onstituents of Withania somnifera Dunal and Centella asiatica Urb., respectively. Both species are recommended as Medhya Rasayana in the ayurvedic traditional Indian medicinal system.39 Various modern scientific studies AZD8931 support the memory enhancing role of W. Patil et al. Page 4 J Nat Prod. Author manuscript, available in PMC 2011 July 23. NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript somnifera and C. asiatica, as has been reported.40,41 Thus, both W. somnifera and C. asiatica, may prove beneficial against AD, where memory and other cognitive functions are severely impaired. Moreover, a crude extract of C. asiatica has been shown to decrease Alevels in a transgenic mouse model of AD.
42 The present study, however, is the first to assess the effects of pure active constituents of these two plants on APP processing pathways and the underlying molecular mechanisms associated with the increased Bergenin 477-90-7 bias towards non amyloidogenic processing of APP. In addition to the increased amyloidogenic processing and/or decreased non amyloidogenic processing of APP, the levels of A may also be increased in the AD brain due to its decreased degradation. IDE, NEP, MMPs, plasmin, and endothelin converting enzymes are some of the major proteolytic enzymes involved in A degradation.43 Growing evidence suggests that defective A degradation may be a central causative factor in the pathogenesis of AD. The genetic deletion or pharmacological inhibition of the A degrading enzymes has been shown to elevate A levels in animal brains significantly.
43 Furthermore, the levels of NEP and IDE proteins are decreased in an age and brain region dependent manner.43,44 Thus, modulation of one or more A degrading enzymes may prove vital in the prevention and treatment of AD. This hypothesis is supported by a recent study, whereby a novel small molecule inhibitor of plasminogen activator inhibitor 1 discovered by Wyeth, which enhances activity of an A degrading enzyme, has been shown to significantly lower plasma/brain A levels and also reverses cognitive deficits in transgenic mouse models of AD.45 In the present study, it was found that 1, but not 2, significantly increased IDE levels in primary rat cortical neurons. As indicated earlier, both 1 and 2 had no significant effects on NEP levels.
The significance of 1 in the up regulation in IDE levels against AD is emphasized by the fact that over expression of IDE by 100% decreases A levels, plaque burden, and associated neuronal death by more than 50%.19 Similarly, a seven fold over expression of NEP is associated with more than a 90% decrease in A levels.19 At present, the underlying mechanism by which 1 and 2 affect the levels of BACE1, ADAM10, and IDE is unclear. The AD brain is characterized by increased oxidative stress46 and the enzymes involved in APP processing and A degradation have been shown to be dependent upon the cellular redox state. Oxidative stress has been demonstrated to increase the expression and activity of BACE1 in NT2 neurons and primary rat cortical neurons, which was accompanied by a proportional elevation of the carboxy terminal fragments of APP.
47,48 Furthermore, both ADAM10 promoter activity and transcription of endogenous ADAM10 have been shown to be increased by treatment with retinoic acid.49 Also, epigallocatechin 3 gallate, from green tea, has been shown to significantly increase ADAM10 maturation.50 EGCG has also been shown to increase the expression levels of both NEP and IDE.51 These data, taken together with the realization that both 1 and 2 possess excellent anti oxidative and antiinflammatory properties52,53, may explain, in part, their effects on BACE1, ADAM10, and IDE levels. However, the lack of an effect of either 1 or 2 on NEP levels and of 2 on IDE le