Shenqi Xingnao Granules ameliorates cognitive impairments and Alzheimer's disease-like pathologies in APP/PS1 mouse model / 中草药·英文版

Objective: Alzheimer's disease (AD) is along with cognitive decline due to amyloid-β (Aβ) plaques, tau hyperphosphorylation, and neuron loss. Shenqi Xingnao Granules (SQXN), a traditional Chinese medicine, significantly ameliorated the cognitive function and daily living abilities of patients with AD. However, till date, no study has investigated the mechanism of action of SQXN on AD. The present study aimed to verify the effects of SQXN treatment on cognitive impairments and AD-like pathologies in APP/PS1 mice. Methods: Four-month-old APP/PS1 transgenic (Tg) mice were randomly divided into a model group and SQXN-treated (3.5, 7, 14 g/kg per day) groups. Learning-memory abilities were determined by Morris water maze and object recognition test. All mice were sacrificed and the brain samples were collected after 75 d. The soluble Aβ contents were detected by Elisa kit; The levels of expression of NeuN, APP, phosphorylated tau and related protein were measured by Western blotting; The inflammation factors were detected by the proinflammatory panel kit. Results: Four-month-old APP/PS1 mice were administered SQXN by oral gavage for 2.5 months. Using the Morris water maze tests and Novel object recognition, we found that SQXN restored behavioral deficits in the experimental group of Tg mice when compared with the controls. SQXN also inhibited neuronal loss (NeuN marker). SQXN treatment decreased soluble Aβ42 through inhibiting the expression of sAPPβ and BACE-1 without regulating full-length amyloid precursor protein (FL APP). Insulin degrading enzyme (IDE), the Aβ degrading enzyme, were increased by SQXN. In addition, SQXN reduced hyperphosphorylated tau protein levels and prevented excessive activation of p-GSK-3β in the brain of APP/PS1 mice. Compared with APP/PS1 transgenic negative mice, IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-12p70, KC/GRO and TNF-α were not obviously changed in the brain of 6.5-month-old APP/PS1 transgenic (Tg) mice. However, SQXN could inhibited the expression of IL-2. Conclusion: These results demonstrate that SQXN ameliorates the cognitive impairments in APP/PS1 mice. The possible mechanisms involve its inhibition of neuronal loss, soluble Aβ deposition, tau hyperphosphorylation and inflammation.

AAD-2004 Attenuates Progressive Neuronal Loss in the Brain of Tg-betaCTF99/B6 Mouse Model of Alzheimer Disease

Alzheimer's disease (AD) is a neurodegenerative disease that proceeds with the age-dependent neuronal loss, an irreversible event which causes severe cognitive and psychiatric devastations. In the present study, we investigated whether the compound, AAD-2004 [2-hydroxy-5-[2-(4-trifluoromethylphenyl)-ethylaminobenzoic acid] which has anti-oxidant and anti-inflammatory properties, is beneficial for the brain of Tg-betaCTF99/B6 mice, a murine AD model that was recently developed to display age-dependent neuronal loss and neuritic atrophy in the brain. Administration of AAD-2004 in Tg-betaCTF99/B6 mice from 10 months to 18 months of age completely repressed the accumulation of lipid peroxidation in the brain. AAD-2004 markedly suppressed neuronal loss and neuritic atrophy, and partially reversed depleted expression of calbindin in the brain of Tg-beta-CTF99/B6. These results suggest that AAD-2004 affords neurodegeneration in the brain of AD mouse model.

Insights into Alzheimer disease pathogenesis from studies in transgenic animal models

Alzheimer disease is the most common cause of dementia among the elderly, accounting for ~60-70 percent of all cases of dementia. The neuropathological hallmarks of Alzheimer disease are senile plaques (mainly containing p-amyloid peptide derived from amyloid precursor protein) and neurofibrillary tangles (containing hyperphosphorylated Tau protein), along with neuronal loss. At present there is no effective treatment for Alzheimer disease. Given the prevalence and poor prognosis of the disease, the development of animal models has been a research priority to understand pathogenic mechanisms and to test therapeutic strategies. Most cases of Alzheimer disease occur sporadically in people over 65 years old, and are not genetically inherited. Roughly 5 percent of patients with Alzheimer disease have familial Alzheimer disease-that is, related to a genetic predisposition, including mutations in the amyloid precursor protein, presenilin 1, and presenilin 2 genes. The discovery of genes for familial Alzheimer disease has allowed transgenic models to be generated through the overexpression of the amyloid precursor protein and/or presenilins harboring one or several mutations found in familial Alzheimer disease. Although none of these models fully replicates the human disease, they have provided valuable insights into disease mechanisms as well as opportunities to test therapeutic approaches. This review describes the main transgenic mouse models of Alzheimer disease which have been adopted in Alzheimer disease research, and discusses the insights into Alzheimer disease pathogenesis from studies in such models. In summary, the Alzheimer disease mouse models have been the key to understanding the roles of soluble b-amyloid oligomers in disease pathogenesis, as well as of the relationship between p-amyloid and Tau pathologies.

