Histamine H3 Inverse Agonist BF 2649 or Antagonist with Partial H4 Agonist Activity Clobenpropit Reduces Amyloid Beta Peptide-Induced Brain Pathology in Alzheimer’s Disease
Authors: Aruna Sharma
José Vicente Lafuente
Hari S Sharma
Stephen D Skaper
Rudy J Castellani
Dafin F Muresanu
Ranjana Patnaik
Ala Nozari
Journal: Molecular Neurobiology (2018)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: Alzheimer’s disease (AD); Amyloid beta peptide (AβP); BF2649; Blood-brain barrier; Brain pathology
Affiliations: School of Biomedical Engineering, Department of Biomaterials, Indian Institute of Technology, Banaras Hindu University, Varanasi, India., Department of Surgical Sciences, Anesthesiology and Intensive Care Medicine, Uppsala University Hospital, Uppsala University, SE-75185, Uppsala, Sweden., International Experimental Central Nervous System Injury and Repair (IECNSIR), University Hospital, Uppsala University, Frödingsgatan 12, Bldg. 28, SE-75421, Uppsala, Sweden., LaNCE, Department of Neuroscience, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain., Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Largo "E. Meneghetti" 2, 35131, Padua, Italy., "RoNeuro" Institute for Neurological Research and Diagnostic, 37 Mircea Eliade Street, 400364, Cluj-Napoca, Romania., Department of Clinical Neurosciences, University of Medicine and Pharmacy, Cluj-Napoca, Romania., Nanoneurosurgery Group, BioCruces Health Research Institute, 48903, Barakaldo, Bizkaia, Spain., Faculty of Health Science, Universidad Autónoma de Chile, Santiago de Chile, Chile., University of Maryland, Department of Pathology, Baltimore, MD, USA., Anesthesiology, Massachusetts General Hospital, Harvard University, Boston, MA, USA., Department of Surgical Sciences, Anesthesiology and Intensive Care Medicine, Uppsala University Hospital, Uppsala University, SE-75185, Uppsala, Sweden. ., International Experimental Central Nervous System Injury and Repair (IECNSIR), University Hospital, Uppsala University, Frödingsgatan 12, Bldg. 28, SE-75421, Uppsala, Sweden. ., LaNCE, Department of Neuroscience, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain. .

Abstract:  Alzheimer's disease (AD) is one of the leading causes for disability and death affecting millions of people worldwide. Thus, novel therapeutic strategies are needed to reduce brain pathology associated with AD. In view of increasing awareness regarding involvement of histaminergic pathways in AD, we explored the role of one H3 receptor inverse agonist BF 2649 and one selective H3 receptor antagonist with partial H4 agonist activity in amyloid beta peptide (AβP) infusion-induced brain pathology in a rat model. AD-like pathology was produced by administering AβP (1-40) intracerebroventricular (i.c.v.) in the left lateral ventricle (250 ng/10 μl, once daily) for 4 weeks. Control rats received saline. In separate group of rats, either BF 2649 (1 mg/kg, i.p.) or clobenpropit (1 mg/kg, i.p.) was administered once daily for 1 week after 3 weeks of AβP administration. After 30 days, blood-brain barrier (BBB) breakdown, edema formation, neuronal, glial injuries, and AβP deposits were examined in the brain. A significant reduction in AβP deposits along with marked reduction in neuronal or glial reactions was seen in the drug-treated group. The BBB breakdown to Evans blue albumin and radioiodine in the cortex, hippocampus, hypothalamus, and cerebellum was also significantly reduced in these drug-treated groups. Clobenpropit showed superior effects than the BF2649 in reducing brain pathology in AD. Taken together, our observations are the first to show that blockade of H3 and stimulation of H4 receptors are beneficial for the treatment of AD pathology, not reported earlier. 

Retracted: No

PubPeer comments:
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