Deposition of amyloid beta-peptide as senile plaques in the brain is one of the neuropathological hallmarks of Alzheimer's disease, which is the most prevalent progressive neurodegenerative disease leading to dementia. Neutral endopeptidase is one of the major beta-amyloid-degrading enzymes in the brain. To examine the influence of different polyphenols and other natural products from green tea extract (from Camellia sinensis, Theaceae), we used the neuroblastoma cell line SK-N-SH and studied the changes in the specific cellular neutral endopeptidase activity after long-term treatment with these substances. We have shown that caffeine leads to an increase in specific cellular neutral endopeptidase activity more than theophylline, theobromine or theanine. We have also shown that the combination of epicatechin, epigallocatechin and epigallocatechingallate with caffeine, theobromine or theophylline induced cellular neutral endopeptidase activity. It is suggested that the enhancement of cellular neutral endopeptidase activity by green tea extract and its natural products might be correlated with an elevated level of intracellular cyclic adenosine monophosphate.

Neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE) belong to the major Aβ-degrading enzymes. We currently demonstrate that apigenin, luteolin, and curcumin are able to enhance the activity of NEP and ACE. In this research, we examined the influence of these substances on the amount of endogenously produced and secreted Aβ of neuroblastoma cells. We found that treatment of the cells for 72 h with apigenin, luteolin, and curcumin decreases the endogenous Aβ1-42 level of SK-N-SH cells significantly, which indicates that the upregulation of both NEP and ACE activity leads to a decrease of Aβ in the medium. Furthermore, we showed that all of these substances are able to increase the intracellular cAMP level, which verifies our previous supposition that the enhancement of cellular NEP activity is correlated with an increase of cAMP level.

The long-term effects of a number of flavonoids (such as apigenin, luteolin and amentoflavone) and vinpocetine on the neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE) were investigated. It was shown that apigenin, luteolin and vinpocetin are able to induce the activity of both NEP and ACE associated with the inhibition of the proliferation of the neuroblastoma cell line SK-N-SH. Amentoflavone has no effect on either NEP or ACE activity. An additional enhancement of cellular NEP activity could be detected after the treatment of the cells with a combination of both arabinosylcytosine and either apigenin or luteolin. This effect supports the assumption that apigenin and luteolin influence directly the gene expression of NEP. Taking into account the significant role of NEP and ACE in the degradation of amyloid beta peptides, the induction of both enzymes by long-term treatment with apigenin, luteolin and vinpocetine may have a beneficial effect regarding the prevention of the formation of amyloid plaques and the effect of these substances may be discussed as neuroprotective.

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