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

https://doi.org/10.1016/j.nlm.2010.10.008Get rights and content

Abstract

Previous research has indicated that the blockade of H3-type histamine receptors may improve attention and memory in normal rodents. The purpose of this study was to determine if ciproxifan, an H3 receptor antagonist, could alleviate the hyperactivity and cognitive deficits observed in a transgenic mouse model (APPTg2576) of Alzheimer’s disease. APPTg2576 mice displayed significantly greater locomotor activity than wild-type mice, but APPTg2576 mice provided with daily ciproxifan treatment showed activity levels that did not differ from wild-type mice. In the swim maze, APPTg2576 mice exhibited significantly longer escape latencies, but the APPTg2576 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 APPTg2576 mice spent more time near the previous platform location and made more crossings of this area than did saline-treated APPTg2576 mice. APPTg2576 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 H3 receptors represents a novel and viable therapeutic strategy in the treatment of Alzheimer’s disease.

Research highlights

► The H3 receptor antagonist, ciproxifan, improves spatial learning and memory in the APP mouse model of Alzheimer’s disease. ► Ciproxifan also alleviates deficits in object recognition memory seen in APP mice. ► APP mice exhibit locomotor hyperactivity and ciproxifan reduces this effect.

Introduction

Over the past decade, preclinical research has identified the H3 histamine receptor as a possible target for cognitive-enhancing drugs (Bonaventure et al., 2007, Esbenshade et al., 2006). The H3 receptor exists as a presynaptic autoreceptor that is expressed in relatively high densities in brain regions associated with memory function, such as the frontal cortex and hippocampus (Pillot et al., 2002). Antagonism (or inverse agonism) of the receptor leads to the release of histamine as well as neurotransmitters involved in learning and memory, such as acetylcholine and dopamine, in the hippocampus and prefrontal cortex (Bacciottini et al., 2002, Clapham and Kilpatrick, 1992, Fox et al., 2005, Ligneau, Perrin, et al., 2007, Ligneau et al., 1998, Medhurst et al., 2007). Moreover, H3 antagonists can generate theta rhythms in the brain (Hajós, Siok, Hoffmann, Li, & Kocsis, 2008) – a form of activity that predicts the onset of new learning (Berry & Seager, 2001). On a behavioral level, drugs that act as H3 antagonists, such as the prototypical imidazole-containing compounds, ciproxifan and thioperamide, have been shown to improve memory function in several tasks – in normal rats and mice, as well as in animals treated with anti-cholinergic or anti-glutamatergic drugs (Bardgett et al., 2010, Bernaerts et al., 2004, Fox et al., 2003, Galici et al., 2009, Ligneau et al., 1998). In addition to their effects on learning and memory, H3 antagonists have also been shown to modulate the elevating effects of psychostimulants on locomotor activity in rats and mice (Clapham and Kilpatrick, 1994, Fox et al., 2005, Ligneau, Landais, et al., 2007, Morisset et al., 2002).

The ability of H3 antagonists to enhance memory in normal animals and in pharmacological models of memory impairment raises the possibility that such compounds may represent an effective treatment strategy for Alzheimer’s disease. As a way of addressing this possibility, we tested the effects of the H3 antagonist, ciproxifan (Ligneau et al., 1998), on the learning and memory deficits and hyperlocomotion observed in the amyloid-precursor protein (APPTg2576) transgenic mouse model of Alzheimer’s disease. Developed by Hsiao and colleagues (1996), APPTg2576 mice express a mutant form of the human APP gene associated with early-onset, familial Alzheimer’s disease. These mice exhibit a phenotype that includes the formation of amyloid plaques with increasing age as well as deficits in spatial learning and memory, and object recognition (Hsiao et al., 1996, Taglialatela et al., 2009). Some studies of APPTg2576 mice have also reported that mutant mice demonstrate elevated locomotor activity (Golub et al., 2008, Tabuchi et al., 2009).

In the first study, the effects of ciproxifan on locomotor activity and performance in the swim maze were compared between APPTg2576 mice and wild-type (WT) littermates of both genders at 12–14 months of age. Using a between-subjects design, approximately half of the mice of each genotype received daily intraperitoneal injections of ciproxifan (3 mg/kg) and the other half received injections of saline. The dose of ciproxifan chosen for study was based on previous research demonstrating its ability to improve attention and memory in normal rats (Bardgett et al., 2010, Fox et al., 2003, Fox et al., 2005, Ligneau et al., 1998) and inhibit stimulant-induced hyperactivity in mice (Morisset et al., 2002). Mice received daily injections for one week prior to testing and daily injections 30 min prior to testing over the subsequent three weeks. In a second study using a within-subjects design, a separate cohort of 12–14 month old APPTg2576 and WT mice was tested in a novel object recognition task. Ciproxifan or saline was injected 30 min prior to testing in this study.

