S. O. Bachurin

Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer's disease: a randomised, double-blind, placebo-controlled study

BACKGROUND Although treatments for Alzheimers disease sometimes improve cognition, functional ability, or behaviour compared with baseline levels, such improvements are inconsistent across studies and measures, and effects diminish over time. More effective treatments are needed. We assessed the safety, tolerability, and efficacy of dimebon in the treatment of patients with mild-to-moderate Alzheimers disease. METHODS We enrolled 183 patients with mild-to-moderate Alzheimers disease (mini-mental state examination [MMSE] scores 10-24) at 11 sites in Russia. Patients were randomly assigned by a computer-generated randomisation scheme to receive oral dimebon, 20 mg three times a day (60 mg/day [n=89]), or matched placebo (n=94). Other antidementia drugs were not allowed. The primary outcome measure assessed cognition, the difference in mean change from baseline to week 26, or last completed observation on the cognitive subscale of the Alzheimers disease assessment scale (ADAS-cog). All patients and study personnel were blinded throughout the study. We compared dimebon with placebo with an intention-to-treat analysis, with last observation carried forward (ITT-LOCF) imputation. Analyses were repeated on the fully evaluable population, defined as all patients in the intention-to-treat population who had an ADAS-cog at week 26 and at least 80% compliance. 134 patients (68 in dimebon group, 66 in placebo group) enrolled in the 6-month blinded extension phase of the study. This trial is registered with Clinicaltrials.gov, number NCT00377715. FINDINGS 155 (85%) patients completed the trial (78 [88%] in dimebon group, 77 [82%] in placebo group). Treatment with dimebon resulted in significant benefits in ADAS-cog compared with placebo (ITT-LOCF) at week 26 (mean drug-placebo difference -4.0 [95% CI -5.73 to -2.28]; p<0.0001). Results of the ITT-LOCF and the evaluable population analyses were much the same for all measures. Patients given dimebon were significantly improved over baseline for ADAS-cog (mean difference -1.9 [-2.92 to -0.85]; p=0.0005). Dimebon was well tolerated: dry mouth and depressed mood or depression were the most common adverse events associated with dimebon (12 [14%] patients for each symptom by week 26). The percentage of patients who had adverse events in the two groups did not differ. INTERPRETATION Dimebon was safe, well tolerated, and significantly improved the clinical course of patients with mild-to-moderate Alzheimers disease.

Antihistamine agent Dimebon as a novel neuroprotector and a cognition enhancer.

Abstract: Dimebon, launched earlier in Russia as an antihistamine drug, was evaluated as a representative of a new generation of anti‐Alzheimers drugs that have two beneficial actions: (1) to alleviate symptoms, and (2) to prevent progression of the disease. The drug demonstrated cognition and memory‐enhancing properties in the active avoidance test in rats treated with the neurotoxin AF64A, which selectively destroys cholinergic neurons. Dimebon protected neurons in the cerebellum cell culture against the neurotoxic action of β‐amyloid fragment (Aβ25−35, EC50= 25 μM). In vitro, Dimebon displayed Ca2+‐blocking properties (IC50= 57 μM, on isolated rat ileum intestine) and pronounced anticholinesterase activity (IC50= 7.9 μM and 42 μM for butyrylcholine esterase and acetylcholine esterase, respectively). It also exhibited strong anti‐NMDA activity in the prevention of NMDA‐induced seizures in mice (EC50= 42 ± 6 mg/kg i.p.). A beneficial effect of Dimebon in the therapy of Alzheimers disease was demonstrated in a pilot clinical trial performed in the Moscow Center of Gerontology. Fourteen patients who participated in the trial were evaluated for their state of personality and for the severity of the disease. The evaluation included orientation (space, place, time, and patient personality), memory for the past and present, life in present, speech, irritability, and so forth. During and after the eight‐week therapy with Dimebon, cognitive and self‐service functions of patients improved significantly, and psychopathic symptoms, anxiety, depression, tearfulness, and headache were substantially diminished. The results of these studies suggest Dimebon as a new candidate for the therapy of Alzheimers‐like disorders.

