Anticholinesterase and Antioxidant Activity of New Binary Conjugates of γ-Carbolines.

The synthesized new binary conjugates of tetrahydro-γ-carbolines, which contained ditriazole spacers of different length, exhibited considerable anticholinesterase and antioxidant activity as well as the potential ability to block the acetylcholinesterase-induced aggregation of ß-amyloid in contrast to the original prototype Dimebon. This makes the compounds promising candidates for further investigation as drugs for the treatment of Alzheimer's disease. Special attention should be given to the conjugate containing the hexamethylene intertriazole spacer, which can be considered as a leader in this series of compounds.

Influence of Al3+, Fe3+ and Zn2+ Ions on Phosphorylation of Tubulin and Microtubulo-Associated Proteins of Rat Brain.

Phosphorylation of τ-protein, a component of microtubules in brain neurons, is a key pathomorphological sign of Alzheimer's disease. The development of this intracellular defect can be promoted by Al3+, Fe3+, and Zn2+ ions. The concentrations of these ions in the brain are considerably elevated in Alzheimer's disease. We performed a comparative study of phosphorylation of microtubular proteins of rat brain in the presence of Al3+, Fe3+, and Zn2+ ions in concentrations of 10-500 µM and microtubular proteins of brain of patients with Alzheimer's disease. The most likely candidate for the role of a factor that promotes hyperphosphorylation of τ-protein is Al3+ in concentrations of 250 and 500 µM.

Effect of Aluminum, Iron, and Zinc Ions on the Assembly of Microtubules from Brain Microtubule Proteins.

Al(3+), Fe(3+), and Zn(2+) ions can disturb microtubule assembly from tubulin and microtubuleassociated proteins in rat brain. The main structural forms of these microtubules are rings and tangled bundles. These structures are formed only in the presence of Al(3+) and Fe(3+) ions. Therefore, Zn(2+) ions can be excluded from possible causes of structural abnormalities in microtubules during Alzheimer's disease. Al(3+) ions are the most probable etiological cause of Alzheimer's disease. The concentration of Al(3+) ions affecting the structure of microtubules is one order of magnitude lower than that of Fe(3+) ions (10 and 100 µM, respectively), which corresponds to their brain concentration reported in Alzheimer's disease.

Effects of anti-Alzheimer drugs on phosphorylation and assembly of microtubules from brain microtubular proteins.

We studied the effects of anti-Alzheimer drugs (tacrine, amiridine, and memantine) on phosphorylation of tubulin and microtubule-associated proteins isolated from rat brain, evaluated the capacity of these proteins to polymerize into microtubules after addition of study pharmacological agents, and analyzed the structure of generated microtubules. It was shown that test substances impair assembly of microtubules to a different extent. Dose-dependent effects of these agents on phosphorylation of tubulin and microtubule-associated proteins were observed. Triazolam (not approved for clinical use as anti-Alzheimer drug) in the same concentrations was used as the reference substance in the same tests. It was observed that this substance even in minimal concentration induced the most pronounced changes in microtubule structure. A direct correlation between the capacity of the test substances to modulate tubulin phosphorylation and to impair microtubule structure was found: the more the substance inhibited tubulin phosphorylation, the more it disordered microtubule structure.

Effect of tacrine, amiridine, akatinol memantine, and triazolam on phosphorylation, structure, and assembly of microtubules from brain microtubular proteins in Alzheimer diseases.

In in vitro experiments, amiridine in concentration of 100, 200, and 300 microM restored disturbed structure of microtubules assembled from tubulin and microtubule-associated proteins isolated from the brain of patients with Alzheimer disease. Tacrine in a concentration of 100, 250, and 500 microM inhibited phosphorylation of tubulin and microtubule-associated proteins isolated from the brain of patients with Alzheimer disease, while memantine and amiridine in the specified concentrations had no effect on phosphorylation.

Disturbed assembly of human cerebral microtubules in Alzheimer's disease.

It is shown for the first time that microtubular proteins isolated from the brain of patients with Alzheimer's disease can in vitro polymerize into microtubules with abnormal structure.

[Two-dimensional electrophoretic analysis of the protein spectrum of human brain structures in schizophrenia and senile dementia of the Alzheimer type]. / Dvukhmernyi élektroforeticheskii analiz belkovogo spektra struktur golovnogo mozga cheloveka pri shizofrenii i senil'noi dementsii al'tsgeimerovskogo tipa.

Analysis was made of the composition of four structures of human brain in health (n-12), schizophrenia (n-10), and Alzheimer's senile dementia (n-8). Protein maps obtained by means of two-dimensional electrophoresis were used to analyze tissue samples of the structures under study. In the investigation, the neocortex was represented by the frontal cortex (field 10), the old cortex by the hippocamp, the midbrain by black substance, and medulla oblongata by the inferior olive. Comparative study of the protein maps revealed quantitative differences in certain brain structures in health as well as differences between these structures in health and mental pathology.