DRUG FOCUS: S 18986: A positive allosteric modulator of AMPA-type glutamate receptors pharmacological profile of a novel cognitive enhancer

Abstract

Alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) type glutamate receptors are critical for synaptic plasticity and induction of long-term potentiation (LTP), considered as one of the synaptic mechanisms underlying learning and memory. Positive allosteric modulators of AMPA receptors could provide a therapeutic approach to the treatment of cognitive disorders resulting from aging and/or neurodegenerative diseases, such as Alzheimer disease (AD). Several AMPA potentiators have been described in the last decade, but for the moment their clinical efficacy has not been demonstrated due to the complexity of the target, AMPA receptors, and the difficulty in studying cognition in animals and humans. A better understanding of the mechanism of action of this type of drug remains an important issue, if knowledge of these compounds is to be increased and if this novel therapeutic approach is to be an interesting research area. Among the AMPA potentiators, S 18986 is emerging as a new selective positive allosteric modulator of AMPA-type glutamate receptors. S 18986, as with other positive AMPA receptor modulators, increased induction and maintenance of LTP in the hippocampus as well as the expression of brain-derived neurotrophic factor (BDNF) both in vitro and in vivo. Its cognitive-enhancing properties have been demonstrated in various behavioral models (procedural, spatial, "episodic," working, and relational/declarative memory) in young-adult and aged rodents. It is interesting to note that memory-enhancing effects appeared more robust in middle-aged animals compared with aged ones and in "episodic" and spatial memory tasks. From these results, S 18986 is expected to treat memory deficits associated with early cerebral aging and neurological diseases in elderly people.

Figure 1

The chemical structure of S 18986—3a, 10‐dihydro‐5,5‐dioxo‐4H‐(S)‐pyrrolidino [1,2‐c][1, 2, 4] benzothiadiazine.

Figure 2

(A) Stereoselectivity of S 18986 on AMPA‐induced current in Xenopus laevis oocytes injected with rat cortex mRNA. Amplitude of the AMPA‐evoked current in the presence of the drug is normalized as a percentage of that induced in the absence of drug on the same oocyte. Two‐way ANOVA (Drug × Dose) followed by Newman–Keuls test. *P≤ 0.05; ***P≤ 0.001vs S 19024 versus (R)‐S 18986; ***P≤ 0.001S versus 17951, racemate. Mean ± SEM (n = 5).
(B) Selectivity of S 18986 for AMPA receptors. Dose effects of S 18986 on AMPA‐, kainate‐, and NMDA‐evoked currents in Xenopus laevis oocytes injected with rat cortex mRNA. Amplitude of the agonist‐evoked current in the presence of the drug is normalized as a percentage of that induced in the absence of drug on the same oocyte. The results are shown as mean ± SEM (n = 4/5).
(C) Effects of S 18986 on AMPA‐induced current in Xenopus laevis oocytes injected either with human hippocampus mRNA or rat cortex mRNA. Amplitude of the AMPA‐evoked current in the presence of the drug is expressed as a percentage of that induced in the absence of drug in the same oocyte. The results are shown as mean ± SEM (n = 4/5). EC_2X corresponds to the concentration of S18986 responsible for a 2‐fold increase in the amplitude of AMPA‐evoked response.

Figure 3

Effects of S 18986 on AMPA‐and NMDA‐mediated excitatory postsynaptic Field potentials evoked in the CA₁ region of hippocampal slices. (A) The amplitude of the AMPA‐mediated EPSfP in the presence of each concentration of S 18986–1 or the vehicle was expressed as a percentage of that recorded before the application (basal value). The percentage of change of the amplitude of the synaptic response is plotted as a function of the concentration. The results are expressed as mean ± SEM, two‐way ANOVA (Drug × Dose) followed by Newman–Keuls test to compare drugs effects. The results are shown as mean ± SEM (n = 6). **P≤ 0.01; ***P≤ 0.001 versus vehicle. (B) Representative examples of AMPA‐mediated EPSfPs evoked in the hippocampal CAI area following stimulation of the Schaeffer Collaterals. Application of S 18986 induced a dose‐dependent increase of both the amplitude and the duration of the AMPA‐mediated EPSP. (C) Representative examples of NMDA‐ mediated EPSfPs evoked in the hippocampal. CAI area following stimulation of the Schaeffer Collaterals in the presence of NBQX, an antagonist of AMPA receptors and without Mg²*. Application of S 18986 (300 μM) did not affected the amplitude of the NMDA‐mediated EPSfP.

