J. Neurochem. (2009) 109, 744–754. Abstract Previous studies have reported that selective sigma‐1 agonists may improve cognitive abilities in experimental animals possibly via a cholinergic mechanism. However, the issue of a direct action on to sigma‐1 receptors in memory‐related brain areas has been much less investigated. The newly synthetised compound methyl(1R,2S/1S,2R)‐2‐[4‐hydroxy‐4‐phenylpiperidin‐1‐yl)methyl]‐1‐(4‐methylphenyl) cyclopropanecarboxylate [(±)‐PPCC] has recently been shown to possess high affinity for the sigma‐1 receptor where it specifically acts as an agonist. Here, the functional effects of (±)‐PPCC were investigated in rat models of mild or severe cognitive dysfunction based on a sub‐total (≤ 70–80%) or complete (≥ 90–95%) central cholinergic depletion induced by different doses of the selective immunotoxin 192 IgG‐saporin injected intraventricularly. At 5–6 weeks post‐surgery, the lesioned animals exhibited dose‐dependent deficits in reference memory, as assessed using the Morris water maze task, whereas working memory abilities, evaluated using the radial arm water maze task, appeared equally impaired in the two dose groups. Daily treatment with (±)‐PPCC significantly improved both reference and working memory performance in all lesioned animals but it did not affect intact or sham‐lesioned subjects. In a separate test, treatment with (±)‐PPCC reversed the learning deficits induced by the muscarinic receptor antagonist atropine sulphate in both control and mild‐lesioned rats. The effect was blocked in lesioned, but not normal animals by pre‐treatment with the sigma‐1 antagonist N‐[2‐(3,4‐dichlorophenyl)ethyl]‐N‐methyl‐2‐(dimethylamino)ethylamine. The results suggest that (±)‐PPCC may efficiently ameliorate perturbed cognitive abilities, and that these anti‐amnesic effects most probably occur via a direct interaction of the compound with sigma‐1 receptors.

Sigma-1 receptor agonists have recently attracted much attention as potential therapeutic drugs for cognitive and affective disorders, however, it is still unclear whether they act via modulation of transmitter release or activation of sigma-1 receptors in memory-related brain regions. In the present study,we have investigated the anti-amnesic and neuroprotective actions of the compound (-)-methyl (1S,2R)-2-{[1-adamantyl(methyl)amino]methyl}-1-phenylcyclopropane-carboxylate) [(-)-MR22],a selective sigma-1 receptor agonist able to protect cultured cortical neurons from amyloid toxicity. To this aim, cognitive deficits, cholinergic loss, and amyloid peptide accumulation were obtained in the rat by simultaneous injections of a selective immunotoxin and pre-aggregated amyloid peptide into the basal forebrain and the hippocampus, respectively. At about five–six weeks post-lesion, the double-lesioned animals exhibited dramatic deficits in spatial learning and memory, whereas animals with single injections of either compound were not or only marginally affected, in spite of equally severe cholinergic loss oramyloid deposition. Administration of (-)-MR22 appeared to reverse cognitive impairments in double lesioned animals, whereas pre-treatment with the selective sigma-1 antagonist BD1047 abolished this effect. Moreover, (-)-MR22 normalized the levels of cell-associated amyloid-β protein precursor (AβPP) in the neocortex and hippocampus, thus sustaining a non-amyloidogenic AβPP processing. By contrast, treatment with (-)-MR22 produced no effects whatsoever in intact animals. Thus, sigma-1 receptor agonists such as (-)-MR22 may ameliorate perturbed cognitive abilities and exert a protective action onto target neurons, holding promises as viable tools for memory enhancement and neuroprotection.

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