A Novel Tetrahydroacridine Derivative with Potent Acetylcholinesterase Inhibitory Properties and Dissociative Capability against Aß42 Fibrils Confirmed by In Vitro Studies.

Alzheimer's disease (AD) is one of the most common causes of dementia, accounting for more than 60% of all cases. It is a neurodegenerative disease in which symptoms such as a decline in memory, thinking, learning, and organizing skills develop gradually over many years and eventually become more severe. To date, there is no effective treatment for the cause of Alzheimer's disease, and the existing pharmacological options primarily help manage symptoms. Treatment is mainly based on acetylcholinesterase (AChE) inhibitors such as donepezil, rivastigmine, and galantamine, which exhibit numerous adverse cardiovascular and gastrointestinal effects due to excessive stimulation of peripheral cholinergic activity involving muscarinic receptors. Therefore, in addition to the obvious drugs that act on the cause of the disease, new drugs based on AChE inhibition that show the fewest side effects are needed. One potential drug could be a new compound under study, tetrahydroacridine derivative (CHDA), which showed significant potential to inhibit the AChE enzyme in previous in vitro studies. The present study shows that while having very potent AChE inhibitory properties, CHDA is a compound with low toxicity to nerve cell culture and living organisms. In addition, it exhibits dissociative activity against amyloid ß fibrils, which is extremely important for applications in Alzheimer's disease therapy.

A tetrahydroacridine derivative and its conjugate with gold nanoparticles: promising agents for the treatment of Alzheimer's disease.

A new tetrahydroacridine derivative (CHDA) with acetylcholinesterase inhibitory properties was synthesized. Using a range of physicochemical techniques, it was shown that the compound strongly adsorbs onto the surface of planar macroscopic or nanoparticulate gold, forming a nearly full monolayer. The adsorbed CHDA molecules reveal well-defined electrochemical behavior, being irreversibly oxidized to electroactive species. The CHDA also exhibits strong fluorescence, which is effectively quenched after adsorption onto gold via a static quenching mechanism. Both CHDA and its conjugate reveal considerable inhibitory properties against acetylcholinesterase activity, which is promising from the perspective of therapeutic application in the treatment of Alzheimer's disease. Moreover, both agents appear to be non-toxic as demonstrated using in vitro studies. On the other hand, conjugation of CHDA with nanoradiogold particles (Au-198) offers new potential diagnostic perspectives in medical imaging.

Preparation of Surface-Supported Polylactide Spherical-Cap Particles.

Biodegradable polymer particles are of considerable importance due to their multiple applications in medical diagnostics and therapy. Spherical-cap particles have been prepared in a very general and simple method by melting a thin polymer film supported on a solid substrate that is in contact with a hydrophilic solvent. The melted polymer forms droplets which transform into solid particles attached to the surface after cooling down the sample. This approach has been demonstrated for polylactide adlayers on glass, which, when melted in glycerol, produce an array of polymer particles supported on the surface. The size of the particles depends on the experimental conditions and ranges from tens of nanometers to several micrometers. The particles can be employed to incorporate guest species, for example, drug molecules or inorganic nanoparticles. This has been confirmed herein through entrapment of an anticancer drug (doxorubicin) and radiogold (Au-198) nanoparticles. The resulting structures have been examined using a number of complementary physicochemical techniques including scanning and transmission electron microscopy, atomic force and optical microscopy as well as Raman and fluorescence spectroscopy.

Hypoxic and Hypercapnic Responses in Transgenic Murine Model of Alzheimer's Disease Overexpressing Human AßPP: The Effects of Pretreatment with Memantine and Rivastigmine.

Despite the severe respiratory problems reducing the quality of life for Alzheimer's disease (AD) patients, their causes are poorly understood. We aimed to investigate hypoxic and hypercapnic respiratory responses in a transgenic mouse model of AD (AßPP V717I) overexpressing AßPP and mimicking early-onset AD. The cholinesterase inhibitor rivastigmine and the NMDA receptor antagonist memantine were used to investigate the effects of drugs, used to treat AD cognitive dysfunction, on breathing in hypoxia and hypercapnia. We found a significant increase in the respiratory response to hypercapnia and no difference in the hypoxic response in APP+ mice, compared with the control group (APP-). Memantine had no effect on respiration in either group, including responses to hypoxia and hypercapnia. Rivastigmine depressed resting ventilation and response to hypercapnia irrespective of the mice genotype. Reduction in hypoxia-augmented ventilation by rivastigmine was observed only in APP+ mice, which exhibited lower acetylcholinesterase activity in the hippocampus. Treatment with rivastigmine reduced the enzyme activity in both groups equally in the hippocampus and brainstem. The increased ventilatory response to hypercapnia in transgenic mice may indicate alterations in chemoreceptive respiratory nuclei, resulting in increased CO2 sensitivity. Rivastigmine is a potent reductant of normoxic and hypercapnic respiration in APP+ and APP- mice.