Abstract
A neuritogenic monoglyceride, 1-O-(myristoyl) glycerol (MG), was isolated from the head of Ilisha elongate using a PC12 cell bioassay system, and its chemical structure was elucidated using spectroscopic methods. MG significantly induced 42% of the neurite outgrowth of PC12 cells at a concentration of 10 μM. To study the structure-activity relationships of MG, a series of monoglycerides was designed and synthesised. Bioassay results indicated that the alkyl chain length plays a key role in the neuritogenic activity of the monoglycerides. The groups that link the propane-1,2-diol and alkyl chain were also investigated. An ester linkage, rather than an amido one, was found to be optimal for neuritogenic activity. Therefore, 1-O-(stearoyl) glycerol (SG), which induces 57% of the neurite outgrowth of PC12 cells at 10 μM, was determined to be a lead compound for neuritogenic activity. We then investigated the mechanism of action of neurite outgrowth induced by SG on PC12 cells using protein specific inhibitors and Western blot analysis. The mitogen-activated kinase/ERK kinase (MEK) inhibitor U0126 and the phosphatidylinositol-3 kinase (PI3K) inhibitor LY294002 significantly decreased neurite outgrowth. At the same time, SG increased phosphorylation of CREB in protein level. Thus, SG-induced neuritogenic activity depends on the activation of the extracellular-regulated protein kinase (ERK), cAMP responsive element-binding protein (CREB) and PI3K signalling pathways in PC12 cells.
Highlights
With the development of aging society, Alzheimer’s disease (AD) has become a leading cause of dementia in the older population
Many potential lead compounds against AD have been found from natural products on land [9,10,11,12], marine organisms remain largely untapped for their potential for AD treatment [13]
Akt phosphorylation by SG began to increase at 5 min and peaked at 30 min (Figure 5E). These results indicate that phosphatidylinositol-3 kinase (PI3K)/extracellular-regulated protein kinase (ERK)/cAMP responsive element-binding protein (CREB) signalling maybe involved in the SG-induced neuronal differentiation of PC12 cells
Summary
With the development of aging society, Alzheimer’s disease (AD) has become a leading cause of dementia in the older population. Administration (USA) for AD treatment include donepezil, rivastigmine, galantamine and memantine. N-methyl-D-aspartic acid (NMDA) receptor antagonist [2]. These drugs can only improve symptoms or slow down AD progression, not cure the disease [3]. Neurotrophic factors are considered potential therapeutic drugs for the treatment of neurodegenerative disorders. Natural products are a great source of compounds for medical uses. Many potential lead compounds against AD have been found from natural products on land [9,10,11,12], marine organisms remain largely untapped for their potential for AD treatment [13]. Isolation of active compounds from marine sources and determination of lead compounds for AD drug development are worthwhile endeavors
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