all cases.8 Unlike FAD, the etiology of SAD is not well understood9 and several possible risk factors in the development of SAD have been identified. Age is the most significant risk factor for the development of AD.9 Additional risk AZD7762 factors based upon epidemiological studies are, a high fat diet, gender, head trauma, and vascular risk factors such as diabetes, ischemia and hypertension.10 Thus, the lack of any cure for AD potentially may be attributed to this complex etiology. The currently available treatments for AD approved by the United States Food and Drug Administration comprise donepezil, tacrine, rivastigmine, and memantine. The first three drugs inhibit acetylcholine esterase, either selectively or non selectively, and thus help in improving memory in AD patients.
However, their use is associated with various adverse side effects.11 In contrast, memantine is a non competitive inhibitor of N methyl D aspartate bcl-2 cancer receptors, which prevents glutamate excitotoxicity and has relatively fewer adverse drug effects.11 All of these approved drugs have beneficial, but short lived effects in mediating the symptoms of AD. Thus, there is a significant need for the development of novel drugs that will not only affect the cholinergic and glutamatergic pathways but also target other cellular pathways and have lasting, disease modifying effects against AD. In this regard, investigation of the A pathway may be the most appropriate. Various molecular, cellular, and animal model studies have been used to establish the A protein as a central factor in the development and progression of AD.
9 The increased production and deposition of A in the AD brain initiates a pathological cascade leading to the formation of NFTs, gliosis, inflammatory changes, synaptic damage, and neurotransmitter loss.12 Thus, there is a major research focus on finding drugs that may decrease A levels in the AD brain, by lowering its production and/or enhancing its degradation and clearance. These pathways offer multiple molecular therapeutic targets, such as BACE1, the presenilins and ADAM10, and insulin degrading enzyme, neprilysin and matrix metalloproteinases . The major drawback of the present drug development strategies, however, is the one drug one target approach, rendering them limited in their ability to modify the apparent complex pathology of AD.
13 Thus, there is an immediate need to develop novel therapeutic molecules that may be able to modulate multiple A related targets simultaneously, thereby providing disease modifying therapeutic efficacy against this devastating disease. The aim of the present study was to examine two pure natural products isolated from two medicinally important plants, for their potential activities against multiple targets associated with APP processing and A clearance. Results and Discussion A PP Processing: Both Withanolide A and Asiatic Acid Enhance Nonamyloidogenic Processing of A PP by Down regulating BACE1 as well as Up regulating ADAM10 Activation in Primary Rat Cortical Neurons To determine whether 1 and 2 affect APP processing, primary rat cortical neurons were treated with various doses of these compounds for 24 h.
Compound 1 was non toxic to neurons at a concentration as high as 100 M, while 2 affected cell viability at 20 M and caused complete cell death at 100 M. Therefore, the highest concentrations of 1 and 2 used in the present study were 100 and 10 M, respectively. The Patil et al. Page 2 J Nat Prod. Author manuscript, available in PMC 2011 July 23. NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript morphologies of neurons treated with 100 M of compound 1 and 10 M of compound 2 are shown using MAP 2 immunostaining. Both 1 and 2 at these concentrations had no significant effect on cell morphology