Mitochondria as a Target for Neurotoxins and Neuroprotective Agents

Abstract: Mitochondrial permeability transition pores represent a multiprotein complex that includes components of both inner and outer membrane. The pores regulate transport of ions and peptides in and out of mitochondria, and their regulation is associated with a general mechanism for maintaining Ca2+ homeostasis in the cell and apoptosis. Various pathologic factors may induce a pathologic activation of the permeability transition and an irreversible opening of mitochondria pores. This event is a major step in the development of neurotoxicity and neurodegeneration. This paper explores the effect of MPP+ and β‐amyloid fragment 25‐35, neurotoxins that are known to generate Parkinsons‐like syndrome and Alzheimers disease, on the regulation of the mitochondrial pores. Both neurotoxins induce opening of mitochondrial pores, which is prevented by cyclosporin A, a specific inhibitor of the permeability transition. The effect of MPP+ and β‐amyloid may be also prevented by an endogenous precursor of melatonin, N‐acetylserotonin, by an anti‐Alzheimers medication tacrine, and by dimebon, which is in development as an agent for the therapy of Alzheimers disease and other types of dementia. The paper illustrates that the effect on mitochondrial pores is an important aspect of the mechanism of neurotoxicity. Substances that may prevent opening of mitochondrial pores induced by neurotoxins may preserve the mitochondrial function and, thus, may have potential as neuroprotective agents.

Comparative Study of Action Mechanisms of Dimebon and Memantine on AMPA- and NMDA-Subtypes Glutamate Receptors in Rat Cerebral Neurons

Dimebon in low concentrations potentiated activity of AMPA-receptors in rat cerebellar Purkinje neurons, while memantine produced only an insignificant potentiation in a small group of these cells. In cortical neurons of rat brain memantine efficiently blocked NMDA-induced currents in dimebon-insensitive neurons. By contrast, its effect was far weaker in neurons, where the blocking action of dimebon on NMDA-receptors was most pronounced. It was hypothesized that the differences in the effects of memantine and dimebon are determined by their interaction with different sites of NMDA-receptors.

Methylene blue and dimebon inhibit aggregation of TDP-43 in cellular models

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD‐U) are major neurodegenerative diseases with TDP‐43 pathology. Here we investigated the effects of methylene blue (MB) and dimebon, two compounds that have been reported to be beneficial in phase II clinical trials of Alzheimers disease (AD), on the formation of TDP‐43 aggregates in SH‐SY5Y cells. Following treatment with 0.05 μM MB or 5 μM dimebon, the number of TDP‐43 aggregates was reduced by 50% and 45%, respectively. The combined use of MB and dimebon resulted in a 80% reduction in the number. These findings were confirmed by immunoblot analysis. The results indicate that MB and dimebon may be useful for the treatment of ALS, FTLD‐U and other TDP‐43 proteinopathies.

Dimebon and Tacrine Inhibit Neurotoxic Action of β-Amyloid in Culture and Block L-type Ca2+ Channels

Dimebon, a Russian-made drug, inhibited toxic effects of beta -amyloid on cultured neurons. Excessive accumulation of beta-amyloid in the brain is characteristic of Alzheimer dementias. Antialzheimer preparations tacrine and dimebon improve survival of cerebellar granule cells during long-term incubation with Ab25-35, the neurotoxic fragment of beta-amyloid. Both preparations can block potential-dependent Ca2+ entry into neurons by about 20%, which is explained by their selective action on L-type Ca2+ channels. It was assumed that the neuroprotective effect of dimebon and tacrine against Ab25-35 partially depends on inhibition of potential-dependent Ca2+ entry.

