Resveratrol: a natural compound with pharmacological potential in neurodegenerative diseases

Abstract

Resveratrol is a phytoalexin structurally related to stilbenes, which is synthesized in considerable amounts in the skin of grapes, raspberries, mulberries, pistachios and peanuts, and by at least 72 medicinal and edible plant species in response to stress conditions. It was isolated in 1940 and did not maintain much interest for around five decades until its role in treatment of cardiovascular diseases was suggested. To date, resveratrol has been identified as an agent that may be useful to treat cancer, pain, inflammation, tissue injury, and other diseases. However, currently the attention is being focused in analyzing its properties against neurodegenerative diseases and as antiaging compound. It has been reported that resveratrol shows effects in in vitro models of epilepsy, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and nerve injury. However, evidences in vivo as well as in human beings are still lacking. Thus, further investigations on the pharmacological effects of resveratrol in vivo are necessary before any conclusions on its effects on neurodegenerative diseases can be obtained.

Figure 1

Mechanisms proposed of neuronal protection of resveratrol in Alzheimers disease. Glial cells play a critical role in the Aβ‐dependant neurodegeneration produced in this disease. Resveratrol reduces damage produced by glial cells activating sirtuin‐1 (SIRT‐1) [1], inhibiting transcription factors as nuclear factor κB (NFκB) [2] or reducing activity and expression of diverse enzymes [3] and the levels of their corresponding metabolites [4]. In addition, resveratrol improves stability of the plasmatic membrane increasing the arachidonic acid incorporation into phospholipids presumably by activation of arachidonyl‐coenzyme A transferase (AA‐CoA‐T) [5]. Likewise, it decreases the formation of senile plaques increasing activity of transthyretin (TTR) [6] and stimulating the degradation proteasomal of the amyloid peptide [7]. Resveratrol also inhibits the activity of acetylcholinesterase (ACh‐E), an enzyme that degrades acetylcholine [8] and it reduces the amount of free radicals directly or increasing free‐radical scanvenger systems as glutathione [9 and 10], likewise it increases the activity or expression of antiapoptotic factors and decreases expression or activity of pro‐apoptotic factors [11 and 12] improving the cell survival [13]. Other abbreviations: IκBα= Inhibitor κBα; Cat B = cathepsin B; iNOS = inducible nitric oxide synthase; COX2 = cyclooxygenase‐2; NO = nitric oxide; PGE₂= prostaglandin E₂; PKG = protein kinase G; PKC = protein kinase C; ERK1/2 = extracellular signal‐regulated kinases 1/2; PLA₂= phospholipase A₂; APP = amyloid precursor protein; ACh‐R = acetylcholine receptor; CDK5 = cyclin‐dependant kinase 5; Cas‐3 = caspase 3; PGC‐1α= peroxisome proliferator‐activated receptor gamma co‐activator 1 alpha; –Ac = deacetylation; +P = phosphorylation.

Figure 2

Proposed metabolic pathway of resveratrol. Metabolites were identified in rat or human urine and in human liver microsomes. The asterisk indicates the metabolites identified as cis‐ and trans‐isomers but were excluded for image clarity. Cis‐isomers are glucuronidated and sulfated faster than trans‐isomers. Data obtained by Piver et al. [106], Wang et al. [126], and Urpi‐Sarda et al. [127].