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

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.

Enigmatic Histamine Receptor H4 for Potential Treatment of Multiple Inflammatory, Autoimmune, and Related Diseases

“…Recently, it has been found that clobenpropit, a selective H 3 R antagonist with partial H 4 R agonist property, caused a significant reduction in amyloid-β deposits in a rat model of Alzheimer-like brain pathology. This effect was accompanied by marked reduction in neuronal or glial reactions so such dual-action compounds may have neuroprotective properties [81].…”

Activation of CREB‐mediated autophagy by thioperamide ameliorates β‐amyloid pathology and cognition in Alzheimer’s disease

“…H3R is a G‐protein‐coupled receptor (GRCR) that activates Gi/o proteins to inhibit adenylyl cyclase (AC) and cAMP‐response element‐binding protein (CREB) activity(Leurs et al, 2005). A number of experiments have provided evidences that inhibition of H3R could alleviate cognitive deficit in AD (Bitner et al, 2011; Brioni et al, 2011; Medhurst et al, 2007; Patnaik et al, 2018). Therefore, it raises the possibility of H3R antagonist for AD treatment.…”

Role of Neuroinflammation in Autism Spectrum Disorder and the Emergence of Brain Histaminergic System. Lessons Also for BPSD?

“…However, clobenpropit showed superior effects than the BF2649 in this AD model. The results suggested that H3 and H4 receptor modulation may induce neuroprotective effect resulting in less deposition of the peptide and reduction in glia activation (Patnaik et al, 2018). Also, earlier preclinical findings showed that activation of brain histaminergic neurotransmission may be a mechanism for cognitive effects of memantine, an NMDA-receptor antagonist widely used for the treatment of AD (Motawaj et al, 2011), demonstrating the role of neurotransmission to NMDA receptors and in BPSD (Lin and Lane, 2019).…”