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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
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Banaras Hindu Univ, Indian Inst Technol, Dept Biomat, Sch Biomed Engn, Varanasi, Uttar Pradesh, India..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala Univ, Univ Hosp, IECNSIR, Frodingsgatan 12,Bldg 28, SE-75421 Uppsala, Sweden..
Univ Padua, Dept Pharmaceut & Pharmacol Sci, Largo E Meneghetti 2, I-35131 Padua, Italy..
RoNeuro Inst Neurol Res & Diagnost, 37 Mircea Eliade St, Cluj Napoca 400364, Romania.;Univ Med & Pharm, Dept Clin Neurosci, Cluj Napoca, Romania..
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2018 (English)In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 55, no 1, p. 312-321Article in journal (Refereed) Published
Abstract [en]

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 (A beta P) infusion-induced brain pathology in a rat model. AD-like pathology was produced by administering A beta P (1-40) intracerebroventricular (i.c.v.) in the left lateral ventricle (250 ng/10 mu l, 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 3weeks of A beta P administration. After 30 days, blood-brain barrier (BBB) breakdown, edema formation, neuronal, glial injuries, and A beta P deposits were examined in the brain. A significant reduction in A beta P 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.

Place, publisher, year, edition, pages
Humana Press, 2018. Vol. 55, no 1, p. 312-321
Keywords [en]
Alzheimer's disease (AD). Histamine. Amyloid beta peptide (A beta P), Clobenpropit, BF2649, H3 receptor inverse agonist, H3 receptors antagonist with partial H4 agonist, Blood-brain barrier, Brain pathology
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:uu:diva-346903DOI: 10.1007/s12035-017-0743-8ISI: 000424702600031PubMedID: 28861757OAI: oai:DiVA.org:uu-346903DiVA, id: diva2:1193607
Available from: 2018-03-27 Created: 2018-03-27 Last updated: 2018-03-27Bibliographically approved

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Sharma, ArunaSharma, Hari S.

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