Elsevier

Neuropharmacology

Volume 60, Issues 2–3, February–March 2011, Pages 460-466
Neuropharmacology

In-vivo histamine H3 receptor antagonism activates cellular signaling suggestive of symptomatic and disease modifying efficacy in Alzheimer’s disease

https://doi.org/10.1016/j.neuropharm.2010.10.026Get rights and content

Abstract

Histamine H3 receptor antagonists enhance cognition in preclinical models and have been proposed as novel therapeutics for cognitive disorders, in particular Alzheimer’s disease (AD). Increased neurotransmitter (e.g. acetylcholine and histamine) release associated with this pharmacology may lead to activation of postsynaptic signaling pathways relevant to cognition and neuroprotection, such as increased phosphorylation of CREB, a transcription factor germane to cognitive function, and the inhibitory residue (Ser-9) of GSK3β, a primary tau kinase associated with AD pathology. In the present studies, acute administration of the H3-antagonist ABT-239 (0.01–1.0 mg/kg i.p.) increased cortical CREB and S9-GSK3β phosphorylation in CD1 mice. Donepezil, while increasing CREB phosphorylation, did not increase pS9-GSK3β expression in contrast to ABT-239. Continuous (2-wk) s.c. infusion of ABT-239 (0.7 mg/kg/day) normalized reduced cortical CREB and hippocampal S9-GSK3β phosphorylation observed in Tg2576 (APP) AD-transgenic mice. In addition, ABT-239 infusion reversed tau hyperphosphorylation in the spinal cord and hippocampus of TAPP (tau × APP) AD-transgenic mice. Interestingly, ABT-239 produced signaling changes (pS9-GSK3β) in α7 nicotinic acetylcholine receptor (nAChR) knockout mice. In contrast to wild type, these mice do not exhibit α7 nAChR agonist induced phosphorylation, thus suggesting that H3-antagonist-mediated signaling is not dependent on ACh-stimulated α7 nAChR activation. In summary, results of these studies suggest that ABT-239 leads to biochemical signaling that promotes cognitive performance as well as attenuation of tau hyperphosphorylation, raising the intriguing possibility that H3 antagonists have potential for both symptomatic and disease modifying benefit in the treatment of AD.

Research highlights

► H3-mediated neurotransmitter release may activate signaling relevant to AD. ► H3-antagonist ABT-239 increased CREB and S9-GSK3β phosphorylation in normal mice. ► ABT-239 normalized CREB and S9-GSK3β hypophosphorylation in Tg-AD mice. ► ABT-239 attenuated hippocampal tau hyperphosphorylation in Tg-AD mice. ► H3 antagonists have potential for symptomatic and disease modifying effects in AD.

Introduction

In the mammalian brain, histamine is widely accepted as a biogenic amine neurotransmitter implicated in a variety of central nervous system (CNS) functions, such as sleep-wake activity, food and water intake, temperature regulation, arousal and cognition (Haas et al., 2008). While histamine-containing neurons reside exclusively in the posterior hypothalamus, specifically the tuberomammillary nucleus (TMN), histaminergic axons project throughout the brain that includes: cortex, striatum, thalamus, hippocampus, hypothalamus, locus coeruleus and spinal cord. As such, neuronal histamine receptors (H1, H2, H3), members of the G-protein coupled receptor superfamily, are also widely expressed within the CNS. The physiological diversity of histamine in the CNS may be in large part due to the discrete location of the H3 subtype on neuronal axon terminals. Originally described as a presynaptic autoreceptor (Arrang et al., 1983), Gi-coupled H3 receptors are also expressed as heteroreceptors located on axoaxonic postsynaptic terminals of non-histaminergic neurons that when occupied by histamine inhibit the release of neurotransmitters that in addition to histamine include: acetylcholine (ACh), dopamine (DA), norepinephrine (NE), and serotonin (5-HT) (Esbenshade et al., 2008). Conversely, H3 antagonism is known to evoke the release of these neurotransmitters in vitro and in vivo.

