Simultaneous versus solitary pharmacological manipulation of NMDA- and AMPA- receptors: effects of new drugs on contextual learning and its extinction

Poster (2012, July 17)

Both the attenuation of the NMDA-receptor mediated transmission via low affinity blockade mechanism, and the stimulation of AMPA receptor-mediated signaling were shown to result in beneficial ... [more ▼]

Both the attenuation of the NMDA-receptor mediated transmission via low affinity blockade mechanism, and the stimulation of AMPA receptor-mediated signaling were shown to result in beneficial neurobiological effects, such as an enhancement of memory and neurogenesis. We aimed to compare the effects of acute pharmacological manipulations of these mechanisms, exerted simultaneously or solely in mice, on learning of two mouse tasks with distinct predominant dependency on either glutamate receptor subtype. In a step-down avoidance task, memantine, low affinity NMDA receptor blocker (5 mg/kg), but not ampakine QQX (5 mg/kg) increased memory scores. In contrast, extinction of contextual fear conditioning was significantly enhanced by the latter, but not by the first drug. Among four new isothiourea derivates used at the doses 0.5-1 mg/kg, one compound that showed a maximal potency with respect to both glutamatergic mechanisms, as well as dimebon (1 mg/kg), had the most prominent memory enhancing effects. Thus, simultaneous low affinity blocade of the NMDA receptor and stimulation of AMPA-mediated transmission can result in eminent pro-cognitive activities. These data point to the importance of multi-target drug mechanism in the regulation of cognitive functions and suggest its potential for clinical implications. [less ▲]

Dimebon enhances hippocampus-dependent learning in both appetitive and inhibitory memory tasks in mice

Poster (2011, January 31)

Dimebon, a compound recently proposed for a treatment of Alzheimer’s disorder was suggested to have memory enhancing properties in pre-clinical and clinical studies. We investigated whether dimebon at ... [more ▼]

Dimebon, a compound recently proposed for a treatment of Alzheimer’s disorder was suggested to have memory enhancing properties in pre-clinical and clinical studies. We investigated whether dimebon at doses acutely (0.1 mg/kg and 0.5 mg/kg) or repeatedly (0.1 mg/kg) administered to mice via i.p. injections, increases memory scores respectively in an appetitive and an inhibitory learning task. Acute treatment with dimebon at the dose 0.1 mg/kg did not affect learning scores in either 3-month-old C57BL/6N or CD1 mice. Acute treatment with higher dose of dimebon (0.5mg/kg) was found to enhance inhibitory learning in 3- and 7-month-old mice as shown in the step-down avoidance paradigm in C57BL/6N mice. No effects on learning were seen in CD1 mice. In a model of appetitive learning, a spatial version of the Y-maze, repeated treatment with dimebon increased the rate of correct choices and decreased the latency of accessing a water reward after water deprivation. Repeated administration of dimebon also increased the duration of drinking behaviour during training/testing procedures although behaviours in others tests or water consumption were not altered. 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. [less ▲]

Limitations in transplantation of astroglia-biomatrix bridges to stimulate corticospinal axon regrowth across large spinal lesion gaps

in Neuroscience Letters (2006), 400(3), 208-212

Regrowth of injured axons across rather small spinal cord lesion gaps and subsequent functional recovery has been obtained after many interventions. Long-distance regeneration of injured axons across ... [more ▼]

Regrowth of injured axons across rather small spinal cord lesion gaps and subsequent functional recovery has been obtained after many interventions. Long-distance regeneration of injured axons across clinically relevant large spinal lesion gaps is relatively unexplored. Here, we aimed at stimulating long-distance regrowth of the injured corticospinal (CS) tract. During development, an oriented framework of immature astrocytes is important for correct CS axon outgrowth. Furthermore, a continuous growth promoting substrate may be needed to maintain a CS axon regrowth response across relatively large spinal lesion gaps. Hence, we acutely transplanted poly(D,L)-lactide matrices, which after seeded with immature astrocytes render aligned astrocyte-biomatrix complexes (R. Deumens, et al. Alignment of glial cells stimulates directional neurite growth of CNS neurons in vitro. Neuroscience 125 (3) (2004) 591-604), into 2-mm long dorsal hemisection lesion gaps. In order to create a growth promoting continuum, astrocyte suspensions were also injected rostral and caudal to the lesion gap. During 2 months, locomotion was continuously monitored. Histological analysis showed that astrocytes injected into host spinal tissue survived, but did not migrate. None of the astrocytes on the biomatrices survived within the lesion gap. BDA-labeled CS axons did not penetrate the graft. However, directly rostral to the lesion gap, 120.9 +/- 38.5% of the BDA-labeled CS axons were present in contrast to 12.8 +/- 3.9% in untreated control animals. The observed anatomical changes were not accompanied by locomotor improvements as analyzed with the BBB and CatWalk. We conclude that although multifactorial strategies may be needed to stimulate long-distance CS axon regrowth, future studies should focus on enhancing the viability of cell/biomatrix complexes within large spinal lesion gaps. [less ▲]