Figure 4

Effects of S 18986 on long‐term potentiation induced in the dentate gyrus of the hippocampus on anaesthetized Wistar rats. The amplitude of the EPSfP was averaged over four stimuli and was expressed as a percentage of the amplitude of EPSfPs averaged during a 1 h of the baseline period preceding the intraperitoneal injection (control value taken as 100%). S 18986 significantly enhanced the amplitude of the EPSfP recorded before the tetanic stimulation at 50 mg/kg compared with control vehicle rats. *P <0.05 S 18986 versus vehicle, two‐way ANOVA followed by Dunnett test. (A) Effect on long‐term potentiation evoked by a 20 bursts tetanus. S 18986 significantly increased the duration of the long term potentiation compared to the vehicle. ns, Two‐way ANOVA; * Treatment's effect: P < 0.05; *** Time's effect P < 0.001. Closed symbols: P < 0.05 versus the average amplitude of EPSPs obtained during a 6‐min‐period preceding the tetanus; one‐way ANOVA followed by Dunnett test. (B) Effect on short‐term potentiation evoked by a four bursts tetanus. S 18986 significantly increased both the induction and duration of the short‐term potentiation compared with the vehicle. *P < 0.05 S 18986 versus vehicle, two‐way ANOVA followed by Dunnett test. Closed symbols: P < 0.05 versus the average amplitude of EPSPs obtained during a 6‐min‐period preceding the tetanus, One way ANOVA followed by Dunnett’ test.

Figure 5

Effect of S 18986 on scopolamine‐induced amnesia in a passive avoidance conditioned response. The bars represent the retention latencies in second (mean ± SEM), n = 10 in each group, Open: saline; grey: scopolamine 1 mg/kg i.p.; stippled: scopolamine in rats pretreated with S 18986 (1, 3, and 10 mg/kg i.p.). *P > 0.05, one‐way ANOVA and Fisher test LSD postcomparison.
Reprinted from Neuroscience Letters, Volume 361, Rosi et al., S 18986, a positive modulator of AMPA receptors with cognition‐enhancing properties, increases Ach release in the hippocampus of young and aged rat, pages 120‐3, 2004, with permission from Elsevier [41].

Figure 6

Effects intraperitoneal treatment with S 18986 in a social recognition task in Wistar rats. S 18986 was administered 30 min before the first presentation. The results are shown as mean ± SEM; n = 7 or 8 animals; *P≤ 0.05 and ***P≤ 0.001 versus control.

Figure 7

(A) Effects of oral treatment with S 18986 in the object recognition test in rats. S 18986 was administered 60 min before each session with low doses (0.3, 1, 3, 10 mg/kg) and higher doses (10, 30, 100 mg/kg). The discrimination index was the difference between the exploration times of the novel and familiar objects on the second trial (T2), which occurred 24 h after the first trial. Values are means ± SEM with the number of animals/group in parentheses. *P≤ 0.05; **P≤ 0.01; ***P≤ 0.001: versus control. ANOVA and Dunnett t‐test. Reprinted from European Journal of Pharmacology, Vol. 401, Lebrun et al., Effects of S 18986‐1, a novel cognitive enhancer, on memory performances in an object recognition task in rats, pages 205‐12, 2000, with permission from Elsevier [48].
(B) Comparisons between S 18986 (S‐isomer), S 17951 (racemic), or S 19024 (R‐isomer) in the object recognition test in rats. Delta is the difference between the exploration times of the novel and familiar objects on the second trial (T2) which occurred 24 h after the first trial. The results are shown as mean ± SEM, n = 14 or 15 animals. ***P≤ 0.001: value significantly different from control.
(C) Effects of delayed treatments with S 18986 in the object recognition test in rats
S 18986 was administered to the rats at the dose of 1 mg/kg by oral route. The administrations were made 1, 2, 3, or 4 h before each session of the test. The discrimination index was the difference between the exploration times of the novel and familiar objects on the second trial, which occurred 24 h after the first trial. Values are the means (± SEM) with the number of animald/group in parentheses. *P≤ 0.05; **P≤ 0.01; ***P≤ 0.001 versus control. Reprinted from European Journal of Pharmacology, Vol. 401, Lebrun et al., Effects of S 18986‐1, a novel cognitive enhancer, on memory performances in an object recognition task in rats, pages 205‐12, 2000, with permission from Elsevier [48].
(D) Effects of S 18986 on memory performance (expressed as recognition index) of Sprague‐Dawley rats in the object recognition task. S 18986 was administered orally as a sinde daily administration (1 × 1 mg/kg) or as three daily distinct administrations (3 × 1 mg/kg) 9, 6, or 3 h before each session during three consecutive days. Results are expressed as mean ± SEM; **P≤ 0.01 versus control. (From Bertaina‐Anglade et al. (2007) [49] with permission from John Wiley and Sons).

