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

Neuropharmacology. 2011 Feb-Mar;60(2-3):460-6. doi: 10.1016/j.neuropharm.2010.10.026. Epub 2010 Oct 31.


Histamine H(3) 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 H(3)-antagonist ABT-239 (0.01-1.0mg/kg i.p.) increased cortical CREB and S(9)-GSK3β phosphorylation in CD1 mice. Donepezil, while increasing CREB phosphorylation, did not increase pS(9)-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 S(9)-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 (pS(9)-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 H(3)-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 H(3) antagonists have potential for both symptomatic and disease modifying benefit in the treatment of AD.

Publication types

  • Comparative Study

MeSH terms

  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / metabolism*
  • Animals
  • Benzofurans / metabolism*
  • Benzofurans / pharmacology
  • Benzofurans / therapeutic use
  • CREB-Binding Protein / metabolism
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism*
  • Female
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Histamine H3 Antagonists / metabolism*
  • Histamine H3 Antagonists / pharmacology
  • Histamine H3 Antagonists / therapeutic use
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Pyrrolidines / metabolism*
  • Pyrrolidines / pharmacology
  • Pyrrolidines / therapeutic use
  • Receptors, Histamine H3 / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Treatment Outcome


  • Benzofurans
  • Histamine H3 Antagonists
  • Pyrrolidines
  • Receptors, Histamine H3
  • benzonitrile, 4-(2-(2-((2r)-2-methyl-1-pyrrolidinyl)ethyl)-5-benzofuranyl)-
  • CREB-Binding Protein
  • Crebbp protein, mouse
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Glycogen Synthase Kinase 3