Expression of GFAP in adult rats hippocampus of onset subclinical seizures following hypoxic brain damage / 重庆医科大学学报

Objective:To explore the mechanism of early onset subclinical seizures following hypoxic brain injury. Methods:SD male adult rats were assigned randomly to control rats and rats exposed to global hypoxia by 8% oxygen nitrogen atmosphere. According to electroencephalogram recording seizure discharge,hypoxie rats were divided into subclinical seizures group and non-subclinical seizures group,then the changes in neuropathology and the expression of GFAP in cortex and hippocampus of rat brain were studied by Nissle-staining immunohisochemistry and western-blot. Results:Subclinical seizures occurred in 19.67% rats following hypoxia. Compared with non-subclinical seizure group,neuronal loss of hippocampal CA1 and CA3 region as wel as temporal cortex were distinct in subclinical seizure group(P

Neuronal Laterality & Postoperative Changes of GABA+Glu. Activity by In Vivo 1H MRS

Object of this study was to to evaluate the laterality of local cerebral cellular metabolism in various locations of the brain related to the symptomatic side of patients with clinically diagnosed idiopathic Parkinson's disease (IPD) and to verify GABA-related pathophysiology in IPD by comparing postoperative changes in (GABA+Glutamate)/Cr ratio from patients with IPD after stereotactic pallidotomy and thalamotomy. Fourteen patients with IPD(10 males and 4 females: age range 39-67 years) participated in the study. The patients were classified into two disease subgroups, one for tremor dominant group(n=7, T group), and the other bradykinesia and rigidity dominant one(n=7, B&R group). For T group, stereotactic VL(Vop, Vim) thalamotomy and subthalamotomy was performed and for the B&R group, stereotactic posteroventrolateral pallidotomy was selected. In Vivo 1H MRS study was performed on a 1.5 T MRI/MRS system(GE Sigma Advantage, version 4.8) using STEAM sequence after water suppression with CHESS RF pulse and dephasing gradients. After peak areas of creatine/phosphocreatine(Cr), choline-containning compound(Cho), N-Acetyl Aspartate(NAA), r-aminobutyric acid, (GABA) and glutamate(Glu) were calculated and processed, the metabolic ratios of NAA/Cr, Cho/Cr, and (GABA+Glu)/Cr in three different locations were calculated and compared with clinical symptoms and its changes after surgery. For the neuronal laterality in patients with IPD, there was significant differences of NAA/Cr ratio between the right and left sides of substantia nigra, thalamus and pallidum(p=0.00170). The magnitude of difference in NAA/Cr ratios between right and left side were significantly larger in substantia nigra(p=0.0141). Compared to the normal control values(1.82+/-0.52 in ages 27-50, 1.71+/-0.54 in ages 51-70 years), the neuronal loss was generally observed in at least one of three locationsin all patients. Moreover, NAA/Cr ratio was substantially lower in ipsilateral than contralateral substantia nigra of the parkinsonian symptomatic side. For preoperative(GABA+Glu)/Cr ratios of thalamus contralateral to the symptomatic side compared to that of ipsilateral, it was significant larger in thalamus of B&R group and significant smaller in T group. In the pallidotomy group, there was significant increase in the operated pallidum, whereas significant decrease in (GABA+Glu)/Cr ratios were noted in the operated side thalamus. And in the thalamotomy group, there were significant increase in the operated thalamus, whereas in the operated side pallidum, significant decrease in (GABA+Glu)/Cr ratios were noted. Neuronal laterality, pallidal neuronal loss and postoperative changes in GABA activity in patients with IPD were demonstrated on the basis of NAA/Cr and (GABA+Glu)/Cr ratio by In Vivo 1H MRS. The neuronal laterality was detected in the substantia nigra of all the parkinsonian patient, and NAA/Cr ratios in unilateral and bilateral disease were consistently lower in ipsilateral than in contralateral substantia nigra of the Parkinsonian disease side. Our result suggests that there may be another ongoing pathological process of ipsilateral neuronal degeneration with contralateral dopaminergic neuronal loss. The result of neuronal loss in pallidum supports with the previous reports concerning striatal degeneration in IPD. Our results concerning postoperative changes of (GABA+Glu)/Cr ratio suggests that separate pathophysiologic mechanisms may be involved in the development of two dominant symptom groups of IPD. That is, for the B&R group, pallidal overinhibition to the thalamus by the GABA-ergic system as previously noted, but for T group, a process other than GABA inhibitory mechanism with or without it may be involved.

Relationship of Longitudinal Extent of Hippocampal Sclerosis to Clinical Characteristics, Hippocampal Neuronal Cell Loss and Dynorphin-Immunoreactivity Patterns in Intractable Temporal Lobe Epilepsy with Hippocampal Sclerosis / 대한간질학회지

PURPOSE: In mesial temporal lobe epilepsy (TLE). Hippocampl sclerosis (HS) is a pathologic substrate and characterized by significant neuronal loss and band-like synaptic reorganization in dentate inner molecular layer (DGIML) og sclerotic hippocampus with either Timm`s staining or Dynorphin (Dyn)-immunohistochemical staining methods. Hippocampus has neuronal synaptic circuitries of both intralamellar and translamellar patterns, from which we may hypothesize that longitudinal extent of HS represents variable pathophysiologic implications of neuronal injury, ictogenesis and epileptogenesis in mesial TLE. We tested the hypothesis. METHODS: Eleven mesial TLE patients with HS on MRI were recruited from epilepsy surgery registry. Resected hippocampal slices were stained with Dyn immunohistochemical method. We classified them into cases with partial HS and thoes with extensive HS according to longitudinal HS extent,. Between the two groups, clinical characteristics of seizures or epilepaies, Hippocampal neuronal density and neuronal loss. and Dynimmunoreactivity (IR) patterns were compared and analyzed. Dyn-IR pattern was classified as presence or absence of DGIML band and of CA3-IR. RESULTS: Nine cases showed extensive HS whereas two were classified as partial HS. There appeared no significant differences in clinical characteristics, neuronal density, neuronal loss and Dyn-IR patterns between those with extensive and partial HS. CONCLUSION: In this study, we could not prove the hypothesis that difference in HS extend on MRI may represent distinctive variabliity in severity of hippocampal neuronal injury and in ictiogenetic or epileptogenetic pathophysiology.