4.7 Article

OLHA (Na-oleoylhistamine) modulates activity of mouse brain histaminergic neurons

Journal

NEUROPHARMACOLOGY
Volume 215, Issue -, Pages -

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2022.109167

Keywords

Histamine receptor H3; PPAR-alpha; Patch-clamp; Posterior hypothalamus; HEK293; In silico electrophysiology

Funding

  1. German Research Society [DFG INST 208/664-1 FUGG, GRK2158]
  2. COST Actions [CA15135, CA18133, CA18240]

Ask authors/readers for more resources

Researchers have found that Nα-oleoylhistamine (OLHA) can modulate the activity of histaminergic (HA) neurons in mice. OLHA has different effects on HA neuron firing depending on its concentration. The excitatory and rise in intracellular calcium caused by OLHA are influenced by specific receptors and inhibitors, possibly related to fatty acid metabolism and the PKA pathway. PPAR-alpha and H3 receptors play important roles in this process.
Histaminergic (HA) neurons are located in the tuberomamillary nucleus (TMN) of the posterior hypothalamus, from where they project throughout the whole brain to control wakefulness. We examined the effects of N alpha- oleoylhistamine (OLHA), a non-enzymatic condensation product of oleic acid (OLA) and histamine, on activity of mouse HA neurons in brain slices. OLHA bidirectionally modulated the firing of HA neurons. At 10 nM OLHA inhibited or had no action, whereas at 1 mu M it evoked excitatory and inhibitory responses. Inhibition was not seen in presence of the histamine receptor H3 (H3R) antagonist clobenpropit and in calcium-free medium. Pre-incubation with a histamine-reuptake blocker prevented the decrease in firing by OLHA. OLHA-evoked increase in firing (EC50 ~44 nM) was insensitive to blockers of cannabinoid 1 and 2 receptors and of the capsaicin re-ceptor, but was significantly impaired by the peroxisome proliferator-activated receptor-alpha (PPAR-alpha) antagonist MK886, which suppressed also the rise in intracellular calcium level caused by OLHA. The OLHA-evoked excitation was mimicked by synthetic PPAR-alpha agonists (gemfibrozil and GW7647) and was abol-ished by the PKA inhibitor H-89. The H3R affinity (Ki) for histamine, measured in HEK293 cells with stable expression of human H3R, was higher than for OLHA (Ki: 42 vs 310 nM, respectively). Expression of PPAR-alpha was not different between TMN regions of males and females, responses to OLHA did not differ. Molecular modelling of PPAR-alpha bound to either OLHA or OEA showed similar binding energies. These findings shed light on a novel biotransformation product of histamine which may play a role in health and disease.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.7
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available