Dimebon, launched earlier in Russia as an antihistamine drug, was evaluated as a representative of a new generation of anti‐Alzheimer's 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 Alzheimer's 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 Alzheimer's‐like disorders.

The prevalence of depression increases with aging. We hypothesized that like humans, old animals exhibit anhedonic-like behavior, along with signs of behavioral despair. In rodents, anhedonia, a reduced sensitivity to reward, which is listed as a core feature of major depression in the DSM-IVR, can be measured by a decrease in intake of and preference for sweet solutions. Here, sucrose intake, forced swimming, immobility in the modified tail suspension test, novelty exploration, grooming, anxiety and locomotor activity were compared in naïve 3-and 18-month-old male C57BL/6 mice. The absolute amounts and the ratio of consumed 1% sucrose solution to water intake was significantly smaller in 18-month-old mice than in 3-month-old mice. The consumption of 5%-sucrose solution requiring high levels of drinking effort, novelty exploration in two setups and grooming behavior in the splash test were reduced in older animals. Analysis of other behaviors suggested that the above-mentioned signs of anhedonic-like traits were unlikely to be attributable to the potential effect of aging on metabolic needs for water, taste perception, motor capabilities or the induction of essential anxiety and neophobia. A 4-week treatment with the antidepressant imipramine (7 mg/kg/day) or dimebon, a compound with suggested neuroprotective proneurogenic properties (1 mg/kg/day) restored sucrose intake and preference in 18-month-old mice. Meanwhile, young and old mice showed no differences in the parameters of behavioral despair evaluated in the forced swim and modified tail suspension tests. Thus, the behavioral profile of aged mice parallels that of humans with elderly depression, in whom the symptoms of hedonic deficits typically outweigh affective disturbances. The assessment of anhedonic-like traits with the sucrose preference test in 18-month-old mice will be useful in preclinical studies of elderly depression.

a b s t r a c t a r t i c l e i n f oPre-clinical and clinical studies on dimebon (dimebolin or latrepirdine) have demonstrated its use as a cognitive enhancer. Here, we show that dimebon administered to 3-month-old C57BL6N mice 15 min prior to training in both appetitive and inhibitory learning tasks via repeated (0.1 mg/kg) and acute (0.5 mg/kg) i.p. injections, respectively, increases memory scores. Acute treatment with dimebon was found to enhance inhibitory learning, as also shown in the step-down avoidance paradigm in 7-month-old mice. Bolus administration of dimebon did not affect the animals' locomotion, exploration or anxiety-like behaviour, with the exception of exploratory behaviour in older mice in the novel cage test. In a model of appetitive learning, a spatial version of the Y-maze, dimebon increased the rate of correct choices and decreased the latency of accessing a water reward after water deprivation, and increased the duration of drinking behaviour during training/testing procedures. Repeated treatment with dimebon did not alter the behaviours in other tests or water consumption. Acute treatment of water-deprived and non-water-deprived mice with dimebon also did not affect their water intake. Our data suggest that dimebon enhances hippocampus-dependent learning in both appetitive and inhibitory tasks in mice.

Effects of tacrine (1,2,3,4-tetrahydro-9-aminocridine) on memory deficits in rats treated with ethylcholine aziridinium ion (AF64A) were studied using active avoidance test in the two-way shuttle box. Neurotoxin AF64A injected at a dose of 6 nmol (i.c.v., bilaterally) causes nonspecific tissue damage in hippocampal fields CA2 and CA3. Two weeks after treatment with 6 nmol, AF64A active avoidance performance of toxin-treated rats was significantly deteriorated compared to vehicle-treated animals estimated in learning test (68 +/- 3.5 and 83 +/- 3.2% of correct responses, respectively; p < 0.01) and in retention test (53 +/- 5 and 76 +/- 3.6%, respectively; p < 0.01). Under these conditions, chronic treatment with tacrine at a daily dose of 1 mg/kg for 12-14 d reverses the effect of AF64A on the active avoidance performance both in learning (78 +/- 3.2%) and retention (72 +/- 4%) tests. It is supposed that behavioral effects of tacrine considerably depend on a severity of neurodegeneration in the hippocampus.

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Based on these results, aminoderivatives of securinine scaffold are promising compounds for development of new drugs for the treatment of neurodegenerative diseases.

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