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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

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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.

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Acknowledgements

This study was supported by grants from the Air Force Office of Scientific Research (EOARD, London, UK) and Air Force Material Command, USAF, under grant number FA8655-05-1-3065; Alzheimer’s Association (IIRG-09-132087), the National Institutes of Health (R01 AG028679), and the Dr. Robert M. Kohrman Memorial Fund (MAS, RJC); Swedish Medical Research Council (Nr 2710-HSS); Göran Gustafsson Foundation, Stockholm, Sweden (HSS); Astra Zeneca, Mölndal, Sweden (HSS/AS); The University Grants Commission, New Delhi, India (HSS/AS); Ministry of Science and Technology, Government of India (HSS/AS); Indian Medical Research Council, New Delhi, India (HSS/AS); and India-EU Co-operation Program (RP/AS/HSS) and IT 901/16 (JVL); Government of Basque Country and UFI 11/32 and PPG 17/51 (JVL) University of Basque Country, Spain; and Society for Neuroprotection and Neuroplasticity (SSNN), Romania. We thank Suraj Sharma, Uppsala, Sweden, for the computer and graphic support. The US government is authorized to reproduce and distribute reprints for government purpose notwithstanding any copyright notation thereon. The views and conclusions contained herein are those of the authors and should not be interpreted as necessarily representing the official policies or endorsements, either expressed or implied, of the Air Force Office of Scientific Research or the US government.

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Authors and Affiliations

  1. School of Biomedical Engineering, Department of Biomaterials, Indian Institute of Technology, Banaras Hindu University, Varanasi, India

    Ranjana Patnaik

  2. Department of Surgical Sciences, Anesthesiology and Intensive Care Medicine, Uppsala University Hospital, Uppsala University, SE-75185, Uppsala, Sweden

    Ranjana Patnaik, Aruna Sharma & Hari S. Sharma

  3. International Experimental Central Nervous System Injury and Repair (IECNSIR), University Hospital, Uppsala University, Frödingsgatan 12, Bldg. 28, SE-75421, Uppsala, Sweden

    Aruna Sharma & Hari S. Sharma

  4. Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Largo “E. Meneghetti” 2, 35131, Padua, Italy

    Stephen D. Skaper

  5. ”RoNeuro” Institute for Neurological Research and Diagnostic, 37 Mircea Eliade Street, 400364, Cluj-Napoca, Romania

    Dafin F. Muresanu

  6. Department of Clinical Neurosciences, University of Medicine and Pharmacy, Cluj-Napoca, Romania

    Dafin F. Muresanu

  7. LaNCE, Department of Neuroscience, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain

    Aruna Sharma, José Vicente Lafuente & Hari S. Sharma

  8. Nanoneurosurgery Group, BioCruces Health Research Institute, 48903, Barakaldo, Bizkaia, Spain

    José Vicente Lafuente

  9. Faculty of Health Science, Universidad Autónoma de Chile, Santiago de Chile, Chile

    José Vicente Lafuente

  10. University of Maryland, Department of Pathology, Baltimore, MD, USA

    Rudy J. Castellani

  11. Anesthesiology, Massachusetts General Hospital, Harvard University, Boston, MA, USA

    Ala Nozari

Authors
  1. Ranjana Patnaik
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  2. Aruna Sharma
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  3. Stephen D. Skaper
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  4. Dafin F. Muresanu
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  5. José Vicente Lafuente
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  6. Rudy J. Castellani
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  7. Ala Nozari
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  8. Hari S. Sharma
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Corresponding author

Correspondence to Hari S. Sharma.

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Compliance with Ethical Standards

All experiments were carried out according to National Institute of Health (NIH) Guide for the Care and Use of Laboratory Animals and approved by the local institutional ethics committee.

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Patnaik, R., Sharma, A., Skaper, S.D. et al. 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. Mol Neurobiol 55, 312–321 (2018). https://doi.org/10.1007/s12035-017-0743-8

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  • DOI: https://doi.org/10.1007/s12035-017-0743-8

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