ligustilide and Alzheimer-Disease

Klotho, an aging-suppressor gene, encodes a protein that potentially acts as a neuroprotective factor by modulating insulin-like growth factor 1 signaling and oxidative stress. In the present study, we investigated the potential role of Klotho in the therapeutic effect of ligustilide against Alzheimer's disease (AD)-like neuropathologies and memory impairment in aged senescence-accelerated mouse prone-8 (SAMP8) mice. Ligustilide treatment (10 and 40 mg/kg for 8 weeks, intragastrically) in 10-month-old SAMP8 mice reduced memory deficits, amyloid-β(1)-42 accumulation, tau phosphorylation, and neuron loss, increased mitochondrial manganese-superoxide dismutase and catalase expression and activity, and decreased malondialdehyde, protein carbonyl, and 8-hydroxydesoxyguanosine levels in the brain. Ligustilide upregulated Klotho expression in the cerebral choroid plexus and serum, decreased Akt and Forkhead box class O1 phosphorylation. Moreover, ligustilide inhibited the insulin-like growth factor 1 pathway and induced Forkhead box class O1 activation in 293T cells along with Klotho upregulation. An inverse correlation was found between Klotho expression and the AD phenotype, suggesting that Klotho might be a novel therapeutic target for age-related AD, and Klotho upregulation might contribute to the neuroprotective effect of ligustilide against AD.

Topics: 4-Butyrolactone; Aging; Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Cells, Cultured; Disease Models, Animal; Forkhead Box Protein O1; Forkhead Transcription Factors; Gene Expression Regulation, Developmental; Glucuronidase; Insulin-Like Growth Factor I; Klotho Proteins; Male; Memory Disorders; Mice; Mice, Inbred Strains; Molecular Targeted Therapy; Neuroprotective Agents; Oxidative Stress; Peptide Fragments; Phosphorylation; Signal Transduction; tau Proteins; Up-Regulation

To investigate the effects of Z-ligustilide (LIG) on Abeta25-35-induced cytotoxicity in human neuroblastoma SH-SY5Y cells.. Cells were incubated with 0.1, 1.0, 2.5, 5.0 microg/mL LIG and then were exposed to 50 micromol/L Abeta25-35 to induce cytotoxicity in SH-SY5Y cell to establish the AD model in vitro. Cell viability was test by MTT method. Pro- and anti-apoptosis protein levels were investigated by Western blot.. After exposure to Abeta25-35, the cell viability decreased significantly, and the expression of pro-apoptosis protein--Bax, cleaved caspase 3, cytochrome C, caspase 8 was up regulated while the anti-apoptosis protein Bcl-2 was down regulated. However, the treatment of LIG (0.1, 1.0, 2.5, 5.0 microg/mL) significantly restored these changes.. LIG has the protective effect against cytotoxicity induced by in SH-SY5Y cells via inhibit the apoptosis induced by Abeta25-35.

Topics: 4-Butyrolactone; Alzheimer Disease; Amyloid beta-Peptides; Apoptosis; Cell Line, Tumor; Humans; Neuroblastoma; Neurons; Neuroprotective Agents; Peptide Fragments

Neuroinflammatory responses induced by accumulation and aggregation of beta-amyloid (Abeta) peptide are mainly involved in Alzheimer's disease (AD) pathogenesis. Z-ligustilide (LIG), a novel neuroprotectant against ischemic stroke, was reported to have significant anti-inflammatory effects via inhibition of TNF-alpha production and bioactivity. The present study investigated the effect of LIG on AD-like cognitive impairment and neuropathological and neuroinflammatory changes induced by bilateral intracerebroventricular injections of Abeta(25-35) at a dose of 50 nmol/rat. Rats received oral administration of 40 mg/kg LIG or volume-matched vehicle 1 h before Abeta(25-35) treatment then once daily for 15 days. Morris water maze was used to detect the cognitive dysfunction induced by Abeta(25-35). Compared to the sham-operated rats, Abeta(25-35) injection significantly prolonged the mean escape latency in vehicle-treated rats in the Morris water maze test (p < 0.01) and increased both AD-related neuropathological signs (i.e., Abeta, amyloid precursor protein, and phosphorylated Tau immunoreactivity) and pro-inflammatory mediators (i.e., TNF-alpha and activated NF-kappaB) in the prefrontal cortex and CA1 subregion of the hippocampus. And these neurotoxic effects of Abeta(25-35) were significantly ameliorated with LIG treatment (p < 0.01 vs. vehicle-treated group). The present data suggest that LIG modulates TNF-alpha-activated NF-kappaB signaling pathway with respect to its protective effect against Abeta(25-35)-induced neurotoxicity. LIG would be a potential candidate for further preclinical study aimed at the prevention and treatment of cognitive deficits in AD.

Topics: 4-Butyrolactone; Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Disease Models, Animal; Humans; Inflammation Mediators; Injections, Intraventricular; Male; Maze Learning; Neuroprotective Agents; NF-kappa B; Rats; Rats, Wistar; Signal Transduction; Tumor Necrosis Factor-alpha