Ciproxifan, an H3 receptor antagonist, alleviates hyperactivity and cognitive deficits in the APPTg2576 mouse model of Alzheimer’s disease

Abstract

Previous research has indicated that the blockade of H 3 -type histamine receptors may improve attention and memory in normal rodents. The purpose of this study was to determine if ciproxifan, an H 3 receptor antagonist, could alleviate the hyperactivity and cognitive deficits observed in a transgenic mouse model (APP Tg2576 ) of Alzheimer's disease. APP Tg2576 mice displayed significantly greater locomotor activity than wild-type mice, but APP Tg2576 mice provided with daily ciproxifan treatment showed activity levels that did not differ from wild-type mice. In the swim maze, APP Tg2576 mice exhibited significantly longer escape latencies, but the APP Tg2576 mice treated daily with ciproxifan had latencies that were indistinguishable from controls. In probe trials conducted one hour after the last training trial, ciproxifan-treated APP Tg2576 mice spent more time near the previous platform location and made more crossings of this area than did saline-treated APP Tg2576 mice. APP Tg2576 mice also demonstrated a significant impairment in the object recognition task that was reversed by acute treatment with ciproxifan (3.0 mg/kg). These data support the idea that modulation of H 3 receptors represents a novel and viable therapeutic strategy in the treatment of Alzheimer's disease.

The human histaminergic system in neuropsychiatric disorders

“…Interestingly, the H 3 R antagonist ciproxifan improved the cognitive performance of APP Tg2576 mice [52] and infusion of the H 3 R antagonist ABT-239 was found to reverse tau hyperphosphorylation in spinal cord and hippocampus of TAPP (tauÂAPP) AD transgenic mice [53]. The animal data and human postmortem data seem to provide a rationale for the use of H 3 R antagonists, in particular in female patients with AD, to improve cognitive processes in the PFC, because H 3 R regulates the release of several neurotransmitters (Box 1) and AD is reported to be associated with decreased release of histamine, acetylcholine, noradrenalin, and dopamine [8].…”

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

“…Thioperamide is highly potent at rat H 3 receptors with K i = 4.3 nM (Arrang et al, 1987a;Hill et al, 1997) that has been found broadly effective in vivo in a large number of behavioral models, including elevated plus maze learning, Morris water maze, Barnes maze (Miyazaki et al, 1995;Komater et al, 2005), and others. Clobenpropit (41) is likewise highly potent in vitro, with pA 2 = 9.92 in the guinea pig ileum assay (Eriks et al, 1992) and activity in vivo, e.g., in models of working memory, seizure, and Alzheimer's disease (Yokoyama et al, 1994;Zhang et al, 2003;Harada et al, 2004;Huang et al, 2004;Bardgett et al, 2011). Clobenpropit and thioperamide, however, also have potent activity at H 4 receptors (Lim et al, 2009), and thioperamide also is active at 5HT 3 receptors (Leurs et al, 1995b).…”

Histamine H3 receptor as a potential target for cognitive symptoms in neuropsychiatric diseases

“…A study addressing the efficacy of ABT-288 in the treatment of cognitive impairment associated with schizophrenia revealed that schizophrenia symptoms remained stable throughout the study, however, an increased incidence of psychosis-related and sleep-related adverse events was associated with ABT-288 (ClinicalTrials.gov trial registration number: NCT01077700) (Figure 10, Table 4) [129]. A previous study characterizing the safety, tolerability and pharmacokinetics of ABT-288 in stable subjects with schizophrenia showed that ABT-288 was tolerated at a 15-fold higher dose and 12-fold higher exposures in subjects with SCH than previously observed in healthy volunteers [130].…”