Figure 8

(A) Effect of oral treatment with S 18986 (0.3–1–3 mg/kg) prior to the acquisition and the long term retention test on memory performances in the retention test of the Morris Water Maze.
The results are shown as mean ± SEM, the number of animals/group is indicated in parentheses.
***P≤ 0.001: significantly different from platform quadrant. (B) Effect of oral treatment with S 18986 (1 mg/kg) prior to the learning sessions of the Morris Water Maze test on memory performances in the retention test.
A+R+: S18986 administered before the acquisition sessions and then before the retention session.
A+R‐: S18986 administered only before the acquisition sessions.
The results are shown as mean ± SEM, n = 9 or 10 animals.
*P≤ 0.05, P≤ 0.01: significantly different from platform quadrant.

Figure 9

Effects of S 18986 in the episodic contextual memory test in middle‐aged mice: comparison with donepezil. Left panel: Percentage of correct responses (head dips into the hole baited on the same floor at the acquisition phase) at the D1 test session.Right panel: Percentage of interfering responses (head dips into the hole baited on the other floor at the acquisition phase) at the D1 test session. Results are mean ± SEM. *P≤ 0.05; **P≤ 0.01 versus placebo treated middle‐aged mice. Dotted lines chance level (25%). With kind permission from Springer Science + Business Media: Psychopharmacology, Improvement of episodic contextual memory by S 18986 in middle‐aged mice: comparison with donepezil, Vol. 193, 2007, pages 63‐73, Beracochea et al. [53].

Figure 10

Effect of S18986 on relational/declarative mernory test (stage 2).
Stage 2: Percentage of correct responses recorded in the 1st and 2nd session.
Performances (mean ± SEM) in stage 2 (discrimination by pairs) of the five groups (Young Aged, A‐0.01, A‐0.1, A‐0.3).
*(Statistically different from young vehicle group) P > 0.05; **P < 0.01; ***P < 0.001.
§(Statistically different from aged vehicle group) P < 0.05.
°(Statistically different from hazard) °P < 0.05; °°P < 0.01; °°°P < 0.001. With permission from Marighetto et al., The AMPA modulator S 18986 improves declarative and working memory performances in aged mice, Behavioural Pharmacology, Vol. 19, issue 3, pages 235‐44 [57].

Figure 11

Effect of S 18986 on short‐term/working memory test. Y, young vehicle mice; A, aged vehicle mice; A‐S, aged mice treated with S 18986 (0.1 and 1 mg/kg). (A) and (B) Working memory by block performance over the 12 sessions of training for each group. °P < 0.05, °°P < 0.01, °°°P < 0.001 versus chance; *P < 0.05, ***P < 0.001 versus A.
(C) and (D) Working memory performance as a function of retention interval for each group. °P < 0.05, °°P < 0.01, °°°P < 0.001, versus chance; *P < 0.05, **P < 0.01, ***P < 0.001 versus A. With permission from Marighetto et al., The AMPA modulator S 18986 improves declarative and working memory performances in aged mice, Behavioural Pharmacology, Vol. 19, issue 3, pages 235‐44 [57].

Figure 12

Chronic treatment (12 months for rats at 24‐month‐old) with S 18986 (0.3, 1, and 10 mg/kg p.o.) in the learning of the Morris Water Maze task. Results are mean ± SEM latency (seconds) to locate and climb into the submerged platform. The number of animals was 8 per group. Testing was completed over five consecutive days with three trials per day. *P > 0.05: significant effect of treatment at 1mg/kg on Day 4 and 5 of testing versus vehicle aged controls.