Procognitive impact of ciproxifan (a histaminergic H₃ receptor antagonist) on contextual memory retrieval after acute stress

Abstract

Summary Aim Although cognitive deficits commonly co‐occur with stress‐related emotional disorders, effect of procognitive drugs such as histaminergic H 3 receptor antagonists are scarcely studied on memory retrieval in stress condition. Methods Experiment 1 . Memory of two successive spatial discriminations (D1 then D2) 24 hours after learning was studied in a four‐hole board in mice. H3 receptor antagonist ciproxifan ( ip 3 mg/kg) and acute stress (three electric footshocks; 0.9 mA; 15 ms) were administered 30 and 15 minutes respectively before memory retrieval test. Fos immunostaining was performed to evaluate the neural activity of several brain areas. Experiment 2 . Effects of ciproxifan and acute stress were evaluated on anxiety‐like behavior in the elevated plus maze and glucocorticoid activity using plasma corticosterone assay. Results Experiment 1 . Ciproxifan increased memory retrieval of D2 in nonstress condition and of D1 in stress one. Ciproxifan mitigated the stress‐induced increase of Fos expression in the prelimbic and infralimbic cortex, the central and basolateral amygdala and the CA1 of dorsal hippocampus. Experiment 2 . Ciproxifan dampened the stress‐induced anxiety‐like behavior and plasma corticosterone increase. Conclusion Ciproxifan improved contextual memory retrieval both in stress and nonstress conditions without exacerbating behavioral and endocrine responses to stress. Overall, these data suggest potential usefulness of H 3 receptor antagonists as cognitive enhancer both in nonstress and stress conditions.

Antagonism of Histamine H3 receptors Alleviates Pentylenetetrazole-Induced Kindling and Associated Memory Deficits by Mitigating Oxidative Stress, Central Neurotransmitters, and c-Fos Protein Expression in Rats

“…Similarly, chronic systemic pretreatment with H3R antagonist E177 (5 and 10 mg/kg) mitigated hippocampus c-Fos expression of PTZ-kindled rats ( Figure 7D,E). These observed findings were supported by a previous study in which H3R antagonist ciproxifan alleviated the stress-evoked increase of cortex c-Fos expression in mice and attenuated the associated memory deficits [140,141]. Moreover, and in a previous study, the H3R antagonist thioperamide mitigated haloperidol-evoked striatum c-Fos expression in rats [141].…”

Amelioration of cognition impairments in the valproic acid-induced animal model of autism by ciproxifan, a histamine H3-receptor antagonist

“…Studies have shown that H3R antagonists improve cognitive impairments in mice (Sadek et al , 2016b; Eissa et al , 2018c). CPX improved memory retrieval in mice with non-stress and stress conditions (Chauveau et al , 2019) and learning and memory in the Alzheimer’s disease model in the Passive avoidance test (Bardgett et al , 2009; Bardgett et al , 2011). The possible mechanism(s) of the involvement of CPX in memory improvement is not clear, but it might be explained by the ability of CPX, as a potent H3R antagonist, to mediate the release of different neurotransmitters in addition to histamine, such as acetylcholine, serotonin, and dopamine, in several specific brain areas (Sadek et al , 2016a).…”

Revisiting Preclinical Observations of Several Histamine H3 Receptor Antagonists/Inverse Agonists in Cognitive Impairment, Anxiety, Depression, and Sleep–Wake Cycle Disorder

“…Conversely, the effect of HA injection on the lateral septal was reported to induce anxiety-like behaviors in the open field test, which was possibly mediated by neurotransmission through H1Rs and H2Rs ( Mohsen et al, 2014 ). The reported results for numerous H3R antagonists/inverse agonists on anxiety models also differed momentously, with the most observed effect being the lack of any effects on anxiety-like behaviors assessed for ABT-239, ciproxifan, clobenpropit, DL77, and E159 in both rats and mice ( Femenía et al, 2015 ; Alachkar et al, 2017 ; Masini et al, 2017 ; Eissa et al, 2018 ; Alachkar et al, 2019 ; Chauveau et al, 2019 ; Eissa et al, 2019 ; Soliani et al, 2020 ; Trofimiuk et al, 2020 ). However, the existing studies found that some H3R antagonists/inverse agonists, e.g., the H3R antagonist/inverse agonist ST-1283, may have an anxiolytic effect using paradigms such as open field test and marble-burying test ( Bahi et al, 2014 ; Eissa et al, 2019 ).…”