4. Therapeutic Strategies in Dementia
Modern therapeutic strategies in AD are addressed to interfering with the main pathogenic mechanisms potentially involved in AD. Major pathogenic events (drug targets) and their respective therapeutic alternatives include the following: genetic defects, β-amyloid deposition, tau-related pathology, apoptosis, neurotransmitter deficits, neurotrophic deficits, neuronal loss, neuroinflammation, oxidative stress, calcium dysmetabolism, neuronal hypometabolism, lipid metabolism dysfunction, cerebrovascular dysfunction, neuronal dysfunction associated with nutritional and/or metabolic deficits, and a miscellany of pathogenic mechanisms potentially manageable with diverse classes of chemicals or biopharmaceuticals [6,7,8,9,10,11,12,13,14,15,16,17,99,104]. Since the early 1980s, the neuropharmacology of AD was dominated by the acetylcholinesterase inhibitors, represented by tacrine, donepezil, rivastigmine, and galantamine [4,5,111]. Memantine, a partial NMDA antagonist, was introduced in the 2000s for the treatment of severe dementia [112]; and the first clinical trials with immunotherapy, to reduce amyloid burden in senile plaques, were withdrawn due to severe ADRs [113,114]. During the past few years no relevant drug candidates have been postulated for the treatment of AD, despite the initial promises of β- and γ-secretase inhibitors [11,115,116]. However, assuming that the best treatment for AD is neuronal death prevention prior to the onset of the disease, novel therapeutic options and future candidate drugs for AD might be a new generation of anti-amyloid vaccines, such as DNA Aβ42 trimer immunization [117], heterocyclic indazole derivatives [inhibitors of the serum- and glucocorticoid-inducible-kinase 1 (SGK1)] [118], NSAID-like compounds [119], IgG-single chain Fv fusion proteins [120], Hsp90 inhibitors and HSP inducers [121], inhibitors of class I histone deacetylases [122], some phenolic compounds [123], agonists of the peroxisome proliferator activated receptor gamma (PPARgamma) [124], microRNAs [125], and gene silencing (RNAi) [126].