Ciproxifan, an H3 receptor antagonist, alleviates hyperactivity and cognitive deficits in the APPTg2576 mouse model 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)
- et al.
Effects of risperidone on locomotor activity and spatial memory in rats with hippocampal damage
Neuropharmacology
(2006) - et al.
Kainic acid lesions enhance locomotor responses to novelty, saline, amphetamine, and MK-801
Behavioural Brain Research
(1997) - et al.
The H3 antagonist, ciproxifan, alleviates the memory impairment but enhances the motor effects of MK-801 (Dizocilpine) in rats
Neuropharmacology
(2010) - et al.
Lead identification of acetylcholinesterase inhibitors–histamine H3 receptor antagonists from molecular modeling
Bioorganic & Medicinal Chemistry
(2008) - et al.
Histamine H3 antagonist thioperamide dose-dependently enhances memory consolidation and reverses amnesia induced by dizocilpine or scopolamine in a one-trial inhibitory avoidance task in mice
Behavioural Brain Research
(2004) - et al.
Hippocampal theta oscillations and classical conditioning
Neurobiology of Learning and Memory
(2001) - et al.
Histamine H3 receptor antagonists: From target identification to drug leads
Biochemical Pharmacology
(2007) - et al.
Thioperamide, the selective histamine H3 receptor antagonist, attenuates stimulant-induced locomotor activity in the mouse
European Journal of Pharmacology
(1994) - et al.
Differential modulation of the D1-like- and D2-like dopamine receptor-induced locomotor responses by group II metabotropic glutamate receptors in the rat nucleus accumbens
Neuropharmacology
(2001) - et al.
A behavioural analysis of rats with damage to the medial prefrontal cortex using the Morris water maze: Evidence for behavioural flexibility, but not for impaired spatial navigation
Brain Research
(1994)
Modulation of hippocampal cell proliferation, memory, and amyloid plaque deposition in APPsw (Tg2576) mutant mice by isolation stress
Neuroscience
Corticosterone and related receptor expression are associated with increased beta-amyloid plaques in isolated Tg2576 mice
Neuroscience
Intraneuronal beta-amyloid accumulation in the amygdala enhances fear and anxiety in Alzheimer’s disease transgenic mice
Biological Psychiatry
Interactions between histamine H3 and dopamine D2 receptors and the implications for striatal function
Neuropharmacology
JNJ-10181457, a selective non-imidazole histamine H3 receptor antagonist, normalizes acetylcholine neurotransmission and has efficacy in translational rat models of cognition
Neuropharmacology
Behavioral consequences of ovarian atrophy and estrogen replacement in the APPswe mouse
Neurobiology of Aging
Behavioral characterization of the Tg2576 transgenic model of Alzheimer’s disease through 19 months
Physiology & Behavior
Transgenic mice expressing the betaAPP695SWE mutation: Effects on exploratory activity, anxiety, and motor coordination
Brain Research
Brain histamine and schizophrenia: Potential therapeutic applications of H3-receptor inverse agonists studied with BF2.649
Biochemical Pharmacology
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
A detailed mapping of the histamine H(3) receptor and its gene transcripts in rat brain
Neuroscience
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
Intermediate- and long-term recognition memory deficits in Tg2576 mice are reversed with acute calcineurin inhibition
Behavioural Brain Research
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