Biochemically, Alzheimeŕs disease (AD) is characterized by the presence of abnormal deposition of beta amyloid peptide (Aβ), which is generated by proteolytic processing from its precursor, the amyloid precursor protein (APP) in a non-physiological pathway. The presence of Aβ in the brain is strongly correlated with cognitive impairment, cholinergic deficiency, bioenergetics disruption, cell death and DNA damage. Galanthamine is an acetylcholinesterase inhibitor (AChEI) used to symptomatic treatment of Alzheimeŕs disease (AD). Several studies have showed that galanthamine has antioxidant properties, anti-apoptotic action and also promotes neurogenesis; however, it is unknown whether galanthamine may present protection mechanisms against Aβinduced genomic instability. To understand the mechanisms of this neuroprotection, we studied the effects of galanthamine on the cell toxicity and DNA strand breaks induced by Aβ using a set of biomarkers such as clonogenic assay, cytokinesis block micronucleus cytome (CBNM-cyt) and comet assay. The results showed that galanthamine treatments were capable to significantly reduce the Aβ-induced cytotoxicity and genotoxicity. In conclusion, this study demonstrated that in addition to inhibition of acetylcholinesterase (AChE), galanthamine exerts antigenotoxic properties. This relevant property of galanthamine is worthwhile exploring further which may improve the development of new diseases-modifying agents.

The lack of an effective treatment for Alzheimer' disease (AD), an increasing prevalence and severe neurodegenerative pathology boost medicinal chemists to look for new drugs. Currently, only acethylcholinesterase (AChE) inhibitors and glutamate antagonist have been approved to the palliative treatment of AD. Although they have a short-term symptomatic benefits, their clinical use have revealed important non-cholinergic functions for AChE such its chaperone role in beta-amyloid toxicity. We propose here the design, synthesis and evaluation of non-toxic dual binding site AChEIs by hybridization of indanone and quinoline heterocyclic scaffolds. Unexpectely, we have found a potent allosteric modulator of AChE able to target cholinergic and non-cholinergic functions by fixing a specific AChE conformation, confirmed by STD-NMR and molecular modeling studies. Furthermore the promising biological data obtained on human neuroblastoma SH-SY5Y cell assays for the new allosteric hybrid 14, led us to propose it as a valuable pharmacological tool for the study of non-cholinergic functions of AChE, and as a new important lead for novel disease modifying agents against AD.

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During the last years, several reports have provided evidence about adverse health effects on personal involved in Antineoplastic Drugs (ANPD) handling. ANPD has the ability to bind DNA, thus produce genotoxic damage. In this way, XRCC1 and XRCC3 proteins are necessary for efficient DNA repair and polymorphisms in this genes can be associated with an individual response to ANPD exposure. Therefore, the aim of this study was to evaluate genetic damage of occupational exposure to antineoplastic drugs and the possible effect of XRCC1 and XRCC3 polymorphisms in oncology employees from Bogotá, Colombia. Peripheral blood samples were obtained from 80 individuals, among exposed workers and healthy controls. The comet assay and Cytokinesis-block micronucleus cytome assay was performed to determinate genetic damage. From every sample DNA was isolated and genotyping for XRCC1 (Arg194Trp, Arg280His and Arg399Gln) and XRCC3 (Thr241Met) SNPs by PCR-RFLP. The exposed group showed a significant increase of comet assay results and micronucleus frequency, compared with unexposed group. It was observed a gender, exposure time and workplace effect on comet assay results. Our results showed no significant associations of comet assay results and micronucleus frequency with either genotype, allele, nor haplotype of XRCC1 and XRCC3 SNPs. The results suggest that occupational exposure to ANPD may lead to genotoxic damage and even be a risk to human health. To our knowledge, this is the first study to assess the genotoxic damage of occupational exposure to APND in South America.