.To test this hypothesis,we used a previously established animal model of Alzheimer's disease,that is,microinjection of aggregated Aβ25–35 into the bilateral brain ventricles of Sprague-Dawley rats.We found that long-term(28 days) oral administration of Bushen Tiansui decoction(0.563,1.688,and 3.375 g/m L;4 m L/day) prevented synaptic loss in the hippocampus and increased the expression levels of synaptic proteins,including postsynaptic density protein 95,the N-methyl-D-aspartate receptor 2 B subunit,and Shank1.These results suggested that Bushen Tiansui decoction can protect synapses by maintaining the expression of these synaptic proteins.Bushen Tiansui decoction also ameliorated measures reflecting spatial learning and memory deficits that were observed in the Morris water maze(i.e.,increased the number of platform crossings and the amount of time spent in the target quadrant and decreased escape latency) following intraventricular injections of aggregated Aβ25–35 compared with those measures in untreated Aβ_(25–35)-injected rats.Overall,these results provided evidence that further studies on the prevention and treatment of dementia with this traditional Chinese medicine are warranted.     

A protease-activated receptor 1 antagonist protects against global cerebral ischemia/reperfusion injury atfer 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. hTerefore, 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 atfer the model was established. Forty-eight hours later, compared with those ad-ministered saline, rabbits receiving SCH79797 showed markedly decreased neuronal damage as assessed by serum neuron speciifc enolase levels and less neurological dysfunction as determined using cerebral performance category scores. Additionally, in the hippocampus, cell apoptosis, polymorphonuclear cell inifltration, and c-Jun levels were decreased, whereas extracellular signal-regulated kinase phosphor-ylation 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. hTese ifndings suggest that SCH79797 mitigates brain injury via anti-inlfammatory 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.     

Blocking beta 2-adrenergic receptor inhibits dendrite ramification in a mouse model of Alzheimer's disease

Dendrite ramification affects synaptic strength and plays a crucial role in memory. Previous studies revealed a correlation between beta 2-adrenergic receptor dysfunction and Alzheimer's disease(AD), although the mechanism involved is still poorly understood. The current study investigated the potential effect of the selective β2-adrenergic receptor antagonist, ICI 118551(ICI), on Aβ deposits and AD-related cognitive impairment. Morris water maze test results demonstrated that the performance of AD-transgenic(TG) mice treated with ICI(AD-TG/ICI) was significantly poorer compared with Na Cl-treated AD-TG mice(AD-TG/Na Cl), suggesting that β2-adrenergic receptor blockage by ICI might reduce the learning and memory abilities of mice. Golgi staining and immunohistochemical staining revealed that blockage of the β2-adrenergic receptor by ICI treatment decreased the number of dendritic branches, and ICI treatment in AD-TG mice decreased the expression of hippocampal synaptophysin and synapsin 1. Western blot assay results showed that the blockage of β2-adrenergic receptor increased amyloid-β accumulation by downregulating hippocampal α-secretase activity and increasing the phosphorylation of amyloid precursor protein. These findings suggest that blocking the β2-adrenergic receptor inhibits dendrite ramification of hippocampal neurons in a mouse model of AD.     

Activation of calcium/calmodulin‐dependent protein kinase IV and peroxisome proliferator‐activated receptor γ coactivator‐1α signaling pathway protects against neuronal injury and promotes mitochondrial biogenesis in the hippocampal CA1 subfield after transient global ischemia

Delayed neuronal cell death occurs in the vulnerable CA1 subfield of the hippocampus after transient global ischemia (TGI). We demonstrated previously, based on an experimental model of TGI, that the significantly increased content of oxidized proteins in hippocampal CA1 neuron was observed as early as 30 min after TGI, followed by augmentation of PGC‐1α expression at 1 hr, as well as up‐regulation of mitochondrial uncoupling protein 2 (UCP2) and superoxide dismutases 2 (SOD2). Using the same animal model, the present study investigated the role of calcium/calmodulin‐dependent protein kinase IV (CaMKIV) and PGC‐1α in delayed neuronal cell death and mitochondrial biogenesis in the hippocampus. In Sprague‐Dawley rats, significantly increased expression of nuclear CaMKIV was noted in the hippocampal CA1 subfield as early as 15 min after TGI. In addition, the index of mitochondrial biogenesis, including a mitochondrial DNA‐encoded polypeptide, cytochrome c oxidase subunit 1 (COX1), and mitochondrial number significantly increased in the hippocampal CA1 subfield 4 hr after TGI. Application bilaterally into the hippocampal CA1 subfield of an inhibitor of CaMKIV, KN‐93, 30 min before TGI attenuated both CaMKIV and PGC‐1α expression, followed by down‐regulation of UCP2 and SOD2, decrease of COX1 expression and mitochondrial number, heightened protein oxidation, and enhanced hippocampal CA1 neuronal damage. This study provides correlative evidence for the neuroprotective cascade of CaMKIV/PGC‐1α which implicates at least in part the mitochondrial antioxidants UCP2 and SOD2 as well as mitochondrial biogenesis in ischemic brain injury. © 2010 Wiley‐Liss, Inc.