Oxidative Stress Mediated Mitochondrial and Vascular Lesions as Markers in the Pathogenesis of Alzheimer Disease

Mitochondrial dysfunction plausibly underlies the aging-associated brain degeneration. Mitochondria play a pivotal role in cellular bioenergetics and cell-survival. Oxidative stress consequent to chronic hypoperfusion induces mitochondrial damage, which is implicated as the primary cause of cerebrovascular accidents (CVA) mediated Alzheimers disease (AD). The mitochondrial function deteriorates with aging, and the mitochondrial damage correlates with increased intracellular production of oxidants and pro-oxidants. The prolonged oxidative stress and the resultant hypoperfusion in the brain tissues stimulate the expression of nitric oxide synthase (NOS) enzymes, which further drives the formation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). The ROS and RNS collectively contributes to the dysfunction of the blood-brain barrier (BBB) and damage to the brain parenchymal cells. Delineating the molecular mechanisms of these processes may provide clues for the novel therapeutic targets for CVA and AD patients.

Dimebon improves learning in animals with experimental Alzheimer's disease

Systemic administration of antihistamine drug dimebon improves active avoidance conditioning in rats with chronic partial deprivation of cerebral cholinergic functions caused by intracerebroventricular injections of AF64A. The effects of dimebon on learning are similar to those of tacrine used in the treatment of Alzheimers disease.

Drugs in Clinical Trials for Alzheimer's Disease: The Major Trends.

Alzheimers disease (AD) is characterized by a chronic and progressive neurodegenerative process resulting from the intracellular and extracellular accumulation of fibrillary proteins: beta‐amyloid and hyperphosphorylated Tau. Overaccumulation of these aggregates leads to synaptic dysfunction and subsequent neuronal loss. The precise molecular mechanisms of AD are still not fully understood but it is clear that AD is a multifactorial disorder and that advanced age is the main risk factor. Over the last decade, more than 50 drug candidates have successfully passed phase II clinical trials, but none has passed phase III. Here, we summarize data on current “anti‐Alzheimers” agents currently in clinical trials based on findings available in the Thomson Reuters «Integrity» database, on the public website www.clinicaltrials.gov, and on database of the website Alzforum.org. As a result, it was possible to outline some major trends in AD drug discovery: (i) the development of compounds acting on the main stages of the pathogenesis of the disease (the so‐called “disease‐modifying agents”) — these drugs could potentially slow the development of structural and functional abnormalities in the central nervous system providing sustainable improvements of cognitive functions, which persist even after drug withdrawal; (ii) focused design of multitargeted drugs acting on multiple molecular targets involved in the pathogenesis of the disease; (3) finally, the repositioning of old drugs for new (anti‐Alzheimers) application offers a very attractive approach to facilitate the completion of clinical trials.

Antioxidant and Antiaging Activity of N-Acetylserotonin and Melatonin in the in Vivo Models

Abstract: It is generally accepted that antioxidant properties of melatonin significantly contribute to its antiaging effect. Antioxidant effects of N‐acetylserotonin (NAS), a melatonin precursor and metabolite, might predict its antiaging action as well. The antiaging effect of NAS was studied in female retired breeders and male C3H mice. Both NAS and melatonin administered with drinking water prolonged life span in male animals by about 20% versus control animals (p < 0.01) but did not affect the life span of female mice. Antioxidative activity was evaluated by determining the malonaldehyde + 4‐hydroxynonenal (MDA + 4‐HNE) and cellular glutathion peroxidase (GPx) levels in male, 11‐month‐old, C57Bl/6J mice with very limited (if any) capacity to convert pineal NAS into melatonin. NAS increased the antioxidant capacity of kidney. Both NAS and melatonin (four weeks daily i.p. injections) increased the antioxidant capacity of brain as demonstrated by decreased MDA + 4‐HNE and increased GPx levels. NAS‐treated C57Bl/6J mice experienced a weight loss of 9%, whereas the saline and melatonin groups only 3%. NAS‐ and melatonin‐treated animals had healthy and luxuriant fur coats with some gray fur in the melatonin group; animals in the saline group had large areas of baldness. This study demonstrates, for the first time, the antiaging effect of NAS. This effect needs to be confirmed in animals with impaired capacity to convert NAS into melatonin.