Specifically, H3 antagonists have been shown to both elevate ACh levels in cortex and hippocampus, anatomical substrates of cognition, as well as enhance memory performance in preclinical rodent models (Fox et al., 2005, Jia et al., 2006, Medhurst et al., 2007). As cholinergic transmission is well recognized as a major neurochemical modulator of cognitive processing (Bartus, 2000), the ability of H3 receptor antagonists to evoke ACh release has led to the investigation of these agents in the treatment of cognitive disorders, in particular Alzheimer’s disease (AD) (Esbenshade et al., 2008). However, the progressive cholinergic cell loss associated with AD likely limits the therapeutic effectiveness of a therapeutic agent dependent on endogenous ACh synthesis. Acetylcholinesterase (AChE) inhibitors that increase synaptic ACh via reduced enzymatic degradation only provide modest symptomatic relief that declines with later stage AD progression. Nonetheless, AChE inhibitors that include donepezil currently represent the primary therapeutic approach for AD (Tsuno, 2009). Thus, there exists a significant unmet need for the development of superior AD drugs that in addition to symptomatic alleviation may slow pathological progression, i.e. disease modifying efficacy. Drug discovery efforts towards developing therapeutics that have disease modifying effects have focused on the two focal proteins involved in AD pathology, viz., β-amyloid (Aβ), a product of aberrant amyloid precursor protein (APP) leading to production of extracellular Aβ plaques; and tau, a microtubule-associated protein that when hyperphosphorylated results in the formation of intracellular neurofibrillary tangles (NFTs) (Giacobini and Becker, 2007). In the latter case, pharmacological activation of cellular pathways that inhibit kinase signaling and subsequent tau hyperphosphorylation may represent a viable approach for targeting AD pathology.

Studies from our laboratory have shown that pharmacological activation of specific signaling pathways in the whole animal can be used to mechanistically assess efficacy of potential AD therapeutics (Bitner et al., 2007, Bitner et al., 2009, Bitner et al., 2010). Specifically, we have affirmed that phosphorylation-activation of CREB (cyclic AMP response element binding protein), a transcription factor germane to cognitive function, and phosphorylation-inhibition of glycogen synthase kinase3β (GSK3β), a primary tau kinase in AD, can be utilized as biochemical endpoints of symptomatic and disease modifying efficacy, respectively, in preclinical assessment of potential AD therapeutics. Indeed reduced CREB and S9-GSK3β phosphorylation are observed in brains of AD patients and transgenic mice. In the present studies, the H3-antagonist ABT-239 was examined in both normal and transgenic (Tg)-AD mice for induction of CREB and S9-GSK3β phosphorylation, as measured immunohistochemically. Similar signaling experiments in normal mice were conducted with the AChE inhibitor donepezil. To provide a more primary endpoint of AD pathophysiology, effects of ABT-239 were also examined for reversal of tau hyperphosphorylation in a Tg tauopathy mouse model.

Section snippets

Animals

Male CD1, Tg2576 and female TAPP mice weighing ∼20–30 g were used. TAPP and Tg2576 AD-transgenic mice (TG), along with wild type (WT) were obtained from Taconic Farms. α7 knockout (KO) mice (C57BI/6 background), along with wild-type (WT) littermates, were obtained from Baylor College of Medicine (Houston, TX). All mice were acclimated to the animal facilities for a period of at least one week prior to the beginning of experimental procedures. Injection volumes for acute administration

Results

The novel H3-antagonist ABT-239 binds to recombinant human and rat H3 receptors with pK(i) values of 9.4 and 8.9, respectively, and is over 1000-fold selective vs human H1, H2, and H4 histamine receptors (Esbenshade et al., 2005). Characterized in vivo, ABT-239 exhibits pro-cognitive activity associated with increased neurotransmitter release that includes ACh (Fox et al., 2005). A series of experiments were conducted in normal and transgenic mice to examine the effects of H3 receptor

Discussion

The ability of H3 receptor antagonists to evoke release of multiple neurotransmitters leading to subsequent activation of various postsynaptic receptor signaling pathways may represent the mechanistic foundation in the development of these agents as novel therapeutics across a variety of CNS cognitive disorders that includes AD. In the present studies, acute administration of the H3-antagonist ABT-239 in normal mice increased cortical CREB and S9-GSK3β phosphorylation, biochemical events

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