Section snippets

Animals and housing

Offspring of an original crossing of APPTg2576 (Taconic Labs, Hudson, NY) male mice with B6SJLF1/J (Jackson Laboratory, Bar Harbor, ME) female mice were backcrossed with C57Bl6/J mice (Jackson Laboratory, Bar Harbor, ME) for five generations. APPTg2576 mice and their wild-type (WT) littermates of each gender representing the sixth generation of this breeding protocol were used in the present studies. They were housed three to four per cage with free access to food and water. Lighting in the

Confirmation of amyloid plaques in APPTg2576 mice

The appearance of amyloid plaques was confirmed in the brain of each APP mouse after the completion of drug and behavioral testing (Fig. 1). Numerous plaque deposits were observed in the dorsal hippocampus and cortex of the APPTg2576 mice. These plaques were not observed in the brains of WT mice. In the first cohort of APPTg2576 mice, statistical analyses did not indicate a difference in the number of hippocampal or cortical plaques between APPTg2576 mice previously exposed to four weeks of

Discussion

These experiments are the first to demonstrate that an H3 antagonist can alleviate hyperactivity and memory impairment in a transgenic mouse model of Alzheimer’s disease. The capacity for ciproxifan to improve cognitive and behavioral outcomes across multiple tests opens the door for the pursuit of H3 antagonism as a therapeutic strategy in the treatment of Alzheimer’s disease. Obviously, more work is needed to discern the types of behavioral deficits in APPTg2576 mice and other transgenic

Conclusions

Current palliative treatments for Alzheimer’s disease include acetylcholinesterase inhibitors and NMDA antagonists, yet these treatments possess only limited efficacy and significant side effects. Receptor binding data has shown that H3 receptor densities are preserved in the brains of people with Alzheimer’s despite disease progression (Medhurst et al., 2007), indicating that the target for H3 antagonists remains a viable one throughout the disease process. Therefore, antagonism of H3

Acknowledgments

This work was supported by National Center for Research Resources Grant 2P20 RR16481 and National Institute of Mental Health Grant R15 MH076788 to M.E.B.

References (47)

  • H. Dong et al.

    Modulation of hippocampal cell proliferation, memory, and amyloid plaque deposition in APPsw (Tg2576) mutant mice by isolation stress

    Neuroscience

    (2004)
  • H. Dong et al.

    Corticosterone and related receptor expression are associated with increased beta-amyloid plaques in isolated Tg2576 mice

    Neuroscience

    (2008)
  • J. España et al.

    Intraneuronal beta-amyloid accumulation in the amygdala enhances fear and anxiety in Alzheimer’s disease transgenic mice

    Biological Psychiatry

    (2010)
  • C. Ferrada et al.

    Interactions between histamine H3 and dopamine D2 receptors and the implications for striatal function

    Neuropharmacology

    (2008)
  • R. Galici et al.

    JNJ-10181457, a selective non-imidazole histamine H3 receptor antagonist, normalizes acetylcholine neurotransmission and has efficacy in translational rat models of cognition

    Neuropharmacology

    (2009)
  • M.S. Golub et al.

    Behavioral consequences of ovarian atrophy and estrogen replacement in the APPswe mouse

    Neurobiology of Aging

    (2008)
  • D.L. King et al.

    Behavioral characterization of the Tg2576 transgenic model of Alzheimer’s disease through 19 months

    Physiology & Behavior

    (2002)
  • R. Lalonde et al.

    Transgenic mice expressing the betaAPP695SWE mutation: Effects on exploratory activity, anxiety, and motor coordination

    Brain Research

    (2003)
  • X. Ligneau et al.

    Brain histamine and schizophrenia: Potential therapeutic applications of H3-receptor inverse agonists studied with BF2.649

    Biochemical Pharmacology

    (2007)
  • M. Lindner et al.

    Blind rats are not profoundly impaired in the reference memory Morris water maze and cannot be clearly discriminated from rats with cognitive deficits in the cued platform task

    Cognitive Brain Research

    (1997)
  • C. Pillot et al.

    A detailed mapping of the histamine H(3) receptor and its gene transcripts in rat brain

    Neuroscience

    (2002)
  • M. Tabuchi et al.

    Ameliorative effects of yokukansan, a traditional Japanese medicine, on learning and non-cognitive disturbances in the Tg2576 mouse model of Alzheimer’s disease

    Journal of Ethnopharmacology

    (2009)
  • G. Taglialatela et al.

    Intermediate- and long-term recognition memory deficits in Tg2576 mice are reversed with acute calcineurin inhibition

    Behavioural Brain Research

    (2009)
  • Cited by (59)

    • Differential contribution of H<inf>3</inf>R antagonism by LINS01 compounds on memory, anxiety-like behaviour and spontaneous locomotor activity in healthy rats

      2020, Behavioural Brain Research
      Citation Excerpt :

      These data indicate that, unlike donepezil, LINS01 compounds and clobenpropit did not impair the spontaneous locomotor activity. Many authors have demonstrated that treatment with H3R antagonists improves memory deficits in animal models of neurodegenerative diseases or reverses memory deficits in animals pretreated with cholinergic or glutamatergic antagonists [12,25,43]. Here, we examined the effects of acute treatment of two novel compounds, LINS01003 and LINS01004, on memory, anxiety and spontaneous locomotor activity, evaluated in healthy young rats.

    • Histaminergic Modulation of Recognition Memory

      2018, Handbook of Behavioral Neuroscience
      Citation Excerpt :

      These animals express a mutant form of the human APP gene associated with familiar early-onset Alzheimer's disease showing an extensive cortical and hippocampal Aβ deposition with increasing age as well as cognitive deficits including the object recognition (Hsiao et al., 1996; Taglialatela et al., 2009). Treatment with ciproxifan 30 min before the retention test prevented the discrimination deficits observed in 12- to 14-month-old APPTG2576 animals (Bardgett et al., 2011). Non-motor symptoms, including sleeping disturbances, affective and cognitive disorders, are increasingly recognized as a major challenge in the treatment of Parkinson's disease.

    View all citing articles on Scopus
    View full text