title: Hydroxyzine inhibits experimental allergic encephalomyelitis (EAE) and associated brain mast cell activation.
abstract: Experimental allergic encephalomyelitis (EAE) has been used as an animal model for the human demyelinating disease multiple sclerosis (MS). In acute MS or EAE, early disruption in the integrity of the blood-brain-barrier (BBB) precedes brain infiltration by inflammatory cells or any clinical evidence of disease. BBB permeability could be affected by vasoactive mediators and cytokines released from perivascular brain mast cells. We investigated the number and degree of activation of brain mast cells in EAE and the effect of the heterocyclic histamine-1 receptor antagonist hydroxyzine, a piperazine compound known to also block mast cells. Acute EAE was induced in Lewis rats by immunization with whole guinea pig spinal cord homogenate and complete Freund's adjuvant (CFA). A second group of animals were treated orally with hydroxyzine for one day before immunization and then continuously for 14 days. Control rats were treated with CFA or hydroxyzine alone. The clinical progression of EAE was assessed on days 10, 12 and 14 after immunization. The number of metachromatic mast cells and the degree of degranulation was assessed in the thalamus with light microscopy. At day 14, there was a three-fold increase in the number of brain mast cells with EAE, as compared to controls. These cells were positive for the immunoglobulin E binding protein (FcepsilonRI), while those from control rats were not. Over 40% of all thalamic mast cells studied in EAE showed partial staining or extruded secretory granule indicative of secretion. Hydroxyzine treatment inhibited (p<0.05) the progression and severity of EAE by 50% and the extent of mast cell degranulation by 70% (p<0.05). These findings indicate that brain mast cells are associated with EAE development and that inhibition of their activation correlates positively with the clinical outcome.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: V
authors.initials: V
authors.lastname: Dimitriadou
authors.forename: X
authors.initials: X
authors.lastname: Pang
authors.forename: T C
authors.initials: TC
authors.lastname: Theoharides
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply / Q000166:cytology / Q000276:immunology*; D015550:Cell Degranulation / Q000187:drug effects; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology*; D005260:Female; D006634:Histamine H1 Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D006919:Hydroxyzine / Q000494:pharmacology* / Q000627:therapeutic use*; D008407:Mast Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D051381:Rats; D011917:Rats, Inbred Lew; D017455:Receptors, IgE / Q000032:analysis
chemical_list: D006634:Histamine H1 Antagonists; D017455:Receptors, IgE; D006919:Hydroxyzine