Anti‐amnesic properties of (±)‐PPCC, a novel sigma receptor ligand, on cognitive dysfunction induced by selective cholinergic lesion in rats

Abstract

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.

The effects of sigma (σ1) receptor‐selective ligands on muscarinic receptor antagonist‐induced cognitive deficits in mice

“…Antonini et al (2009; demonstrated that occupation of the rat σ1 receptor by PPCC and (-)-MR22 can prevent cognitive impairment caused by the combined administration of the muscarinic receptor antagonist atropine and immunotoxin 192 IgG-saporin, which leads to a loss of cholinergic neurons in the basal forebrain. Those authors suggest that the observed PPCC and (-)-MR22 mediated neuroprotection might be due to stabilization of IP3 receptors that prolong the flow of calcium into the mitochondria.…”

“…Administration of the competitive cholinergic muscarinic receptor antagonist scopolamine causes cognitive dysfunctions similar to those observed in normal aging and AD (Ebert and Kirch, 1998;Bejar et al, 1999;Klinkenberg and Blokland, 2010). A scopolamine-dependent model of cognitive deficits has been used to screen for potential cognition-enhancing drugs (Flood and Cherkin, 1986;Ennaceur and Meliani, 1992;Antonini et al, 2009;Klinkenberg and Blokland, 2010). Since the sigma σ1 receptor is known to potently modulate cholinergic neurotransmission at different levels (van Waarde et al, 2011), we investigated the effect of our novel σ1 receptorselective ligand, LS-1-137, on scopolamine-dependent cognitive deficits.…”

“…A scopolamine-dependent model of cognitive deficits has been used to screen for potential cognition-enhancing drugs (Flood and Cherkin, 1986;Ennaceur and Meliani, 1992;Antonini et al, 2009;Klinkenberg and Blokland, 2010). Since the sigma σ1 receptor is known to potently modulate cholinergic neurotransmission at different levels (van Waarde et al, 2011), we investigated the effect of our novel σ1 receptorselective ligand, LS-1-137, on scopolamine-dependent cognitive deficits.…”

The cholinergic system, sigma-1 receptors and cognition

“…a total absence of cholinergic neurons in the basal forebrain nuclei [2]. Pretreatment of animals with the sigma-1 receptor antagonist BD1047 blocked the anti-amnesic effects of (±)-PPCC [2].…”

Anti-Amnesic and Neuroprotective Actions of the Sigma-1 Receptor Agonist (-)-MR22 in Rats with Selective Cholinergic Lesion and Amyloid Infusion

“…In a recent investigation, we have reported that the compound (±)-PPCC, a highly selective sigma-1 receptor agonist, with virtually no affinity for cholinergic receptors, effectively ameliorates spatial learning and memory performance in rat paradigms of mild or severe cognitive dysfunction via a direct interaction with sigma-1 receptors [35].…”