Experimental Research on Nitric Oxide and the Therapy of Alzheimer Disease: A Challenging Bridge

Raffaella      Siciliano; Eugenio      Barone; Vittorio      Calabrese; Vincenzo      Rispoli; D.      Allan Butterfield; Cesare      Mancuso

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by severe cognitive impairment due to neuronal death. Although the lost of cognitive function is the main problem for AD subjects, death occurs due to secondary issues such as concomitant infections, respiratory complications or multi-organ failure. Current drugs used in AD are acetylcholinesterase inhibitors and antagonists of the N-methyl-D-aspartate receptor. These drugs may only slightly improve cognitive functions but have only very limited impact on the clinical course of the disease. Over the last 5 years, new targets were identified and innovative drugs against AD have been designed and developed. Worthy of mention are β-secretase inhibitors, monoclonal antibodies against amyloid-β-peptide and tau inhibitors. However, although promising beneficial effects were highlighted in the data from preclinical studies, only few of these new drugs improved cognitive functions for a significant time frame in AD subjects. Controversial is the therapeutic effect on AD obtained through the manipulation of the nitric oxide synthase/nitric oxide system since the potential toxic effects on brain function could overcome the beneficial effects. The aim of this review is to analyze from a pharmacologic point of view both old and new drugs developed for the treatment of AD. In addition, the risk/benefit ratio related to the modulation of the nitric oxide synthase/nitric oxide system in AD brain will be analyzed.

Keywords: Acetylcholinesterase inhibitors, Alzhiemers disease, Amyloid β peptide, Memantine, Nitric oxide, Secretases, Tau Protein, APOE, CREB, Latrepirdine, EVT 101